ArticlePDF AvailableLiterature Review

Selenium in Human Health and Disease

April 2011
Antioxidants and Redox Signaling 14(7):1337-83

DOI:10.1089/ars.2010.3275

Source
PubMed

Authors:

Susan Fairweather-Tait

University of East Anglia

Yongping Bao

University of East Anglia

Martin R Broadley

Rothamsted Research

Rachel Berry

Norwich BioScience Institutes

Show all 7 authorsHide

This review covers current knowledge of selenium in the environment, dietary intakes, metabolism and status, functions in the body, thyroid hormone metabolism, antioxidant defense systems and oxidative metabolism, and the immune system. Selenium toxicity and links between deficiency and Keshan disease and Kashin-Beck disease are described. The relationships between selenium intake/status and various health outcomes, in particular gastrointestinal and prostate cancer, cardiovascular disease, diabetes, and male fertility, are reviewed, and recent developments in genetics of selenoproteins are outlined. The rationale behind current dietary reference intakes of selenium is explained, and examples of differences between countries and/or expert bodies are given. Throughout the review, gaps in knowledge and research requirements are identified. More research is needed to improve our understanding of selenium metabolism and requirements for optimal health. Functions of the majority of the selenoproteins await characterization, the mechanism of absorption has yet to be identified, measures of status need to be developed, and effects of genotype on metabolism require further investigation. The relationships between selenium intake/status and health, or risk of disease, are complex but require elucidation to inform clinical practice, to refine dietary recommendations, and to develop effective public health policies.

Contribution of each food group to total population dietary exposure in the UK. Adapted from data presented in the UK Food Standards Agency document (136).

…

. Current Dietary Reference Intakes for Adults (mg Selenium=Day) of Selected Countries and Bodies

…

Wheat imports to UK. (A) Wheat imports to UK from all sources 1961-2007. Wheat imports to UK from all sources 1961-2007 data obtained from reference (120). The introduction of the Chorleywood Bread Process in 1961 is highlighted with a dashed line; this process enabled use of UK and EU wheat in bread making instead of North American wheat. The second dashed line represents the year when the UK became a member of the European Economic Community in 1973. (B) Wheat imports to UK from United States and Canada 1986-2005. Wheat imports to UK from United States and Canada 1986-2005 data obtained from reference (120).

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COMPREHENSIVE INVITED REVIEW

Selenium in Human Health and Disease

Susan J. Fairweather-Tait,

Yongping Bao,

Martin R. Broadley,

Rachel Collings,

Dianne Ford,

John E. Hesketh,

and Rachel Hurst

Abstract

This review covers current knowledge of selenium in the environment, dietary intakes, metabolism and status,

functions in the body, thyroid hormone metabolism, antioxidant defense systems and oxidative metabolism, and

the immune system. Selenium toxicity and links between deﬁciency and Keshan disease and Kashin-Beck

disease are described. The relationships between selenium intake=status and various health outcomes, in par-

ticular gastrointestinal and prostate cancer, cardiovascular disease, diabetes, and male fertility, are reviewed,

and recent developments in genetics of selenoproteins are outlined. The rationale behind current dietary ref-

erence intakes of selenium is explained, and examples of differences between countries and=or expert bodies are

given. Throughout the review, gaps in knowledge and research requirements are identiﬁed. More research is

needed to improve our understanding of selenium metabolism and requirements for optimal health. Functions

of the majority of the selenoproteins await characterization, the mechanism of absorption has yet to be identiﬁed,

measures of status need to be developed, and effects of genotype on metabolism require further investigation.

The relationships between selenium intake=status and health, or risk of disease, are complex but require elu-

cidation to inform clinical practice, to reﬁne dietary recommendations, and to develop effective public health

policies. Antioxid. Redox Signal. 14, 1337–1383.

I. Introduction 1338

II. Selenium in the Environment 1338

A. Soil selenium 1338

B. Food sources and selenium species 1339

1. Bread and cereals 1339

2. Meat, ﬁsh, and eggs 1339

3. Milk, dairy products, and beverages 1340

4. Fruit and vegetables 1340

5. Selenium-enriched foods 1340

C. Selenium intake 1340

1. Dietary surveys 1340

2. Global variation in selenium intake 1341

3. Selenium intake from dietary supplements 1342

III. Selenium Absorption and Metabolism 1342

A. Absorption of dietary selenium 1342

B. The biochemical interconversion of selenium species 1342

C. Systemic transport of selenium 1343

IV. Selenium Status 1344

A. Measurement of status 1344

B. Global variation in status 1345

C. Changes in selenium status in relation to environmental factors 1345

Reviewing Editors: Carla Boitani, Marcus Conrad, Arthur Cooper, Vadim Gladyshev, Kum Kum Khanna, William Manzanares,

Jakob Moskovitz, Laura Papp, K. Sandeep Prabhu, Lutz Schomburg, Gerhard N. Schrauzer, Alan Shenkin, and Fulvio Ursini

School of Medicine, Health Policy and Practice, University of East Anglia, Norwich, Norfolk, United Kingdom.

School of Biosciences, University of Nottingham, Loughborough, Leicestershire, United Kingdom.

Institute for Cell and Molecular Biosciences, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom.

ANTIOXIDANTS & REDOX SIGNALING

Volume 14, Number 7, 2011

ªMary Ann Liebert, Inc.

DOI: 10.1089=ars.2010.3275

1337

V. Functions of Selenium in the Human Body 1347

A. Thyroid hormone metabolism 1347

1. Thyroid hormone synthesis and the role of selenoproteins

in thyroid gland function and protection

1347

2. Prioritization of the selenium supply to the thyroid gland and to DIOs 1347

3. Functions of the DIOs and their potential role in health and disease 1348

B. Antioxidant defense system and oxidative metabolism 1349

1. Glutathione peroxidases 1349

2. Thioredoxin reductases 1349

3. Other selenoproteins involved in the antioxidant defense system 1349

C. Immune system 1350

VI. Clinical Disorders 1351

A. Deﬁciency 1351

1. Keshan disease 1351

2. Role of selenium in Kashin-Beck disease 1352

B. Toxicity 1353

VII. Effects on Health 1354

A. Cardiovascular disease 1354

B. Cancer 1354

1. Total cancer incidence and mortality 1355

2. Gastrointestinal cancers 1355

3. Prostate cancer 1356

4. Other cancers 1357

5. Summary of selenium and cancer research, and ranges that may offer protection 1358

6. Selenium supplementation as an adjuvant therapy in radiation or chemotherapy treatment 1358

7. Effect of genotype and polymorphisms relating to selenium and cancer risk 1359

C. Diabetes 1359

D. Inﬂammation and inﬂammatory disorders 1360

E. Fertility 1361

F. Genetics of selenoproteins 1362

VIII. Selenium in Critical Illness 1364

IX. Dietary Reference Intakes 1365

X. Conclusions and Perspectives 1367

I. Introduction

In the last century, interest in selenium and health was

focused primarily on the potentially toxic effects of high

intakes in humans, stimulated by reports of alkali disease in

livestock raised in seleniferous areas (341). The essentiality of

selenium was demonstrated in the mid-1950s (326), when rats

fed a highly puriﬁed casein diet developed a fatal liver disease,

which was prevented by certain foods, including brewer’s

yeast; selenium was identiﬁed as the active ingredient (327).

In recent years, there has been growing interest in selenium

in relation to Keshan disease (an endemic cardiomyopathy)

and also possible protective effects against cancer and other

chronic diseases. In a large-scale supplementation trial, sele-

nium had an anticarcinogenic effect (86), and although in-

vestigations into the protective role of selenium had been

undertaken for many years before this, both in animals and

case–control studies in humans, the results were difﬁcult to

interpret because neoplastic tissue sequesters selenium (311

cited in 402), and therefore the impact of selenium status on

the initiation and progression of various cancers could not be

evaluated.

There is a relatively narrow margin between selenium in-

takes that result in deﬁciency or toxicity, with health effects

being related to level of exposure and selenium status. Fur-

ther, the species of selenium is another determinant of its

health effect. This review covers the functions of selenium,

absorption and metabolism, dietary intakes and recommen-

dations, clinical deﬁciency disorders and toxicity, the effects

of environmental factors and genotype on selenium status,

and the relationship between selenium and health outcomes,

including cardiovascular disease (CVD), cancer, diabetes, in-

ﬂammatory disorders, and male fertility.

II. Selenium in the Environment

A. Soil selenium

Globally, total soil selenium concentrations typically lie

within the range 0.01–2.0 mg=kg with an overall mean of

0.4 mg=kg (130). Much greater concentrations (up to

1200 mg=kg) are found in soils derived from seleniferous

parent materials, including shales, sandstones, limestones,

slate, and coal series (130, 191). Seleniferous soils are wide-

spread in parts of the United States, Canada, South America,

China, and Russia. Although parent geology is the primary

long-term determinant of selenium in soils, signiﬁcant inputs

of selenium to soils occur following deposition of selenium

from natural (volcanoes, sea spray, volatilization=recycling

via biotic cycling) and anthropogenic (e.g., fossil fuel com-

bustion, sewage, and agricultural inputs such as fertilizers

and lime) sources (64, 191). Annually, ﬂuxes of selenium to

soils from anthropogenic activities are greater than those from

1338 FAIRWEATHER-TAIT ET AL.

all natural sources combined. The effect can be seen in long-

term agricultural experiments, where fossil fuel combustion

practices correlate with selenium deposition to crops and soils

(157).

Crop selenium uptake is inﬂuenced greatly by the avail-

ability and chemical species of selenium in soils. Inorganic

selenium occurs in three soil-phases—ﬁxed, adsorbed, and

soluble—and only adsorbed=soluble forms of selenium are

thought to be available for plant uptake. In addition, avail-

ability of selenate (þ6 oxidation state) and selenite (þ4) forms

to plants varies markedly, with selenate taken up much more

rapidly than selenite under most soil conditions. Until re-

cently, it was possible to quantify selenium species in different

soil phases only from soils with high adsorbed=soluble sele-

nium loads (50–9000 mg soluble selenium per kg soil) using

Hydride Generation Atomic Absorption Spectroscopy tech-

niques (351). However, anion-exchange liquid chromatogra-

phy (LC) coupled to inductively coupled plasma mass

spectrometry (ICP-MS) have enabled selenium species to be

quantiﬁed in soils of low selenium concentrations (<20 mg

soluble selenium per kg soil) (351). In UK soils of low selenium

status, adsorbed=soluble selenium concentrations are gener-

ally two orders of magnitude lower than total soil selenium,

and consist primarily of selenite and organic selenium forms

(351).

B. Food sources and selenium species

The amount of selenium in the diet largely depends on

where crops are grown and cultivated, the soil=fodder to

which animals are exposed, and the actual foods consumed.

The effect of selenium species on bioavailability has been re-

viewed recently (117) and data on the selenium content of

foods are available (117, 135, 302, 372). The main food groups

providing selenium in the diet are bread and cereals, meat,

ﬁsh, eggs, and milk=dairy products (Fig. 1). Some Brazil nuts

are a particularly rich source, with selenium concentrations

ranging from *0.03–512 mg=kg fresh weight (302).

1. Bread and cereals. The selenium content of bread and

cereals can vary widely from *0.01–30 mg=kg (302). On av-

erage, bread and cereals provide a quarter of the selenium

intake in the UK (Fig. 1). The predominant species of selenium

in wheat and bread are selenomethionine (usually *55%–

85%), selenocysteine (*4%–12%), and selenate=ite (*12%–

19%) (400, 405).

2. Meat, ﬁsh, and eggs. The selenium content of meat

depends on many factors. Offal contains relatively high levels

of selenium, in particular liver and kidneys; the selenium

concentrations of kidney, liver, and heart tissue from beef

were 4.5, 0.93, and 0.55 mg=kg, respectively, whereas muscle

was in the region of 0.2 mg=kg (193). Supplementation of

cattle with selenium-enriched yeast increased muscle sele-

nium concentration to *0.6 mg=kg (193). In the United States,

the average selenium content of chicken is *0.2 mg=kg and

beef *0.25–0.3 mg=kg (372). Meat generally provides a rela-

tively large proportion of the selenium intake in omnivorous

populations, and in the UK, it provides one quarter of the total

estimated intake (Fig. 1). The predominant species of sele-

nium in edible portions of meat may be selenomethionine

(*50%–60% of total extractable selenium species) and sele-

nocysteine (20%–31% and *50% of total extractable selenium

species in chicken and lamb, respectively) (47). However, the

total content and species depends mainly on the animals’ diet.

The selenium content in ﬁsh is between 0.1 and

*5.0 mg=kg (117, 302, 310); some marine ﬁsh are relatively

high in selenium; for example, the selenium content of cod,

shark, and canned tuna is *1.5, 2.0, and 5.6 mg=kg, respec-

tively (117, 310). In the UK, the average selenium content of

ﬁsh is *0.42 mg=kg (136). The main selenium species in ﬁsh

are selenomethionine (29%–70%) and selenite=selenate (12%–

45%) (77, 117, 302) with the species proﬁle differing between

ﬁsh species and the total selenium content.

Hens’ eggs contain from *3to*25 mg selenium per whole

egg (224). Selenium supplementation of the hen’s diet may

increase the selenium content of eggs to 0.34–0.58 mg=kg

FIG. 1. Contribution of each

food group to total population

dietary exposure in the UK.

Adapted from data presented in

the UK Food Standards Agency

document (136).

SELENIUM AND HUMAN HEALTH 1339

(232); selenium-enriched eggs are widely produced around

the world (125). The main selenium species in eggs are se-

lenocysteine, selenomethionine, and possibly selenite, with

selenomethionine and selenocysteine as the predominant

species (>50%) in egg white and egg yolk, respectively

(224).

3. Milk, dairy products, and beverages. The selenium

content of milk and dairy products varies widely; in the UK,

milk and dairy products contain *0.01–0.03 mg=kg selenium.

The predominant selenium species in cows’ milk are seleno-

cysteine and selenite (256). Supplementation of dairy cows

with selenium-enriched yeast alters the species proﬁle in the

milk and the major species after supplementation are sele-

nocysteine, selenomethionine, and selenite (256).

4. Fruit and vegetables. Fruit and vegetables typically

contain relatively small amounts of selenium. In unenriched

vegetables with low levels of selenium, the major species

may be, for example, selenate in onions (207) or seleno-

methionine (53%), g-glutamyl-Se-methylselenocysteine (31%),

Se-methylselenocysteine (12%), and selenate (4%) in garlic

with natural selenium content of <0.5 mg=kg (207). However,

certain vegetables, such as onions, garlic, and broccoli when

grown on selenium-rich soil can accumulate selenium, re-

sulting in selenium-enrichment from <0.5 mg=kg up to 140–

300 mg=kg. The main selenium species in Se-enriched food

such as onions is g-glutamyl-Se-methylselenocysteine, ac-

counting for *63% of the species, with a relatively smaller

proportion of *10% selenate and 5% selenomethionine, plus

other species (174, 207). In Se-enriched garlic, similar to Se-

onions, g-glutamyl-Se-methylselenocysteine may be the pre-

dominant species (*73%) with also *13% selenomethionine,

4% g-glutamyl-selenomethionine, 3% Se-methylselenocys-

teine, and 2% selenate (181). Selenium-enriched broccoli

sprouts may contain predominantly Se-methylselenocysteine

(*45%) with smaller amounts (*12%–20%) of selenate and

selenomethionine, plus other species of selenium (e.g., ade-

nosylselenohomocysteine) (124). In summary, in vegetables

such as broccoli, onions, and garlic the selenium species

proﬁle is variable depending on the total level of selenium

enrichment, the forms of selenium used for enrichment, and

the type of vegetable; predominant species in selenium-en-

riched vegetables analyzed to date are Se-methylselenocys-

teine or g-glutamyl-Se-methylselenocysteine; these forms of

selenium in foods have received attention due to purported

protection against cancer in animal models when compared

with other forms of selenium (123, 183).

5. Selenium-enriched foods. The only permitted species

of selenium added to foods for particular nutritional use in

Europe, including baby formula milk and total parental nu-

trition foods, are sodium selenate, sodium selenite, and so-

dium hydrogen selenite (127), whereas the predominant

selenium species in most natural and unenriched foods is

selenomethionine (Fig. 2). Selenium-enrichment through fer-

tilization or feeding supplements to animals changes the se-

lenium species proﬁle in some foods, for example, eggs,

onions, garlic, and broccoli (124, 183, 207, 224), but wheat and

meat tend to retain the predominant selenium species as se-

lenomethionine (47, 405). The selenium speciation of foods

and the effect of processing and cooking on the species proﬁle

is a priority for future research.

C. Selenium intake

1. Dietary surveys. The contribution to selenium intake

from drinking water (130) and air is insigniﬁcant, except for

individuals working in industries with an occupational ex-

posure risk (e.g., metal recovery and paint production). Diet-

ary selenium intakes can be estimated from dietary surveys,

food composition tables, market basket type surveys, and=or

composite dietary analyses. There are inherent uncertainties

in using all of these data, since dietary surveys are prone to

misreporting, and robust primary data on the selenium con-

centration of different foodstuffs are often lacking or below

FIG. 2. Species of selenium in

natural un-enriched foods, %

contribution of each type of sele-

nium to total=extractable seleni-

um. This ﬁgure was produced

from data presented in references

(47, 117, 207, 302, 400, 405) with

the percentage of total=extractable

selenium species presented for

natural un-enriched foods with

typical selenium contents (fresh

weight) for wheat, 0.1–30 mg=kg;

garlic, <0.5 mg=kg; potatoes,

0.12 mg=kg; chicken, 0.5 mg=kg;

lamb, 0.4 mg=kg; ﬁsh (cod),

1.5 mg=kg.

1340 FAIRWEATHER-TAIT ET AL.

technical limits of detection and=or quantiﬁcation. For ex-

ample, in the UK, the most recent published dietary survey

reporting mineral intakes is the National Diet and Nutrition

Survey (NDNS) (158, 165). However, under-reporting is

*25% (307), and there can be over-reporting of foods per-

ceived to be healthy, for example, cereals and vegetables (275,

385). Food composition tables may lack robust selenium

concentration data for many food groups. For example, the

Sixth Summary Edition of McCance and Widdowson’s The

Composition of Foods contains mineral concentration data for

up to 3423 types of food and drink products (135). Of these,

selenium data are not reported for 1161 products, ‘‘trace’’ or

zero selenium is reported for 467 products, and the selenium

contents of a further 470 products are estimates. Among the

1325 products for which selenium concentration data are re-

ported, 241 products have the lowest reported selenium

concentration of 1 mg=100 g, which may introduce rounding

errors. In the UK’s 2006 Total Diet Survey, a market basket

survey of 24 UK towns reported selenium concentration data

above the limit of quantiﬁcation for only 7 out of 20 food

groups (136). However, subject to these caveats, it is still

possible to provide estimates of selenium intake, and even

target-speciﬁc food groups, by integrating dietary survey data

with food composition data (62).

2. Global variation in selenium intake. Individual dietary

selenium intakes across the world are estimated to range from

3 to 7000 mg=day (130, 297, 300, 410). The highest levels of

intake have been recorded in seleniferous regions of China

[>4990 mg=day (422)] and Venezuela (130, 298, 299). For Eu-

ropean countries where estimates are available, mean intakes

are typically <50 mg=day per person (298, 299), which is close

to or below the recommended nutrient intake level (127, 300).

In regions of relatively high selenium intake in India, intakes

were estimated to be 475 mg=day for women and 632 mg=day

for men, with >80% of the selenium intake provided by

consumption of cereals grown in high selenium soil in the

local region (164). For large areas of the world (e.g., Africa and

many parts of Asia and Latin America), dietary selenium in-

take estimates are unavailable. Examples of selenium intakes

across the world are shown in Figure 3.

With respect to selenium intake from habitual diet, the UK

is one of the countries with the lowest estimated selenium

intake (Fig. 3). The mean selenium intake from food sources

for men and women (aged 19–64) were 55 and 43 mg=day,

respectively. In comparison, intakes in the United States are

much higher: the mean intake from food in the United States

was 133.5 2.42 mg=day for men and 92.6 1.57 mg=day for

women (370). There is a very wide variation in selenium

FIG. 3. Global variation in selenium intake. Data shown in Figure 3 were compiled from selenium intake data presented

in references (127, 137, 300, 370). Data are presented for the intakes for males (M) and females (F) where available, with the

latter shown in a lighter shade. The dotted lines represent the intake required to reach maximal plasma GPx3 and seleno-

protein P expression, at *70 and *105 mg=day (174, 365).

SELENIUM AND HUMAN HEALTH 1341

intake around the world, and when undertaking risk–beneﬁt

analysis, an important task due to the narrow safe range of

selenium, it is also important to take the use of dietary sup-

plements into account.

3. Selenium intake from dietary supplements. There are

many different formulations of supplements available

worldwide with varying doses and species of selenium, and

selenium is often included in multivitamin=mineral supple-

ments. The selenium content of supplements analyzed in the

United States indicates that they provide between 10 and

200 mg=day (371). Dietary supplement use in the United States

and Europe is common, with over 50% of the population

surveyed in the United States regularly consuming dietary

supplements (289). In the UK, 35% of adults (27% of men and

41% of women) reported taking supplements, predominantly

ﬁsh oils and multivitamins=minerals (137), some containing

selenium. Denmark and Finland report 32%–60% use of

supplements, and in Poland and Spain 8%–11% of men and

10%–18% of women consume dietary supplements (127). A

recent evaluation and comparison of national intake survey

data from several countries in Europe, comparing intake from

supplements and habitual diet, estimated that the contribu-

tion from dietary supplements was between 6% and 45% of

the total estimated selenium intake for adult men and women,

with country-speciﬁc differences (127). In Finland, where se-

lenium fertilizers are mandatory, the mean estimated sele-

nium intake from the habitual diet for men and women is 79.5

and 56.1 mg=day, respectively. Consumption of dietary sup-

plements by 32% of men and 58% of women was calculated to

provide an extra 5.3 mg=day for men and 10.5 mg=day for

women (127).

The contribution of selenium-containing supplements is

likely to provide an average additional intake of 5–30 mg=day,

but obviously this will vary widely depending on habitual

diet and the content=formulation of the supplement. Also, the

absorption and metabolism of selenium depends on the se-

lenium species in the supplement as well as the dose=amount

consumed and selenium status of the individual. A substan-

tial proportion of supplements available contain one species

of selenium (mainly in multivitamin=mineral supplements),

as selenomethionine, Se-methylselenocysteine, selenite, or

selenate. However, selenium-enriched yeast is a complex

mixture of several different species of selenium and usually

contains more than four different species, including *23%–

84% selenomethionine, 3%–21% selenocysteine, 1%–20% Se-

methylselenocysteine=g-glutamyl Se-methylselenocysteine,

0.5%–5% Se-adenosyl-selenohomocysteine, *4% selenate,

plus other selenium species that may vary according to the

media and growth conditions of the selenium-enriched yeast

(302, 400).

III. Selenium Absorption and Metabolism

There is limited knowledge about the biochemical inter-

conversions involved in the metabolism of the different se-

lenium species in mammals, and information concerning

tissue speciﬁcity of pathways remains scant. The absorption

of selenium for assimilation and excretion through these

pathways potentially involves multiple membrane transport

mechanisms, but it is a topic that has received little attention

to date.

A. Absorption of dietary selenium

The identity of the transporter proteins responsible for the

absorption of dietary selenium remains uncertain. Membrane

transport proteins with the capacity to mediate uptake of

organic forms of selenium have been identiﬁed on the basis of

quantiﬁcation of the total selenium content of Xenopus laevis

oocytes expressing individual transporters (from injected

in vitro-transcribed mRNA) and provided with different test

substrates. These studies revealed that the selenoamino acids

selenomethionine, methylselenocysteine, and selenocysteine,

but not the seleonoderivatives selenobetaine or selenocysta-

mine, are transported effectively by a suite of intestinal (and

renal) amino acids transporters, in particular by the B

and

0þ

rBAT systems (263). The SLC26 multifunctional anion

exchanger family are good candidates for intestinal selenate

transport, based on published observations concerning inhi-

bition of selenate transport in various experimental epithelial

systems by the SLC26 inhibitor, 4,40-diisothiocyano-2,20-

disulfonic acid stilbene (DIDS), and by substrates including

sulfate and oxalate (336, 406). This view is substantiated by

unpublished data demonstrating expression of several SLC26

family members in human intestine and in the intestinal cell

line Caco-2 and inhibition by selenate of sulfate uptake by

Caco-2 cells (Dianne Ford, pers. comm.).

B. The biochemical interconversion

of selenium species

Assimilation of dietary selenium into selenoproteins occurs

through a series of interconversions about which many details

are still lacking. An overview of the metabolic pathways is

given in Figure 4. For clarity, selenide (H

Se) is considered as a

central point in the metabolic interconversions of both organic

and inorganic selenium compounds. Dietary selenomethio-

nine is converted to selenocysteine (also obtained directly

from the diet, as is Se-methylselenocysteine) via the interme-

diate selenocystathionine through the action of cystathionine

b-synthase and then cystathionine g-lyase (97, 267). Seleno-

methionine released through protein catabolic processes en-

ters the process of metabolic interconversion in the same way

and, unlike selenocysteine, is incorporated nonspeciﬁcally in

place of methionine into proteins, depending on availability.

Selenocysteine b-lyase releases selenide (H

Se) from seleno-

cysteine (97, 267); an alternative route for the release of sele-

nide from selenomethionine may be through the action of gut

bacterial methionase (97). Dietary Se-methylselenocysteine

can be converted to methylselenol (CH

SeH) in a cystathione

g-lyase-catalysed reaction (287), which can in turn be de-

methylated to produce selenide (356). Selenite can be reduced

to selenide directly through the action of thioredoxin reduc-

tase (TXNRD, itself a selenoprotein) plus thioredoxin (229) or

it can react with glutathione to form selenodiglutathione

(229). Selenodiglutathione is a substrate for reduction to glu-

tathioselenol by glutathione reductase (229); glutathioselenol

then reacts with glutathione to yield selenide (229). Selenate

is, presumably, assimilated into proteins through reduction to

selenide via the same pathways; however, the mechanism for

reduction of selenate to selenite remains unclear but may in-

volve the activity of TXNRD in the presence of glutathione

and thioredoxin (229). Further steps in the assimilation of

selenide into selenoproteins involve generation of the highly

reactive selenium donor selenophosphate through the activity

1342 FAIRWEATHER-TAIT ET AL.

of selenophosphate synthetase (360) and then incorporation of

selenium into selenocysteyl-tRNA

[Ser][Sec]

through conversion

of O-phospho-l-seryl-tRNA

[Ser][Sec]

(141). Selenide is also the

intermediate metabolite for selenium excretion; at lower lev-

els of intake it is incorporated into selenosugar for excretion in

urine, and at higher levels of intake methyltransferases add

methyl groups sequentially to convert selenide to methylse-

lenol then dimethylselenide, which is excreted in the breath

and in the feces, then trimethylselonium, which is excreted in

the urine (210, 267).

C. Systemic transport of selenium

Plasma selenoprotein P (SePP) is the major circulating

transport form of selenium, accounting for the majority of

selenium in plasma [up to 60% (162)], and is responsive to

changes in level of dietary exposure (99, 174, 414). In humans,

full-length SePP is a glycosylated protein of 366 amino acids.

Approximately two-thirds of the molecule (amino acid resi-

dues 1–244) is folded into an N-terminal domain that includes

one selenocysteine residue, whereas the smaller C-terminal

domain includes nine selenocysteines, providing the selenium

transport capacity (67). Thiol-redox function has been attrib-

uted to the N-terminal domain, based on the presence of a

thioredoxin fold and on measured functional properties (314,

359). Truncated isoforms of SePP have been described (67)

and in humans two major forms resolve as proteins with

different molecular mass (*50 and *60 kDa) on SDS-PAGE.

The relative ratio of the two isoforms has been reported to be

inﬂuenced by genotype with respect to two single nucleotide

polymorphisms (SNPs) in the SePP gene, the effect of which

was abrogated under conditions of selenium supplementa-

tion (243). SePP synthesis is reduced under conditions of di-

etary selenium deﬁciency and plasma concentrations fall (67).

The phenotypic features of SePP knockout mice are con-

sistent with a role in systemic selenium transport. These fea-

tures include reduced body selenium content and reduced

concentration in some tissues, with accompanying changes in

FIG. 4. A scheme for selenium absorption, metabolism, and distribution. Tissues=cells represented are the enterocyte,

liver, kidney, brain, and testis, as labeled. The metabolic interconversions of selenium compounds shown may include

ubiquitous reactions; other reactions may be speciﬁc to particular tissues. The scheme serves to show the details of the

pathways through which selenium obtained as dietary selenocysteine, selenomethionine, Se-methylselenocysteine, selenite,

and selenite, absorbed from the intestinal lumen potentially involving transport proteins as indicated, are converted to

selenide (H

Se), and how this intermediate is incorporated into selenoproteins as selenocysteine. Enzymes catalyzing the

various steps are shown in italics. Major routes of excretion for selenosugar and the methylated metabolites (breath, feces,

and urine) are indicated. For full details, refer to the text. Incorporation of absorbed dietary selenium into secreted GPx3 is

proposed as a pathway through which dietary selenium may enter the portal circulation, to reach the liver for incorporation

into SePP. Other, unidentiﬁed mechanisms may also=alternatively transport dietary selenium to the liver. Uptake of SePP by

the testis, brain, and kidney via the apoER2 receptor and megalin is indicated. Other mechanisms for delivery of selenium

carried as SePP to tissues are unknown. Local synthesis, release, and reuptake of SePP by the brain (SePP cycle; important

under selenium-depleted conditions) is indicated. B

, amino acid transport system B

; GPx3, glutathione peroxidase 3; GS-

Se-GS, selenodiglutathione; GS-SeH, glutathioselenol; GSSG, glutathione disulﬁde; SeCys, selenocysteine; SeMet, seleno-

methionine; SePP, selenoprotein P.

SELENIUM AND HUMAN HEALTH 1343

the activity of selenoproteins (163, 325). A noteable exception

is the thyroid gland, for which mechanisms for prioritization

of selenium supply (see section V.A.2) appear to include

SePP-independent supply of selenium (323). Although SePP

is expressed in most tissues, the current model is that SePP

synthesis in the liver incorporates selenium into SePP for

distribution to other tissues (306). Local SePP biosynthesis

appears to be important in protecting the brain against sele-

nium loss under selenium-deﬁcient conditions (328).

Uptake of SePP from the plasma into tissues, including

testis, kidney, and brain, is emerging as a receptor-mediated

process. For example, mouse Sertoli cells were observed by

immunohistochemistry to contain SePP1-positive vesicles,

and apolipoprotein E receptor-2 (apoER2) was found to be

associated with SePP in preparations of mouse testis (273).

Another member of the lipoprotein receptor family—megalin

(Lrp2)—is believed to mediate SePP uptake from the glo-

merular ﬁltrate in the kidney (271).

In summary, the form in which absorbed dietary selenium

enters the portal circulation appears to have received little

attention, and is likely to vary depending on the dietary

source (e.g., organic or inorganic). The scheme proposed for

the absorption and metabolic interconversion of selenium

compounds (Fig. 4) reveals multiple potential points of in-

teraction with other molecules and=or processes that may

lead to inﬂuences of selenium on health and disease and so

provide important targets for future research. Membrane

transport proteins that are involved in the absorption of die-

tary selenium should be identiﬁed, and potential interactions

with dietary components and oral pharmaceuticals investi-

gated to aid the development of dietary recommendations

and health policy. Establishing the extent to which speciﬁc

metabolic interconversions of selenium compounds are

tissue- or organ-speciﬁc, or ubiquitous, will provide a more

detailed model for selenium handling on a whole-body level,

including identiﬁcation of the molecular forms in which se-

lenium is transported between the tissues; the view that SePP

produced in the liver is the major circulating from of selenium

is substantiated by robust evidence, but it is likely that other

selenoproteins, or other forms of selenium, are also important

transported forms, perhaps with some element of tissue

speciﬁcity with respect to production and uptake. Notable in

this context is the form in which selenium leaves the intestinal

enterocyte and in which it is presented to the liver, ultimately

for incorporation into SePP. While receptor-mediated endo-

cytosis, involving speciﬁc receptor molecules, is emerging as

the mechanism for uptake of SePP in speciﬁc tissues, the

mechanisms involved in delivery of selenium to the tissues in

general remains unknown. A good understanding of sele-

nium metabolism and transport on a whole-body level is es-

sential if research aimed to establish the relationships between

selenium, health, and disease is to be optimally targeted, so

these gaps in knowledge should be addressed as a matter of

priority.

IV. Selenium Status

A. Measurement of status

Methods to assess the selenium status of populations have

been reviewed extensively (23, 130, 191). In some situations,

the overall selenium status of large populations can be pre-

dicted by examining the chemical composition of the terres-

trial environment, in particular soil selenium content, and by

analyzing the selenium composition of generic foodstuffs

and dietary habits. At an individual level, selenium status can

be assessed from hair, toenail, and urinary analysis, or more

directly by assaying the selenium concentration of blood (whole

blood, plasma, serum, or erythrocyte=platelet fractions), and

bioassays of selenoproteins in different blood fractions may

provide more accurate estimates of functional=physiological

selenium status.

The analysis of selenium in hair and toenails is useful as a

long-term biomarker (23). As both tissues are easy to access

and are noninvasive, they are also suitable for ﬁeldwork, but

samples must be prepared with care to avoid contamination.

For example, hair samples can be affected by selenium-

containing shampoo residues. Wide variation in hair selenium

concentration has been reported in populations of contrasting

selenium status in China (<0.1 to >100 mg=kg hair) (130), but

positive correlations have been found between selenium status

and toenail selenium concentrations (316). Urinary selenium

excretion can also be used to determine absorption in bio-

availability studies, or to assess compliance in intervention

studies and is a useful responsive biomarker (23).

Plasma or serum selenium is one of the most commonly

used biomarkers of selenium status, and in a meta-analysis

of 14 studies plasma selenium responded to selenium-

supplementation or selenium-depletion across all subgroups

(23). Plasma selenium is relatively easy to obtain provided

trace element-free collection tubes are available. Whole blood

selenium also responds signiﬁcantly to supplementation and

is therefore also a useful biomarker. However, there are only a

limited number of studies reporting whole blood selenium, so

the interindividual heterogeneity is unclear and the length of

time needed to incorporate selenium into red blood cells

renders it less responsive than plasma to changes in selenium

intake. It is possible to assess the selenium concentration of

erythrocytes and platelets although samples require almost

immediate processing. Since much of the selenium in red

blood cells is associated with hemoglobin (144), erythrocyte

selenium is again less responsive than plasma selenium.

Although serum=plasma selenium is a useful measure of

selenium status and short-term responses to changes in in-

take, it is not ideal for assessing selenium status in popula-

tions due to the high level of interindividual heterogeneity

(23). Serum=plasma selenium is also affected by confounding

factors, including smoking, alcoholism, and some disease

states. For example, HIV=AIDS appears to lower plasma se-

lenium levels (9, 105). There is also an apparent decline in

plasma selenium in the elderly in certain populations (92, 269,

380), which may occur independently of intake, and one study

suggested that the bioavailability of selenium is inﬂuenced by

aging (269). In addition, there is a large effect of dietary se-

lenium species on plasma selenium concentrations. For ex-

ample, organic species of selenium are readily incorporated

into plasma albumin unlike inorganic species (68, 262).

Expression of individual selenoproteins may be useful

measures of selenium status (23, 174, 281). There are a total of

25 human genes that express selenoproteins (211); quantiﬁ-

cation of a combination of the selenoproteins may be needed

to measure selenium status (111). The most commonly used

group of selenoproteins are the glutathione peroxidases;

GPx1, GPx3, and GPx4. GPx activities in plasma, erythrocytes,

and platelets generally respond to supplementation only in

1344 FAIRWEATHER-TAIT ET AL.

selenium-deﬁcient populations since plasma GPx3 activity

normally plateaus with intakes 65 mg=day. The selenium

intake required to achieve maximal activity of plasma GPx

activity has been used to set dietary reference intake (DRI)

values in the United States (274) (section XI). Plasma SePP

responds in a dose-dependent way to selenium supplemen-

tation (23, 99, 162, 174, 253, 414) and may be a more sensitive

selenium status biomarker over a wider range of intake=status

than some other markers, for example, platelet GPx1 or GPx3

(174, 414); SePP concentration may reach a maximum at a

plasma selenium concentration in the region of 125 ng=ml (to

convert to mMdivide by 78.96) and an intake *100 mg=day (174).

B. Global variation in status

As with global estimates of selenium intake, there is very

wide geographical variation in plasma and serum selenium

concentrations (87, 130, 297, 377, 410). In areas of China in

which Keshan Disease and Kashin-Beck Disease (an endemic,

chronic, degenerative osteoarthropathy—see section VI.A)

are prevalent, serum selenium concentrations as low as *12–

20 ng=ml have been reported, whereas in seleniferous regions

of the United States, serum selenium can rise to 200 ng=ml

(410). For healthy adults, the proposed reference range is 39.5–

197.4 ng=ml (410). However, this range carries considerable

uncertainties with regard to sufﬁciency since maximal plasma

GPx activity occurs at plasma selenium concentrations *70–

90 ng=ml (262, 365), and maximal SePP activity occurs at a

plasma selenium concentration *120 ng=ml (174). Fordyce

reports a more conservative normal range of serum selenium

of 60–105 ng=ml (130). In a review of 65 studies published

between 1995 and 2003, serum or plasma selenium concen-

trations in European healthy adults ranged from 50.22 to

145.29 ng=ml but with the skewed range, most fell below the

mean selenium concentration of 78.96 ng=ml (1.00 mM) (377).

C. Changes in selenium status in relation

to environmental factors

Case studies from New Zealand, China, Finland, and the

UK clearly demonstrate a link between supply of selenium in

the soil-to-crop pathway and changes in selenium intake and

status among populations. In New Zealand, increased sele-

nium intakes correlated with imports of Australian wheat that

contain higher levels of selenium (366, 368, 395). In China, a

detailed geochemical analysis of areas with high incidence of

Keshan disease in the late 1990s showed that total soil sele-

nium was not inversely correlated with Keshan disease inci-

dence, as expected, but Keshan disease incidence was,

however, inversely correlated with water soluble soil sele-

nium [reviewed by Johnson et al. (191)].

In Finland, the link between the supply of selenium in the

soil-to-crop pathway and changes in selenium intake and

status among populations has been demonstrated [reviewed

by Broadley et al. (64)]. In 1983, legislation was introduced to

incorporate selenium into all multinutrient fertilizers (20, 114–

116, 297, 378, 379). The policy aimed to produce a 10-fold

selenium-enrichment of cereal grains (379). Multinutrient

fertilizer formulations were altered to include 16 mg selenium=

kg fertilizer for arable and horticultural crops and 6 mg sele-

nium=kg fertilizer for fodder crop and hay production. In-

itially, crop selenium concentrations increased by more than

10-fold and a single level of supplementation of 6 mg seleni-

um=kg fertilizer commenced in June 1990 (379). In 1998, se-

lenium supplementation was increased to 10 mg selenium=kg

fertilizer for all crops (64).

Selenium fertilizers in Finland increased crop selenium

content, dietary intakes, and the selenium status of the Finnish

population (64, 116, 297). The selenium concentration of

wheat bran increased 10-fold and fruit and vegetable crops

10-to-100-fold (114); pig muscle meat and liver increased from

0.08 and 0.49 mg=kg, respectively, in 1985 to a peak of 0.30

and 0.73 mg=kg in 1989 (379). Average selenium intakes rose

from 25 mg=day in 1975=1976 to 124 mg=day in 1989 (116).

Between 1975=6 and 1989, intake of selenium from cereals

increased from 9 to 30 mg=day, from fruit and vegetables from

0.4 to 4 mg=day, and more modest (<10-fold) increases were

reported in meat, ﬁsh, dairy products, and eggs (116). In-

creases in blood (378) and serum (392) selenium concentra-

tions were also reported, including a study of Finnish children

(<15 years), whose serum selenium increased from a mean of

69 ng=ml (range: 43–114 ng=ml) in 1985 to 100 ng=ml (range:

76–124 ng=ml) in 1986 (392). In adults, serum selenium in-

creased from 82 ng=ml (range: 49–107 ng=ml) in 1985 to 103

(range: 69–136 ng=ml) in 1986.

In the UK, there is also evidence to support an environ-

mental link between selenium supply and selenium status,

although more subtle than in Finland. Selenium intake is

relatively low, *50–60 mg per day, and some populations

may not be consuming sufﬁcient selenium for optimal plasma

GPx3 activity or optimal SePP concentration [*100 mg=day

(174)]. The evidence for a decline in selenium intake in the UK

since the 1970–80s shows that in 1974 and 1985 estimates of

selenium intake were *60 mg=day, but by 1991, estimated

intakes of 24–31 to 60 mg=day per person were reported (136,

248). In studies from 1994, 1995, 1997, and 2000, selenium

intakes ranged from 29 to 43 mg=day, but in 2006 an increase to

48–58 mg=day per person was reported, with the caveat that

there are analytical uncertainties for 13 out of 20 food groups

analyzed for selenium (136).

There are several reasons for the apparent decline in sele-

nium intake and status in the UK over the last 30 years (2, 49,

163, 252). Cereals, and especially wheat, comprise *30% of

the energy intake of the average UK diet (137) and the single

largest dietary change affecting selenium intake and status is

likely to be a reduction in consumption of imported milling

wheat containing higher levels of selenium in the grain, and

increased consumption of UK-grown wheat containing low

levels of grain selenium. In 1970 >5 Mt of wheat was im-

ported into the UK, mostly used for milling and human con-

sumption (Fig. 5A) (120). Of this, 2.2 Mt came from the United

States and Canada (235). Since 1990, wheat imports to UK

have averaged 1.2 Mt=year (range 0.73–1.67 Mt). In 2005, of

the 1.35 Mt=year imported to UK, 0.37 Mt was imported from

Canada and 0.10 Mt from the United States (Fig. 5B), and by

the 2007=08 season, 82% of wheat for human consumption

was reportedly being grown in the UK (64). The primary

reason for the decline in imports was the widespread adop-

tion of the Chorleywood Bread Process in the early 1960s,

which enabled UK (and other European Union, EU)-grown

milling wheat to replace higher protein content North

American–grown wheat in bread production. Subsequently,

the UK became a member of European Economic Community

(EEC) in 1973, which introduced EU import tariffs and led to a

rapid decline in non-EU sourced wheat.

SELENIUM AND HUMAN HEALTH 1345

Recently, it has been shown that UK wheat grain selenium

concentration can be increased by 16–26 ng=g fresh grain, for

each gram of selenium applied per hectare (applied as sodium

selenate (Na

SeO

)) (63). The concentration of selenium in

UK-sourced wheat grain is usually 28 ng=g, with a narrow

interquartile range of 19 ng=g, n¼452). There has been little

apparent change since the early 1980s (2), although increased

sulfur usage may cause a decrease in selenium uptake by

wheat (352). In contrast, the selenium concentration of U.S.

-sourced wheat grain is 457 [n¼190; (148)] and 370 [n¼290;

(407)] ng=g and Canadian-sourced wheat grain is reportedly

760 ng=g (58). The higher concentration of selenium in U.S.

and Canadian wheat grain is primarily due to the higher

plant-available selenium concentrations found naturally in

soils of their wheat-growing regions and lower-yielding (i.e.,

typically more mineral dense) grain. Most soils in the UK are

naturally low in selenium (64, 130) and there is no evidence for

soil selenium depletion due to more intensive cropping (119).

However, since coal is a rich source of selenium, general re-

ductions in coal usage and desulfurization technologies may

also have reduced selenium inputs to crops (2, 157). Changes

in dietary patterns, such as decreased consumption of offal, is

a further contributing factor (191).

Rice is another staple food that affects selenium status in

certain populations. Williams et al. recently conducted a

spatially resolved analysis of variation in selenium concen-

tration in polished rice grains (403). Over 1000 samples of rice

were purchased from major rice-producing=exporting coun-

tries and there is wide variation between and within coun-

tries. For example, rice sourced from the United States and

India had average levels of selenium >30 times greater than

rice sourced from Egypt (Fig. 6). Within countries, rice sele-

nium concentration varied by up to 10-fold. Therefore, for

public health policy spatial links between geochemistry, crop

uptake, dietary intake, and plasma=serum selenium concen-

tration need to be resolved.

FIG. 5. Wheat imports to

UK. (A) Wheat imports to UK

from all sources 1961–2007.

Wheat imports to UK from all

sources 1961–2007 data ob-

tained from reference (120).

The introduction of the Chor-

leywood Bread Process in

1961 is highlighted with a

dashed line; this process en-

abled use of UK and EU

wheat in bread making in-

stead of North American

wheat. The second dashed

line represents the year when

the UK became a member of

the European Economic Com-

munity in 1973. (B) Wheat

imports to UK from United

States and Canada 1986–2005.

Wheat imports to UK from

United States and Canada

1986–2005 data obtained from

reference (120).

1346 FAIRWEATHER-TAIT ET AL.

V. Functions of Selenium in the Human Body

A. Thyroid hormone metabolism

The redox-protective effects of selenoproteins may be of

particular importance in the thyroid gland, whose long-lived

cells generate H

(and so also reactive oxygen species

[ROS]) required for the synthesis of thyroid hormones. This

likely role is reﬂected in the abundance of selenium in the

thyroid gland (206) and perhaps by the high priority given to

maintaining selenium supply to the thyroid gland under

conditions where availability is restricted. Also of particular

relevance is the direct involvement of selenoenzymes,

the iodothyronine deiodinases (DIOs), in thyroid hormone

metabolism.

1. Thyroid hormone synthesis and the role of selenopro-

teins in thyroid gland function and protection. The pathway

for synthesis of the thyroid hormones tetra-iodothyronine

(T4) and 3,30,50tri-iodothyronine (T3) is shown schematically

as Figure 7, based on evidence from a variety of sources (48,

134, 145, 322, 343), and highlighting the roles of selenopro-

teins. Expression in the thyrocyte of several selenoproteins,

including glutathione peroxidases (GPx1, GPx3 [secreted],

and GPx4), thioredoxin reductases 1 and 2 (TXNRD1 and

TXNRD2), deiodinases 1 and 2 (DIO1 and DIO2), Sep15, SePP,

and selenoproteins M and S (319) may contribute to its high

selenium content, and the ability of some of these (GPx1,

GPx3, GPx4, TXNRD1, and TXNRD2), along with intracellu-

lar catalase and peroxiredoxins, to degrade excess H

, may

be important in antioxidant defense and redox control (205).

An additional protective role for selenium in the thyroid

gland is indicated by the positive outcomes of clinical trials

involving selenium supplementation to reduce antibody load

in cases of autoimmune thyroiditis (257).

2. Prioritization of the selenium supply to the thyroid gland

and to DIOs. Observations made in rats fed severely selenium-

deﬁcient diets provided early evidence that selenium supply

to the thyroid gland is prioritized. Whereas levels of GPx

activity and GPx1 mRNA became virtually undetectable in

liver and heart, mRNA levels were maintained in the thyroid

gland and activity was reduced by only 50%. Similarly, DIO

activity and DIO1 mRNA were maintained in thyroid but

reduced in liver (43). There is also evidence that the DIOs,

both in the thyroid gland and in nonthyroid tissues, are

preferentially supplied above other selenoproteins with sele-

nium to retain activity. For example, 50-deiodinase activity

and DIO1 mRNA were retained under conditions of selenium

depletion sufﬁcient to reduce GPx activity and GPx1 mRNA

in an epithelial cell line (147). The clinical phenotype of an

abnormality in thyroid hormone metabolism resulting from

a mutation in SBP2 (selenocysteine insertion sequence

[SECIS] binding protein 2, which interacts with the 30UTR

SECIS of selenoproteins to recode the UGA [stop] codon to

facilitate selenocysteine incorporation) appeared to be

dominated by effects on DIO activity (103), perhaps reﬂect-

ing an important role for SBP2 in the prioritization of sele-

nium supply to the DIOs. Further evidence that functionality

of the SECIS is important in selenium prioritization more

generally includes the identiﬁcation of a wide range (up to

1000-fold) in the UGA-recoding activity of different human

SECIS sequences (213).

FIG. 6. Selenium content in rice produced from different

countries. Selenium concentration of white (polished) rice from

market stores between 2005 and 2008, from countries re-

presenting 61.5% of production and 71.1% export pools glob-

ally. Redrawn from Williams et al. (403). Data are given as

percentage frequency distributions from a sample size n¼1092.

SELENIUM AND HUMAN HEALTH 1347

3. Functions of the DIOs and their potential role in health

and disease. Thyroid hormones are important signaling

molecules with essential roles in cell function and in tissue

development and physiology; thus, perturbations in their

levels, potentially including through effects of selenium status

on their synthesis, have potential consequences for health.

While some T4 deiodination occurs in the thyroid gland, it has

been estimated that around 80% of circulating T3 is generated

through DIO activity in the peripheral tissues (345). DIO2 is

now recognized to be the deiodinase primarily responsible for

deiodination of the pro-hormone T4 at the 50position to

generate active T3 (345). The roles of the three DIOs in inter-

conversion of the thyroid hormones, including inactivation by

5-deionidation, are shown in Figure 7.

A wealth of evidence supports the view that the relative

levels of expression of the different DIOs in speciﬁc tissues

and at speciﬁc developmental stages or in response to chal-

lenges such as tissue injury, illness, and nutritional deﬁ-

ciency is balanced to promote appropriate control of cell

proliferation and=or differentiation through control of thy-

roid hormone activation and inactivation, as reviewed re-

cently (345). For example, compensatory increases in tissue

DIO2 activity observed in iodine deﬁciency or hypothy-

roidism increased local T3 production (112, 282). Adequate

selenium nutrition may thus be particularly important in

cases of hypothyroidism to facilitate increased DIO activity

in tissues for which the selenium supply is a lower priority

than for the thyroid gland.

FIG. 7. Thyroid hormone

metabolism, highlighting

roles of selenoproteins. (A)

The generation of T3 and T4 in

the thyrocyte. Apical and ba-

solateral membranes are indi-

cated, facing the colloid lumen

and plasma, respectively. The

route for passage of iodide for

thyroid hormone synthesis

from plasma to colloid lumen

is indicated, and then incor-

poration as MIT, DIT, T3, and

T4 side chains of the thyro-

globulin backbone (produced

in the ER then secreted) (thy-

roglobulin iodination) is

shown. Thyroglobulin iodin-

ation (organiﬁcation of iodine)

is catalyzed by TPO and re-

quires an H

cofactor, gen-

erated by Duox. Excess H

is indicated as being in-

activated by secreted GPx3 or

by intracellular selenoproteins

(GPx1, GPx2, TNXRD1, and

TXNRD2). Iodinated thyro-

globulin is taken across the

apical membrane by micro-

pinocytosis, as indicated, and

then fusion of vesicles with

lysosomes leads to cathepsin-

catalyzed cleavage to release

T4 and T3, which diffuse into

the plasma, and DIT and MIT,

from which iodide is released

by dehalogenase and recycled.

The form and route through

which selenium enters the

thyrocyte is unknown, as in-

dicated. Selenoproteins are

highlighted in bold-italic text

in shaded shapes. (B) Chemi-

cal interconversions of the

major thyroid hormones and their metabolites by the DIOs. Deiodination at the 50-position is an activating step and is

catalyzed by DIO1 and DIO2. Deiodination at the 5-position is an inactivating step and is catalyzed by DIO1 and DIO3. DIO1,

iodothyronine deiodinase 1; DIO2, iodothyronine deiodinase 2; DIO3, iodothyronine deiodinase 3; DIT, diiodothyronine;

Duox, dual oxidase (thyroxidase); ER, endoplasmic reticulum; GPx1, glutathione peroxidase 1; GPx3, glutathione peroxidase

3; GPx4, glutathione peroxidase 4; MIT, monoiodothyronine; NIS, sodium-iodide symporter; TXNRD1, thioredoxin reductase

1; TXNRD2, thioredoxin reductase 2.

1348 FAIRWEATHER-TAIT ET AL.

Variation in DIO genes appears to inﬂuence thyroid hor-

mone metabolism and activity (283). Two SNPs in the DIO1

gene that have been associated with alterations in the ratio of

active T3 to the inactive metabolite 3,30,50triiodothyronine

(rT3) are of particular interest because they are located in the

30UTR of the mRNA, so may [in a manner similar to SNPs in

the 30UTR regions of GPX4 and SePP (241, 243)] mediate ef-

fects through selenocysteine incorporation into DIO1, and so,

speculatively, may show an interaction with selenium status.

In conclusion, given the evidence that the nonthyroid tis-

sues have lower priority for supply with selenium under

conditions of restriction and that DIO induction may be an

important adaptive response of tissues to particular chal-

lenges, more information on the interactions and processes is

required to understand links between selenium, health, and

disease.

B. Antioxidant defense system

and oxidative metabolism

1. Glutathione peroxidases. Among the selenoproteins

are four GPxs: cytosolic GPx (GPx1), gastrointestinal-speciﬁc

GPx (GPx2), plasma GPx (GPx3), and phospholipid hydro-

peroxide GPx (GPx4). These are well-characterized major se-

lenoenzymes of the human antioxidant defense systems (230).

GPx1-3 catalyzes the reduction of hydrogen peroxide and

organic hydroperoxides, whereas GPx4 can directly reduce

phospholipid hydroperoxides and cholesterol hydroperox-

ides. GPx6 is an olfactory epithelium and embryonic tissue-

speciﬁc GPx (211). GPx1 and GPx2 have well-characterized

antioxidant functions, as indicated by the greater suscepti-

bility of mice lacking both GPx1 and 2 to an oxidative

challenge (85). Responses of transgenic mice lacking or over-

expressing GPx1 suggest novel roles for GPx1 in relation to

both reactive oxygen species and reactive nitrogen species,

and a link to insulin secretion and insulin resistance (217, 394).

GPx3 is a key antioxidant enzyme in the plasma and acts as a

functional parameter for selenium status assessment, and

GPx3 deﬁciency has been associated with CVD and stroke (46,

399).

GPx activity and expression have been used in many

human studies as biomarkers for selenium status (355). It has

been shown in GPx1

(=)

mice that GPx1 deﬁciency plays a

major role in cardiac dysfunction in angiotensin II-dependent

hypertension (18). Further, there have been attempts to cor-

relate genetic polymorphism of selenoenzymes with risk of

disease, including cancer and heart disease. A recent study

provided some evidence that SNPs in GPx1 and GPx4, and

their interaction with variants in other selenoprotein genes,

may inﬂuence colorectal cancer risk (242). In another study,

with a population that had advanced distal colorectal carci-

noma, SNPs in SEPP1 and TXNRD1 were identiﬁed to be

associated with adenoma risk but not the GPX1-4 variants

investigated (286).

2. Thioredoxin reductases. TXNRDs are involved in the

control of cellular proliferation, cell survival, and apoptosis

through the control of thioredoxin (Trx) activity and redox

state, and play a crucial role in biological response to oxida-

tive stress. Three TXNRDs have been identiﬁed in mammals:

TXNRD1 in the cytosol=nucleus, TXNRD2 in mitochondria,

and thioredoxin glutathione reductase in the testis, with the

last also possessing glutathione and glutaredoxin reductase

activity (279). TXNRD, Trx, and NADPH constitute the

thioredoxin system, a major cellular redox system present in

all living organisms (19). TXNRDs have a wide range of

substrates, including small molecules such as hydrogen per-

oxide, lipid hydroperoxides, and ascorbate, lipoic acid, ubi-

quinone, and Trx (413). ROS are a major contributing factor to

the pathogenesis of CVD. The thioredoxin system plays an

important role in scavenging ROS. Trx, glutaredoxin, perox-

iredoxin, and their isoforms are involved in interaction with

signaling pathways, thus making them attractive targets for

clinical intervention (3). TXNRD is the only known enzyme

able to reduce oxidized Trx, which regulates a plethora of

redox signaling events (153). Reduced Trx provides electrons

to ribonucleotide reductase, essential for DNA synthesis, by

converting ribonucleotide to deoxyribonucleotides. More-

over, the Trx system participates in many cellular signaling

pathways by controlling the activity of transcription factors

containing critical cysteines in their DNA-binding domains,

such as nuclear factor kappa B (NFkB), activator protein-1

(AP-1), p53, and the glucocorticoid receptor (223).

There is growing evidence that redox regulation by the

TXNRD systems plays a crucial role in the biological response

against oxidative stress and in cell proliferation, apoptosis,

and the modulation of inﬂammation (70, 342, 362). Trx can

bind to apoptosis signal regulating kinase 1 (ASK1) and

modulates apoptosis (223, 258, 315). TXNRD is also over-

expressed in many tumor cells and contributes to drug re-

sistance; therefore, TXNRD was considered a new target for

anticancer drugs (140). In addition to selenium, dietary phy-

tochemicals such as isothiocyanates and polyphenols can also

upregulate TXNRD and GPx2 expression in both tumor and

normal cell lines via the Keap1-Nrf2-ARE pathway (203, 220,

429).

3. Other selenoproteins involved in the antioxidant de-

fense system. Recently, it has been suggested that seleno-

proteins, including SelW, SelM, SelT, and the 15 kDa

selenoprotein, are members of a novel redox protein family

that share the common feature of containing a thioredoxin-

like fold with a CxxSec redox fold (1, 39). Further, over-

expression of SelW in cultured cells led to lower sensitivity to

challenge from hydrogen peroxide (190), suggesting that

SelW has an antioxidant function. Selenoprotein H (SelH) is a

nucleolar thioredoxin-like protein with a unique expression

pattern, and structural studies suggest that SelH is a redox-

sensing DNA binding protein (266, 278). A recent study de-

scribed a knock-out mouse deﬁcient in selenoprotein MsrB1

(SelR) with increased levels of malondialdehyde, protein

carbonyls, protein methionine sulfoxide, and glutathione

disulﬁde as well as reduced levels of free and protein thiols,

indicating that MsrB1 plays an important role in redox regu-

lation (128). SePP has a purported thiol-redox function as a

member of the thioredoxin superfamily (67) and may protect

against oxidative damage (347). In addition, selenoproteins N

and K may have antioxidant roles (17, 228).

In summary, several of the selenoproteins may be involved

in the antioxidant defense system as highlighted in section

V.B. above; there are many other important functions of the

human selenoproteins such as the role of SelW and SelN

in muscle function, reviewed recently in Lescure et al. (218),

and other functions discussed throughout this review, for

SELENIUM AND HUMAN HEALTH 1349

example, throughout chapter VI: clinical disorders section

below. For recent reviews focused in detail on selenoproteins,

refer to refs. (39, 230, 279, 301, 332, 433).

C. Immune system

Studies in experimental and farm animals indicate that

selenium deﬁciency affects both cell-mediated and humoral

components of the immune response (21, 167, 344). In hu-

mans, limited data suggest that when intakes of selenium are

sub-optimal selenium supplements can enhance immune re-

sponses (167). Low serum selenium in humans is associated

with low levels of natural killer cells (304), and selenium sup-

plementation (200 mg=day) increased T-lymphocyte-driven tu-

mor lysis and lymphocyte proliferation (200). In rats, selenium

deﬁciency lowers levels of IgA, M, and G; selenium-deﬁcient

lymphocytes show lower mitogen-stimulated proliferation,

and in cell culture, selenium promotes human neutrophil

function (21). Despite these observations the details of how

selenium intake inﬂuences the immune system remain poorly

understood, with the most information being available on the

effects of severe selenium deﬁciency and selenoprotein knock-

out in response to viral infection.

A landmark discovery in selenium biology during the past

30 years was the observation by Chinese scientists that Ke-

shan disease, a myocarditis found in selenium-deﬁcient areas

of China, is associated with a combination of low selenium

intake and Coxsackie virus B (CVB) infection (see section

VI.A.1). Molecular hybridization and immunohistochemistry

analysis of postmortem material has shown CVB3 to be

present in the majority of Keshan diseases cases. Further,

feeding mice a selenium-deﬁcient diet in combination with

CVB infection leads to pathological changes in the myocar-

dium similar to those found in Keshan disease (multiple ne-

crosis lesions of the myocardium and inﬂammatory cell

inﬁltration). Overall, these data demonstrate that en-

teroviruses, especially CVB, are closely associated with the

viral myocarditis of Keshan disease (107, 431).

Selenium intake has subsequently been found to affect the

progression of other viral infections in animals (34). For ex-

ample, selenium deﬁciency results in greater lung pathology

in mice infected with inﬂuenza virus compared with seleni-

um-adequate mice; selenium-deﬁcient mice showed an al-

tered immune response to an infection with a virulent strain of

inﬂuenza virus and the viral genome changed to a more vir-

ulent genotype. Selenium deﬁciency also has a signiﬁcant

impact on the morphology and inﬂuenza-induced host de-

fense responses in human airway epithelial cells (35). Porcine

circovirus type 2 replication in PK-15 cells is inhibited by DL-

selenomethionine in a concentration-dependent manner

(277). Except for Keshan disease no causal links between se-

lenium intake and viral response have been demonstrated in

humans, but selenium status and viral responses are associ-

ated. For example, selenium supplementation was shown to

modulate the response of healthy volunteers of marginally

low plasma selenium status to a disabled polio virus (65),

conﬁrming that selenium status determines the ability to re-

spond to a viral infection. In addition, epidemiological studies

suggest a correlation between severity of AIDS and selenium

deﬁciency, but to date it is not clear whether this reﬂects a

protective role for selenium during HIV infection or an altered

nutritional selenium status as a result of the disease (31, 167,

227). Similar observations have been made with the inﬂuenza

virus. Not only does selenium status modulate responses to

inﬂuenza virus (261), but also GPx1 activity is important in

determining the response (33, 337). However, the extent to

which other selenoproteins are involved in determining the

effects of selenium status on responses to viral infection is

poorly understood, although selenium depletion was shown

in a cell culture model to affect inﬂuenza virus-induced cy-

tokine production in bronchial epithelial cells (189).

Immune responses are intimately linked to inﬂammatory

processes and these in turn are inter-related to production of

ROS and redox control processes. For example, ROS pro-

duction can increase expression of inﬂammatory cytokines

through increased NF-kB activity (369). It is possible that se-

lenium modulates inﬂammatory and immune processes

through redox functions. To some extent this is illustrated by

the observations that transgenic mice with a mutant Secys-

tRNA that causes depletion of all selenoproteins, but with

variations in extent between selenoprotein and tissues,

showed changes in the pattern of certain cytokines (e.g.,

interferon–g) (337). In addition, the potential importance of

redox signaling via selenoproteins is also shown by the effects

of GPx1 knockout on viral infection. However, mutant Secys-

tRNA mice failed to show differences in lung pathology after

inﬂuenza virus infection, suggesting that a basal threshold

level of GPx1 is sufﬁcient to maintain response to the virus. It

was recently reported that the selenoprotein thioredoxin re-

ductase 1, also a key factor in redox control, can negatively

regulate the activity of the HIV-1-encoded transcriptional

activator, Tat, in human macrophages (194).

White blood cells such as lymphocytes, macrophages, and

neutrophils require ROS and pro-inﬂammatory molecules for

their activation, differentiation, and phagocytosis (132). Thus,

since selenoproteins may inﬂuence these signaling pathways

they may in turn be expected to be crucial for these cell

functions. For example, neutrophils require oxidative radical

production to achieve microbial killing and selenium deﬁ-

ciency lowers the ability of neutrophils to kill ingested mi-

crobes, probably partly due to lower GPx1 activity and thus

impaired radical metabolism (21). Macrophages are key cells

in the signaling and activation of inﬂammatory responses, but

this action also produces ROS; therefore, it must be carefully

controlled and counteracted. Studies in which selenium-

supplemented macrophages were stimulated with LPS (a bac-

terial endotoxin) found that supplementation with selenium

suppressed TNF-aand COX-2 (cyclooxygenase-2) expression

(386). However, Carlson et al. (79) found that macrophages

without any selenoproteins still exhibited normal inﬂamma-

tory responses, although higher levels of ROS were seen. In a

similar experiment, mice with selenoprotein-less T-cells also

exhibited increased ROS levels, reduced numbers of mature

T-cells, and defective antibody responses (340).

Low selenium status has been associated with reduced

serum IL6 in elderly people (388), an observation that is

consistent with links between selenium, selenoproteins, and

inﬂammatory signaling. In addition to potential metabolic

links between GPx1, ROS, and inﬂammatory cytokines such

as the interleukins, results from a series of studies suggest that

selenium levels affect eicosanoid metabolism. Studies of both

severely selenium-deﬁcient animals and selenium-deﬁcient

cells in culture suggest that selenium supply, through its

inﬂuence on GPxs, has an inhibitory regulatory effect on

1350 FAIRWEATHER-TAIT ET AL.

50lipoxygenase activity in lymphocytes (179, 397) and thus on

generation of pro-inﬂammatory leukotrienes. In addition,

overexpression of GPx4 in transfected basophils has also been

reported to suppress 50lipoxygenase activity. Further evi-

dence for a metabolic link between GPx4 and leukotrienes has

come from the ﬁnding that individuals with different allelic

variants of a common SNP in the GPX4 gene (rs713041) have

been found to have different levels of 50lipoxygenase product

in their lymphocytes (382), suggesting that lymphocyte GPx4

activity inﬂuences pro-inﬂammatory leukotriene activity in

lymphocytes.

A combination of severe selenium and iodine deﬁciency

causes a thyroid atrophy that does not respond to iodine

supplementation due to inﬂammatory damage to the thyroid,

and this has led to studies of selenium in thyroiditis (205).

Indeed, several clinical trials have reported that selenium

supplementation reduces inﬂammatory markers in patients

with autoimmune thyroiditis, and this has led to the hy-

pothesis that even a moderate selenium deﬁciency can be a

causative factor in autoimmune thyroid disease in patients

who have genetic susceptibility to autoimmune disorders.

In summary, there is a growing body of evidence that se-

lenium status affects immune function, in particular the

ability to respond to viral infection. The mechanisms under-

lying these effects are poorly understood but may involve

modulation of ROS and inﬂammatory signaling pathways

through the antioxidant and redox functions of selenopro-

teins.

VI. Clinical Disorders

A. Deﬁciency

1. Keshan disease. Keshan disease is an endemic car-

diomyopathy observed in selenium-deﬁcient areas of China.

Its name originates from a severe outbreak in Keshan County,

Heilongjiang Province, China in 1935. The main clinical fea-

tures of Keshan disease are acute or chronic episodes of a

heart disorder characterized by cardiogenic shock and=or

congestive heart failure. Keshan disease can be clinically

classiﬁed into four types: acute, sub-acute, chronic, and latent.

Dilatation of the heart is commonly observed (143).

The etiology of Keshan disease is not yet fully understood.

Originally, the proposed risk factors included Coxsackie virus

(CVB), type A streptococci, and organic toxicants produced

by parasitic fungi on cereals or putrid organic substances in

water and=or soil environments. In the 1970s, the low sele-

nium status of the inhabitants in Keshan disease-endemic

areas became evident, and subsequently, the preventive effect

of selenium supplementation on Keshan disease was identi-

ﬁed. Further improvements in selenium status were associ-

ated with a decline in Keshan disease in the endemic areas and

conﬁrmed the link between selenium and Keshan disease.

In China, the selenium-deﬁcient zone from the northeast to

the southwest involves 16 provinces, and historical data in-

dicated that the population at risk was >100 million. Keshan

disease surveillance has been a national program since 1990,

an important component of which is the determination of

selenium levels in Keshan disease-endemic areas (425).

The geographical distribution of topsoil selenium in China

and its relationship to Keshan disease (and Kashin-Beck dis-

ease) indicates that the selenium concentrations in topsoil of

affected areas are typically below 0.125 mg=kg. In contrast,

the concentration in areas without disease is 0.224 mg=kg, and

the excessive level is >3mg=kg (361). Nutritional studies

showed that the mean hair selenium contents were <0.122

mg=kg in endemic areas and >0.200 mg=kg in non-Keshan

disease–endemic zones, whereas the average blood selenium

concentration of people in Keshan disease endemic areas was

no more than 253 nM(20 ng=ml). The selenium content of

muscle, heart, liver, and kidney in Keshan disease patients is

up to 10-fold lower than that in healthy subjects (143).

Recent studies suggest that genetic polymorphisms in sele-

noproteins may be associated with susceptibility to Keshan

disease. Lei et al. measured the concentration of blood selenium

and the activity and polymorphisms of cellular GPx1 in 71

Keshan disease patients and 290 controls (216). Results sug-

gested that selenium deﬁciency in carriers with the GPx1 leucine-

containing allele is associated with low GPx1 enzyme activity,

which may, in turn, increase the incidence of Keshan disease.

The link between selenium and Keshan disease was further

strengthened with results of a selenium supplementation trial.

Between 1974 and 1977, sodium selenite or placebo tablets

were given to children at high risk of Keshan disease. Con-

current with an increase in blood selenium concentrations in

the treated group (n¼6767), 17 acute and sub-acute Keshan

disease cases were reported compared with 106 in the placebo

group (n¼5445). After 4 years, there had been 53 deaths in the

controls, whereas only one selenium-treated subject had died

(421). Supplementation of individuals with selenium tablets

(as sodium selenite) has been effective in preventing the de-

velopment of Keshan disease (418). However, as not all peo-

ple living in the low selenium areas suffered from Keshan

disease, other causal factors such as virus infections were

proposed.

In animal studies, Bai et al. demonstrated that mice fed

grains from Keshan disease areas developed a deﬁciency in

selenium (28). When these mice were infected with a strain of

Coxsackie virus B4 that was isolated from a Keshan disease

victim, the mice developed severe heart pathology, whereas

mice that were fed grains from non-Keshan disease–endemic

areas developed only mild heart pathology when infected

with the virus. This study suggested that together with the

deﬁciency in selenium, an infection of CVB was required for

the development of Keshan disease (28). A further study

demonstrated that selenium deﬁciency was responsible for

driving changes in the viral genome and changing a normally

avirulent pathogen into a virulent one (36). Moreover, inﬂu-

enza virus exhibits increased virulence toward the selenium-

deﬁcient mice (34).

Selenium deﬁciency may affect expression of sele-

noenzymes such as GPX1. One study showed that 50% of

GPx1 knockout mice (GPx=) infected with CVB3=0 de-

veloped myocarditis, whereas infected wild-type mice

(Gpx1þ=þ) were resistant (no mice developed myocarditis)

(33). This study suggests that antioxidant protection is im-

portant for protection against CVB3-induced myocarditis.

After the isolation of enteroviruses from patients with

Keshan disease during outbreaks of the disease in selenium-

deﬁcient rural areas of southwestern China, an association of

enterovirus infection with Keshan disease and its outbreaks in

selenium-deﬁcient areas has been established (284). To date,

many studies strongly suggest a dual etiology that involves

both a nutritional deﬁciency of selenium as well as an infec-

tion with an enterovirus (34, 173).

SELENIUM AND HUMAN HEALTH 1351

There is an interest in identifying potential protective dietary

compounds, for example, sulforaphane (SFN), a hydrolysis

product of glucosinolate from cruciferous vegetables that is a

potent inducer for a battery of antioxidant enzymes, including

quinone oxidoreductase, glutathione transferases, UDP-glu-

curonyltransferase, g-glutamylcysteine synthetase, heme oxy-

genase, aldo-keto reductase, thioredoxin reductase, and GPxs.

The mechanism of interactions between selenium and SFN in

antioxidant enzyme expression was mainly via Nrf2=Keap1

system (60). Sun et al. conducted a study to investigate whether

SFN can protect the myocardium of selenium-deﬁcient mice

against viral infection and demonstrated that GPx activity in

groups given SFN was signiﬁcantly higher than in the control

groups without SFN (353). Further, both the incidence and

extent of myocardium injury in viral groups with SFN were

signiﬁcantly lower than those in the viral groups without

SFN. It was therefore concluded that SFN affords a degree

of protection against Coxsackie virus B3m-induced mouse

cardiomyopathy.

2. Role of selenium in Kashin-Beck disease. Kashin-

Beck disease (KBD) is an endemic, chronic, degenerative os-

teoarthropathy that is present in selenium-deﬁcient areas in

the world, and is mainly found in a diagonal belt from

northeast to southwest China, and also in Mongolia, Siberia,

and North Korea. The disease was ﬁrst described in 1848 by

Nickolay Kashin in the Bajkal area of Russia (196) and later in

1906 by Eugene Beck (32). The etiology of KBD is largely

unknown. The risk factors seem to include mycotoxins such as

Trichothecene mycotoxin (T-2) from contaminated storage

grains, and organic substances such as humic acid and fulvic

acid in drinking water, Coxsackie B3 virus infection, and de-

ﬁciency in trace elements, mainly selenium and iodine (348).

The original theory proposed by Russian researchers was that

KBD had been caused by a mycotoxin. However, the focus on

the disease gradually shifted to China, where the causal the-

ory was based on the effects of selenium deﬁciency and in-

teractions with mycotoxins (8). Among all the risk factors,

selenium was the most studied, and disturbances of seleno-

protein expression and=or function are associated with both

Keshan and Kashin-Beck diseases (204).

In the KBD-endemic areas the levels of selenium in both soil

and human biological samples are much lower than that in

areas without KBD. Ge and Yang reported that average hair

selenium concentrations in residents of KBD-endemic areas

were 1.19 0.34 nmol=g compared with 4.81 2.27 nmol=g

in nonendemic areas (143). Blood GPx activities were

74.0 12.8 kU=l in endemic groups of the population and

95.6 8.9 kU=l in nonendemic groups. Oral supplementation

of the endemic group with sodium selenite (1–2 mg=wk) for 2

months increased GPx activity to 94.0 11.5 kU=l, indicating

that the population was selenium deﬁcient (389). Many epi-

demiological studies conclude that KBD is mainly common in

low selenium areas where patients are in a selenium-deﬁcient

condition, and selenium supplementation is effective at pre-

venting a worsening of metaphysis change and in promoting

repair (75, 83). For example, in the KBD region in China, se-

rum selenium concentration was on average 36–37 17

ng=ml, compared with a similar region with no evidence of

KBD where serum selenium was *63 15 ng=ml. A majority

(>50%) of participants in the KBD area had serum selenium

<37 ng=ml, compared with only 16% in the nondisease area

[data from 2006–reported in Shi et al. (338)]. There was 13%

prevalence of Kashin-Beck in certain regions of China (338).

In areas where severe selenium deﬁciency is endemic, io-

dine deﬁciency is also a risk factor for KBD (252) and correc-

tion of iodine deﬁciency should be undertaken before

selenium supplementation to avoid hypothyroidism. How-

ever, in another study, Zhang et al. studied selenium, iodine,

and fungal contamination in the Yulin District, including

three villages where KBD was endemic, whereas there were

no cases of KBD in the fourth village. Results showed that low

hair selenium concentration and presence of fungal cereal

contamination were signiﬁcantly associated with an increased

risk of KBD, but low urine iodine was not (430).

T-2 is a naturally occurring mold byproduct of Fusarium sp.

fungus that is toxic to humans and animals and was found at

high levels (2.0*1549.9 ng=g) in contaminated grain (353). T-

2 toxin-containing food can lead to some pathologic changes

in the cartilage of guinea pigs that are similar to the changes

observed in KBD patients (415). Therefore, the T-2 toxin

contamination was proposed as a possible cause of KBD (424).

In support of this hypothesis, cell culture studies demon-

strated that T-2 toxin can inhibit aggrecan synthesis in human

chondrocytes, promote aggrecanases and pro-inﬂammatory

cytokines expression, and aggrecan degradation; selenium

can inhibit the effects of T-2 toxin (222). A previous study by

the same group showed that selenium can partly block T-2

toxin-induced apoptosis in chondrocytes (82).

In human studies, Cao et al. demonstrated that there was

signiﬁcant aggrecanase-mediated proteoglycan degradation

in both adult and child KBD patients and altered CD44 me-

tabolism was also involved in KBD pathogenesis (76). Again

in a cell culture study, Wojewoda et al. found that selenium

decreased ROS generation and increased the level and activity

of antioxidant enzymes such as GPx and TXNRD (404).

So far, the contribution of any particular genotype toward

the risk of developing KDB is unknown. Recently, the associ-

ations between genetic variation in selenoprotein genes and

susceptibility to KBD were studied. The genotypic and allelic

frequency of GPx1 Pro198Leu were signiﬁcantly different

between KBD patients and the control group ( p¼0.013,

p¼0.037, respectively). A signiﬁcant increased KBD risk was

observed in individuals with Pro=Leu or Leu=Leu (odds ratio,

OR ¼1.78; 95% conﬁdence interval: 1.13*2.81) compared with

Pro=Pro. Moreover, the GPx activity in whole blood decreased

signiﬁcantly in a subgroup of individuals representing

Pro=Leu and Leu=Leu compared with Pro=Pro ( p<0.01) (416).

In contrast, in this study, no associations were found between

KBD risk and other gene polymorphisms such as TXNRD2,

SEPP1,andDIO2. Moreover, Shi et al. suggest that variants of

the chromosomal short tandem repeats D11S4094, D11S4149,

D2S338, and D2S305 might be associated with KBD (338).

Downey et al. studied the effects of skeletal selenoprotein de-

ﬁciency using a transgenic mouse line to trigger Trsp gene

deletions in osteochondroprogenitors (96). Trsp encodes sele-

nocysteine tRNA[Ser]Sec, which is required for the incorpora-

tion of selenocysteine residues into selenoproteins. The mutant

mice exhibited growth retardation, epiphyseal growth plate

abnormalities, and delayed skeletal ossiﬁcation, as well as

marked chondronecrosis of articular, auricular, and tracheal

cartilages. Phenotypically, the mice replicated a number of the

pathological features of KBD (96), supporting the notion that

selenium deﬁciency is important to the development of KBD.

1352 FAIRWEATHER-TAIT ET AL.

Moreno-Reyes et al. reported that selenium supplementa-

tion in Tibet had no effect on established KBD, growth, or

thyroid function once iodine deﬁciency was corrected (251).

Therefore, it was suggested that iodine, but not selenium,

deﬁciency should be corrected in Tibetan children with KBD.

The results of a systematic review demonstrated no convinc-

ing evidence that selenium, vitamin A, vitamin C, or the

combination product of selenium, vitamin A, C, and E is ef-

fective in the treatment of any type of arthritis (75). A meta-

analysis of ﬁve randomized controlled trials (RCTs) and 10

non-RCTs assessed the efﬁcacy of selenium supplementation

for prevention of KBD osteoarthropathy in children (435).

Signiﬁcant effects were demonstrated and the results indi-

cated that current evidence supports the beneﬁts of selenium

supplementation for prevention of KBD in children although

evidence was limited by potential biases and confounders.

Results from a 3-year trial in which 1064 children aged 3–10

have been given iodine and selenium and either a cocktail

of micronutrients (copper, manganese, zinc, and vitamins A,

C, and E), or a placebo are expected to be published soon

by Mathieu and colleagues, which may help resolve the

controversy.

Recent comparative microarray analysis of gene expression

proﬁles between primary knee osteoarthritis (OA) and KBD

demonstrated a clear difference in the gene expression proﬁle

in cartilage from patients with KBD compared with that from

patients with OA (98), implying that there are different

mechanisms responsible for the development and progres-

sion of these two diseases (393). The genes with a lower ex-

pression in KBD than normal cartilage included chondrocyte

metabolism, ECM, DNA modiﬁcation, and transcription fac-

tors, and genes with a higher expression in KBD than normal

cartilage included signaling transduction, cell cycle, and ap-

optosis. The differential gene expression speciﬁc for KBD may

indicate a speciﬁc mechanism that is responsible for the de-

struction of the articular cartilage in KBD. The data also

suggest that cartilage degeneration, apoptosis induction

pathways, and matrix metabolism might be more important

in KBD cartilage.

Finally, the development of protein chip technology has

enabled the application of high-throughput proteomics to

identify potential biomarkers for a variety of diseases, in-

cluding KBD. Wang et al. reported marked serum pro-

teomic changes in KBD using surface-enhanced laser

desorption=ionization time-of-ﬂight mass spectrometry

(391), and it would be plausible to use this technique in

human intervention trials to examine the effect of selenium

supplementation.

B. Toxicity

Although much less common than selenium deﬁciency,

selenium toxicity can affect individuals as a result of over-

supplementation (234), accidental or deliberate (suicidal) in-

gestion of very high doses (215), or through high levels in the

food supply. Characteristic features of selenosis occur in

population groups exposed to unusually high levels of dietary

selenium, and include brittle hair and brittle, thickened,

stratiﬁed nails, leading to loss in some cases, along with an

odor of garlic on the breath and skin (234, 300). Additional

symptoms, including vomiting and pulmonary oedema, are a

feature of more acute selenium poisoning (215).

In Enshi, in the Chinese province of Hubei, an outbreak of

illness in which the most notable and prevalent symptoms

were loss of nails and hair reached a peak between 1961 and

1964, when it affected almost half of the population. This

condition was later diagnosed as severe selenosis, attributed to

soil with very high selenium content (422). It was identiﬁed that

the period of peak prevalence of selenosis was due to drought

causing failure of the (lower selenium) rice crop, leading to

consumption of alternative crops, with higher selenium con-

tent. Analysis of vegetables and cereals grown in the area after

the period of peak prevalence conﬁrmed high levels of sele-

nium, which were up to 1500-fold greater than levels measured

in the same foods taken from a nearby selenium-deﬁcient area,

where Keshan disease was endemic. Average daily intake of

selenium was estimated to be 4990 mg. Analysis of samples of

human hair, blood, and urine from residents of the affected

area revealed that selenium concentrations were far in excess of

concentrations measured in samples from individuals resident

in a selenium-adequate area.

In parts of the Punjab State, in the northwestern region of

India, crops and fodder contain very high selenium levels and

selenosis is observed in cattle. Signs of selenium toxicity are

observed in people consuming locally grown food (Fig. 8)

(164). Daily intakes of selenium were estimated to be 632 and

475 mg=day in men and women, respectively, and corre-

sponding values from nonseleniferous areas were 65 and

52 mg=day (94). Policies to manage the situation include non-

consumption of crop produce by the farmers, dilution with

produce from nonendemic regions, and application of ma-

nures to reduce selenium accumulation in crops (95).

Levels of dietary exposure at which selenium becomes

toxic and selenosis develops are difﬁcult to establish, because

toxicity is affected by the form in which selenium is available

in the food supply, and probably also by combination with

other dietary components and, possibly, interactions with

FIG. 8. Effects of consuming

locally grown foods from se-

lenium toxic areas in Punjab.

(A) Hair loss, (B) keratosis, and

vided by Dr. N. Tejo Prakash of

Thapar University, Patiala, In-

dia, and Professors K.S. Dillon

and U.S. Sadana, Punjab Agri-

cultural University, Ludhiana,

India.

SELENIUM AND HUMAN HEALTH 1353

genotype. High levels of selenium in diets based predomi-

nantly on meat sources appear to be particularly well-toler-

ated, as exempliﬁed by the high daily selenium intake of the

Inuit of North Greenland, estimated as 193–5885 mg (150). This

intake results in blood selenium concentrations in the order of

1000 mg=l (300), but is not associated with symptoms of tox-

icity. Comparison of levels of selenium in blood and urine in

the Enshi study population and also in samples from popu-

lations in South Dakota (169) revealed toxicity associated with

lower concentrations than those that result in symptoms of

selenosis in Venezuela (422), probably reﬂecting exposure to

dietary selenium in different forms. Suicide by exposure to

very high levels of selenium has been associated generally

with ingestion of selenite or selenate (215), an observation that

probably reﬂects the form of selenium in substances used in

suicide attempts, rather than necessarily being indicative of

greater toxicity of inorganic compared with organic selenium

compounds.

The mechanisms underlying selenium toxicity remain un-

known; suggested mechanisms include induction of oxidative

stress (375) and the replacement of sulfur with selenium in hair

and keratin, leading to structural defects (376). Research on this

topic, based on various in vitro and in vivo models [reviewed in

Valdiglesias et al. (375)] is complicated by likely effects on

measured outcomes of the form and dose of selenium admin-

istered and limitations with respect to extrapolating results

from in vitro assays to human exposure. The eventual evolution

of systems-biology-based approaches to describing selenium

metabolism and interactions with cells and tissues will guide

the most relevant experimental systems for understanding se-

lenium toxicity at a molecular and whole body level.

VII. Effects on Health

A. Cardiovascular disease

Selenium is essential for selenium-dependent antioxidant

enzymes such as GPxs, TXNRD, SePP, and other selenopro-

teins. Because of the antioxidant properties of selenium an-

d=or selenoenzymes, it has been hypothesized that selenium

may prevent CVD. Many observational studies investigating

the association of low selenium concentrations with cardio-

vascular outcomes and randomized trials investigating whe-

ther selenium supplements prevent coronary heart disease

(CHD) have been inconclusive.

A meta-analysis (126) synthesized results from observa-

tional studies of the association of selenium biomarkers with

CHD endpoints and from results of clinical trials of the efﬁ-

cacy of selenium supplements in preventing CHD. The con-

clusions were that observational studies showed an inverse

association between selenium concentrations and CHD inci-

dence, although the data need further validation, whereas

randomized trials were inconclusive with respect to the effect

of selenium supplementation. Another meta-analysis of 13

prospective cohort studies found a moderate inverse rela-

tionship between plasma=serum selenium and CHD although

the interpretation of these data are complicated by potential

residual confounding and publication bias (260). Finally, a

recent report by Xun et al. examined the longitudinal associ-

ation between toenail selenium levels and subclinical ath-

erosclerosis over an 18-year period, and no associations were

observed between toenail selenium and measures of sub-

clinical atherosclerosis among young American adults (417).

Selenium supplementation does not appear to reduce the

risk of CVD in healthy individuals. Supplements of

200 mg=day in individuals free of CVD at baseline were not

signiﬁcantly associated with any CVD endpoints during

7.6 years follow-up of the entire blinded phase of the Nutri-

tional Prevention of Cancer Trial (1983–1996) (350), and a

randomized, placebo-controlled trial in healthy men given

300 mg=day of selenium as high-selenium yeast for 48 weeks

suggested that selenium supplements were not likely to im-

prove endothelial function or peripheral arterial responsive-

ness in healthy North American men receiving adequate

selenium from their diets (155). Moreover, increased con-

sumption of wheat biofortiﬁed with selenium does not

modify biomarkers of cancer risk, oxidative stress, or immune

function in healthy Australian males (412).

Although it appears that selenium supplementation has no

effect on CVD risk in healthy individuals, in a very recent

AtheroGene study, low selenium concentration was associ-

ated with future cardiovascular death in patients with acute

coronary syndrome, although no effect on stable angina

pectoris (232). Further, in the selenium Therapy in Coronary

Artery disease Patients (SETCAP) Study, supplementation of

sodium selenite increased GPx1 activity in endothelial cells

and in coronary artery disease (CAD) patients. Therefore,

long-term studies are needed to demonstrate whether CAD

outcome can be improved by selenium (320). A cross-sectional

study on the association of serum selenium with the preva-

lence of peripheral arterial disease among 2062 U.S. men and

women 40 years of age or older participating in the National

Health and Nutrition Examination Survey (NHANES), 2003–

2004, suggested that the effects of selenium on athlerosclerosis

are nonlinear and may follow a U-shaped relationship (54).

In summary, the observational evidence that low selenium

concentrations are associated with cardiovascular risk should

be treated as suggestive but not deﬁnitive. There is uncer-

tainty about cause and effect; therefore, time-resolved and

prospective studies are needed in different pathological set-

tings. Further, when investigating the relationship between

selenium and disease risk, future studies need to determine

not only selenium status but also genotype in relation to se-

lenoproteins and related pathways (301).

B. Cancer

There are a multitude of studies investigating the effect of

selenium on cancer; several recent reviews focus on the po-

tential mechanisms of action using evidence from in vitro cell

culture studies and in vivo, mainly animal model, studies (187,

231, 332, 433). Proposed mechanisms of the effects of selenium

on cancer are summarized in Figure 9. They include regula-

tion of cell cycle and apoptosis, antioxidant effect through the

action of selenoproteins, in particular, GPx1, GPx4, Sep15,

SEPP1, and TXNRD1 (301, 433), modulation of angiogenesis

(231), and the extracellular matrix (79, 175), histone deacety-

lase inhibition (287), carcinogen detoxiﬁcation, induction of

GSTs, alteration of DNA damage, and repair mechanisms,

and also immune system modulation (187, 231, 332, 433). How-

ever, the effects of selenium on cancer are species-speciﬁc,

dose-speciﬁc, and cancer type-speciﬁc and may be affected by

genotype and the bioavailability of selenium (Fig. 9), dis-

cussed in more detail below. In this review we discuss data

from human studies, including RCTs and epidemiological

1354 FAIRWEATHER-TAIT ET AL.

data, with a particular focus on the species and dose of sele-

nium in interventions and plasma=serum selenium status.

1. Total cancer incidence and mortality. Willett et al.

(401) reported an association between selenium and cancer in

which the relative risk (RR) of cancer was higher in individ-

uals with low plasma selenium concentrations (<115 ng=ml

compared with 128 to >154 ng=ml) (Fig. 10A). The Nutritional

Prevention of Cancer (NPC) trial showed a protective effect of

selenium-enriched yeast supplements (200 mg=day) on total

cancer mortality (86), and also total cancer incidence, but only

for men with low plasma selenium concentrations (<121.6

ng=ml at baseline) (101). Participants with baseline plasma

selenium >121.6 ng=ml who consumed selenium-enriched

yeast 200 mg=day had a trend toward elevated cancer inci-

dence (101).

In one of the large nutrition intervention trials in Linxian,

China, with over 20,000 participants, supplementation for *5

years with 15 mg b-carotene, 30 mg a-tocopherol and

50 mg=day selenium resulted in a small signiﬁcant decrease in

total cancer mortality (55, 56, 390). In the SU.VI.MAX trial

(138) the antioxidant status of participants at baseline was

related to the risk of cancer in men but not women, and a large

2-year intervention study with selenium and allitridum (a

synthetic compound similar to bioactive forms in garlic) with

follow-up of cancer incidence for 5 years showed a reduced

RR of all tumors in men but not women (221). A meta-analysis

investigating the effect of antioxidant supplements on pri-

mary cancer incidence and mortality by Bardia et al. con-

cluded that selenium supplementation was associated with

reduced cancer incidence in men but not women (29).

2. Gastrointestinal cancers. A meta-analysis of ﬁve

studies published up to 2007 on the effect of selenium on

gastrointestinal cancers showed that selenium supplementa-

tion was associated with a *25%–60% reduction in gastro-

intestinal cancers (overall RR: 0.59, 95% CI: 0.46–0.75) (49);

gastrointestinal cancer included esophageal, gastric, small

intestine, colorectal, pancreatic, liver, and biliary tract (49).

The RR for esophageal cancer was 0.40, and for gastric, co-

lorectal, and hepatocellular carcinoma the RRs were 0.76, 0.48,

and 0.56, respectively.

A dietary intervention trial in China showed a signiﬁcant

decrease in esophageal cancer prevalence (364), and also a

signiﬁcant decrease in total mortality and gastric cancer

mortality (56, 288, 390). The reduction in esophageal cancer

mortality was observed after 10 years of supplementation in

the population group <55 years of age (288). Overall, while

the results are very striking, the anticancer effects cannot be

attributed to selenium alone since the population was also

supplemented with vitamin E and b-carotene.

Another large intervention trial in China, with over 5000

participants, investigated the effect of a combined dose of

selenium (50 mg=day as sodium selenite) and garlic com-

pound, allitridum (200 mg=day), compared with placebo

group on gastric cancer and total cancer incidence (221). The

concentration of plasma=serum selenium was not reported in

this study, and it is not known whether the effects were due

to selenium alone, allitridium alone, or the combination.

However, the intervention with selenium and allitridium for

2 years and the follow-up of cancer incidence for 5 years

following the intervention period showed that the RRs of

all tumors and gastric cancer were reduced, but in men

only (221).

As part of a large prospective study conducted in the

Netherlands (The Netherlands Cohort Study), the selenium

status (toenail selenium) of a subgroup of cases with esoph-

ageal cancer and controls (total n¼2750) were compared. An

inverse association between toenail selenium content and

esophageal squamous cell carcinoma and gastric cardia car-

cinoma was observed (346). The multivariable adjusted RR for

esophageal squamous cell carcinoma and gastric cancer were

0.37 (95% CI: 0.16–0.86) and 0.52 (95% CI: 0.27–1.02) respec-

tively, for the highest quartile selenium status (toenail sele-

nium >0.613 mg=g) compared with the lowest quartile (toenail

selenium 0.498 mg=g) (346). The blood selenium concentrations

FIG. 9. Purported mechanisms of action of selenium against cancer and key factors modulating the effect of selenium.

SELENIUM AND HUMAN HEALTH 1355

and selenium intakes were not reported, but the mean intake

of selenium in the Netherlands is estimated to be relatively

low, *43 and 57 mg=day for women and men, respectively

(127).

Selenium-enriched yeast supplements (200 mg=day) in the

NPC trial signiﬁcantly reduced the incidence of colorectal

cancer and adenomas in participants with low baseline sele-

nium status who were current smokers (304); the mean

baseline plasma selenium concentration for all volunteers on

the study was 114 ng=ml, and only the group with baseline

plasma selenium <105.5 ng=ml had a signiﬁcantly reduced

risk of colon cancer after selenium supplementation. Color-

ectal adenoma cancer patients in Norway were given a daily

supplement containing 101 mg selenium, 15 mg b-carotene,

150 mg vitamin C, 75 mg vitamin E, and 1.6 g calcium for 3

years, but there was no overall effect of the supplement on the

incidence of colon polyps or the growth of adenomas. How-

ever, patients <60 years and those with lower incidence of

adenomas at inclusion potentially beneﬁted more from the

supplement compared with the placebo (168).

Patients with colon adenomas had signiﬁcantly reduced

serum selenium concentration (57 3.97 ng=ml) and other

markers of selenium status compared with a control group

(serum selenium of 71 ng=ml) (10). Supplementation of these

patients with 500 mg=day selenite increased serum selenium

concentration to *87 ng=ml, and in the colon tissue there

were speciﬁc effects on different biomarkers; for example,

GPx increased slightly in response to supplementation.

However, markers of cancer growth and progression and

biomarkers of effect were not quantiﬁed in this study (10).

Comparing colorectal cancer tissue with normal mucosa

showed a signiﬁcant reduction or even a loss of SePP mRNA

in colon cancer tissue compared with normal tissue. This re-

sult was speciﬁc for SePP since gastrointestinal GPx differed

between tumor and normal tissues, but overall was not sig-

niﬁcantly different (12). In colon cancer there is likely to be a

differential regulation of various selenoproteins and initial

evidence points to the relative importance of SePP.

Pooled analysis of the effects of blood selenium concen-

tration on colorectal adenoma risk, from three randomized

trials, the polyp prevention trial (317), the wheat bran ﬁber

trial (239), and the polyp prevention study (146), as described

by Jacobs et al. (188), demonstrated that those who had plasma

selenium concentrations in the highest quartile (median

150 ng=ml) had statistically signiﬁcant lower odds of devel-

oping new colorectal adenomas than those with selenium

levels in the lowest quartile (median 113 ng=ml), refer to

Figure 10B (188). The baseline blood selenium concentration

in the three studies was *130 ng=ml.

Generally, the relationship between selenium and risk of

esophageal or gastric cancer is unclear since the human

studies to date have investigated low dose selenium

(50 mg=day) with a combination of other supplements, or have

looked at the association with selenium over a relatively

narrow range of selenium status. There is, however, an indi-

cation of a protective effect of selenium against colorectal

cancer, although the dose–response has not yet been eluci-

dated.

3. Prostate cancer. A case–control study in the United

States showed that serum selenium concentrations >151

ng=ml were associated with reduced risk of prostate cancer

FIG. 10. Cancer risk over a range of blood selenium

concentrations=levels from several studies. (A) Relative risk

of cancer by quintile of serum selenium level as described by

Willet et al. (401). (B) Pooled analysis of adjusted odds ratios

for colorectal adenoma as published by Jacobs et al. (188). (C)

Odds ratios of prostate cancer by quartile of serum selenium

as described by Vogt et al. (384). (D) Adjusted odds ratios

for hepatocellular carcinoma by quintile of plasma selenium

level as described by Yu et al. (426).

1356 FAIRWEATHER-TAIT ET AL.

compared with serum selenium below 119 ng=ml (Fig. 10C).

The effect was also associated with serum a-tocopherol con-

centration: men with low serum a-tocopherol and high serum

selenium concentration were at decreased risk of prostate

cancer (384). A meta-analysis of epidemiological studies, in-

cluding case–control and nested case–control studies report-

ing selenium status (in toenail, serum, or plasma) and prostate

cancer incidence (n¼20 studies included up to 2005) shows

an inverse association between serum levels and risk of cancer

(61). Another meta-analysis of epidemiological data of sele-

nium intake and prostate cancer risk (113) indicated that the

level of selenium intake and the stage of prostate cancer were

important factors. In a comparison of studies reporting

prostate cancer risk relative to selenium intake and disease

status Etminan et al. reported that men with late stage prostate

cancer and high level of selenium intake had a pooled RR of

0.69 (95% CI: 0.48–1.01), suggesting that in this population a

relatively high selenium intake may reduce cancer risk by

*30% (113). West et al. found that for men (aged 68–74) with

aggressive prostate cancer and with estimated high intake of

selenium (in the two highest quartiles, 139–183 mg=day and

>183 mg=day) the RR was increased up to 1.8 (95% CIs were

0.7–4.3 and 0.8–4.4 respectively), compared with lower in-

takes of selenium (<106 mg=day) (398). This indicates that

there is likely to be a relatively narrow range of beneﬁt in

terms of selenium intake and chemopreventive effect, and the

optimal intake requires further elucidation in different pop-

ulations.

Selenium supplementation, together with other antioxi-

dants, decreased the risk of prostate cancer (244), but the ef-

fects were related to prostate speciﬁc antigen (PSA) score; in

men with normal PSA concentration <3mg=l, the reduction in

prostate cancer risk was signiﬁcant, whereas with PSA >3

mg=l the supplementation was associated with slightly in-

creased risk. In the Nutritional Prevention of Cancer (NPC)

trial, baseline PSA also appeared to be linked to the effect of

selenium, the protective effect of the selenium-yeast supple-

ment being more effective for men who had baseline PSA

4ng=ml (100). In a group of men with high-grade prostatic

intraepithelial neoplasia (PIN), daily supplementation with

200 mg selenium (as selenomethionine) plus 60 mg vitamin E

and 100 mg isoﬂavanoids (42 mg genistein, 22.8 mg glycitin,

and 35.2 mg daidzin) for 6 months decreased PSA concen-

tration and was associated with a trend in decreased prostate

cancer diagnosis in repeat biopsy prostate tissue (192). Un-

fortunately, the study design did not include a placebo or

control group (192) and further research is required to in-

vestigate the potential reduction in prostate cancer with the

supplementation regimen and to investigate which supple-

ment component(s) may be most effective.

More recently, the largest randomized placebo-controlled

trial to date investigating the effect of selenium (as seleno-

methionine) on prostate cancer risk, the SELECT trial (226)

did not show a reduction in prostate cancer risk for the pop-

ulation of relatively healthy men studied who consumed

200 mg=day selenomethionine supplement (n¼8752) com-

pared with the placebo group (n¼8696) over 5 years. Sup-

plementation with L-selenomethionine (200 mg=day) plus

vitamin E (400 IU=day all rac-a-tocopheryl acetate) as part of

the SELECT study, in a healthy selenium replete group, did

not reduce prostate cancer risk either (226). This can probably

be attributed to the relatively high selenium status (median

baseline plasma selenium concentration *135 ng=ml) of the

population studied, and because selenomethionine may not

be the most effective anticarcinogenic form of selenium (182,

183, 290). The NPC trial showed that selenium-enriched yeast

may be associated with a reduction in prostate cancer risk,

and this protection was conﬁned to those men who had a low

baseline plasma selenium concentration <123.2 ng=ml (86,

100). All participants on the SELECT trial were also allowed to

consume a multivitamin tablet (containing 400 IU=day of vi-

tamin D

, plus other multivitamins) and were freely supplied

with this multivitamin (225). Other studies have shown that

multivitamin use may not protect against cancer, and may

increase the risk of certain types of cancer (214). Finally, the

World Cancer Research Fund (WCRF) meta-analyses of the

studies to date published on selenium and prostate cancer

suggest that selenium may be more effective in protecting

against aggressive prostate cancer and its progression (408),

so selenium may be beneﬁcial for patients who already have

prostate cancer.

The effects of selenium are clearly speciﬁc to cancer type

and stage (61, 113, 408), and the relative risks and beneﬁts of

low=replete=high selenium status should be considered

carefully. For example, the NPC trial (86) demonstrated that

200 mg=day selenium-enriched yeast reduced prostate, lung,

and colon cancer risk but slightly increased the risk of skin

cancer in the cohort who had previously had skin cancer (86).

The dose is critical as illustrated by the fact that a relatively

high dose of selenium-yeast, 400 mg=day, did not reduce total

cancer incidence (303), whereas 200 mg=day selenium-yeast

did (86). For selenium and prostate cancer the dose, species,

status of the population, and cancer type=grade are all im-

portant factors linked to outcome and cancer preven-

tion. From a review of the literature, it seems probable that

plasma=serum selenium between >120 and <160 ng=ml may

be associated with a protective effect; this level of plasma se-

lenium is normally achieved through consumption of *100–

150 mg selenium=day. Improving our understanding of the

relationship between selenium and risk and progression of

prostate cancer and the underlying mechanisms is a current

research priority. One such interesting future research area

may surround the action of selenium on viral infection in

cancer; for example, some patient cohorts in the United States

with malignant prostate cancer have recently been found to

have xenotrophic murine leukemia virus-related (XMRV)

virus present (318). The relative importance of SePP in pros-

tate may also be a key interesting target, since SePP concen-

tration has been found to be signiﬁcantly reduced in serum

(245) and SEPP1 gene expression downregulated in some

types of malignant prostate cancer compared with normal

prostate tissue (74). Studies in healthy humans show that

SePP reaches a maximum at *120–125 ng=ml plasma sele-

nium (174), and optimal selenium intake for certain popula-

tions with prostate cancer requires further determination.

4. Other cancers. Many cell culture and animal model

experiments have focused on the mechanisms of action of

selenium on breast cancer, reviewed by El-Bayoumy and

Sinha (109), but there are only a few human studies investi-

gating selenium status and breast cancer. An association be-

tween GPx1 polymorphism and breast cancer risk was

reported (295). Further, a large study investigating the as-

sociation between several polymorphisms in 10 key genes

SELENIUM AND HUMAN HEALTH 1357

associated with oxidative damage repair in >4000 women

with breast cancer linked two polymorphisms in GPx4 with

increased risk of mortality (373). In a population-based case–

control study, using data from the Shanghai breast cancer

study with over 1000 participants, breast cancer risk was in-

creased in women with the manganese superoxide dismutase

(SOD2) Ala=Ala genotype compared with the Val=Val geno-

type, especially in those women who were premenopausal

and had a higher body mass index (73). In a recent study,

toenail selenium content was inversely associated with levels

of chromosome damage in BRCA1 carriers with estimated

selenium intake of 90 mg=day and toenail selenium concen-

tration of 1.00 mg=g (208). The authors suggested that ‘‘sele-

nium supplementation may be beneﬁcial for BRCA1 carriers.’’

However, any potential effect of selenium supplementation

on the reduction in chromosome damage is likely to be limited

to low intake=status populations.

A meta-analysis of epidemiological studies published on

selenium and lung cancer concluded that selenium may pro-

tect against lung cancer in low selenium regions, intake

<55 mg=day and serum selenium <100 ng=ml (432).

In relation to skin cancer, a combined supplement con-

taining selenium-enriched yeast (providing a daily dose of

120 mg vitamin C, 30 mg vitamin E, 6 mg b-carotene, 100 mg

selenium and 20 mg zinc) was associated with increased in-

cidence, in particular melanoma skin cancer, in women when

compared with the placebo group over a follow-up period of

*7.5 years in the SU.VI.MAX trial (159). In patients who had a

history of skin cancer (nonmelanoma), consumption of

200 mg=day selenium-enriched yeast increased the risk of skin

cancer (squamous cell carcinoma and total melanoma skin

cancer) compared with the placebo group (86, 102). It seems

unlikely that ‘‘optimal selenium status’’ or selenium supple-

mentation regimes can offer protection against skin cancer

from the human study data to date and higher selenium status

and intakes may be associated with increased risk of skin

cancer.

A long-term intervention trial in China with selenized table

salt fortiﬁed with 15 ppm sodium selenite for over 8 years in

over 20,000 individuals showed that the incidence of primary

liver cancer decreased by 35% in the selenium-supplemented

group compared with the control nonsupplemented group

(427). Supplementation with selenium-enriched yeast

(200 mg=day) reduced the incidence of primary liver cancer in

hepatitis B surface antigen-positive individuals compared

with the placebo group (427). Hepatitis B viral infection was

prevalent in *15% of the population in the Qidong region of

China, where this intervention study was completed; those

who had hepatitis B had a 200-fold increased risk of primary

liver cancer. Selenium reduced the incidence in this popula-

tion but the exact mechanisms for this protection against liver

cancer are not known.

In a study carried out in Taiwan, men who were hepatitis B

positive and had hepatocellular carcinoma had a signiﬁcantly

lower mean plasma selenium level of 131.6 ng=ml compared

with the hepatitis B negative control group (150.2 ng=ml)

(426). Among the men who had hepatitis virus infection, the

plasma selenium concentration was associated with a differ-

ence in odds ratio for hepatocellular carcinoma (Fig. 10D).

There was a decrease in hepatocellular carcinoma with an

increase in plasma selenium concentration, but the effect in

terms of cancer protection was nonlinear; >162.3 ng=ml the

number of hepatocellular carcinoma cases started to increase

and the odds ratio was on a trend upward, indicating perhaps

>160 ng=ml was above the associated protective range of

plasma selenium. Overall, men who had hepatitis virus in-

fection and plasma selenium between 150 and 160 ng=ml had

signiﬁcantly less risk of developing hepatocellular carcinoma

compared with men who had plasma selenium <124.9 ng=ml.

5. Summary of selenium and cancer research, and ranges

that may offer protection. Although direct comparisons of

odds ratios, hazard ratios (HR), and relative risks for many

studies are not possible because the results are study spe-

ciﬁc, there is a consistent trend throughout several of the

human studies demonstrating potential protective effects

with plasma=serum selenium between *120–160 ng=ml and

reduced risk of some types of cancer when compared with the

low plasma selenium status, namely <120 ng=ml. Above

160 ng=ml the cancer protective effect is likely to diminish and

the risk perhaps increases for some types of cancer. Literature

from the 1950s and 1960s showed that an inappropriately

high dose range of selenium may actually increase the inci-

dence of certain types of cancer in animal models and sele-

nium used to be classed as a carcinogen in animals when used

at high exposure (84, 334). Therefore, a careful balance en-

suring selenium intakes and selenium status fall in the rel-

atively narrow base of the U-shaped risk-response curve

is critical for potential modulation of certain cancer-type-

speciﬁc risk proﬁles.

6. Selenium supplementation as an adjuvant therapy in

radiation or chemotherapy treatment. Initial evidence for

the role of optimal selenium status in protecting against tox-

icity and unwanted effects of chemotherapy and radiotherapy

in cancer patients seems to be promising, especially consid-

ering the often observed depleted selenium status in many

cases of cancer. Several studies have shown the potentially

protective and beneﬁcial effects of selenium (mainly selenite)

supplementation, to protect against toxicity and side effects of

radiotherapy and chemotherapy treatments, in particular

cisplatin therapy (22, 66, 170, 434, 255). However, the effect of

selenium and other antioxidants may only be beneﬁcial for

reducing the chemotherapy side effects for certain types of

cancer in certain combinations. For example, Weijl et al. found

no reduction in organ toxicity or other markers of toxicity

with a supplementation regimen of selenium plus vitamins C

and E (110, 396). The potential beneﬁcial effects of selenium

supplementation and therapy treatment for cancer patients

are also likely to be selenium dose and species speciﬁc, and are

also treatment and cancer speciﬁc. For example, large super-

doses (>2000 mg=day) of selenomethionine to increase plasma

selenium to >15–20 mM in cancer patients (various types of

cancer including colorectal, small and nonsmall lung cancer,

sarcoma, and urachal) undergoing treatment with irinotecan

did not seem to provide any overall additional beneﬁt to the

patient and did not decrease the toxicity of the treatment

(118).

In certain at-risk populations, selenium supplementation

and optimization of selenium status should be tested further

as an adjuvant to radio- and chemotherapy. The potential

mechanisms of action of selenium and radiotherapy treatment

of prostate cancer may include effects on DNA damage

pathway, cell cycle control, and antioxidant effects (357).

1358 FAIRWEATHER-TAIT ET AL.

7. Effect of genotype and polymorphisms relating to se-

lenium and cancer risk. Various SNPs in selenoprotein

genes SEPP1, GPX1, GPX4, and SEP15 have been associated

with cancer risk in humans (including lung, colorectal, head

and neck, prostate, breast, bladder, lymphoma, and liver

cancers) (section VII.F below) (160, 301, 433).

Other SNPs have also been linked to the effect of selenium

on cancer. In a case–control study investigating selenium in-

take and esophageal squamous cell carcinoma risk and the

involvement of two polymorphisms (in aldehyde dehydro-

genase-2, ALDH2 and x-ray repair cross-complementing 1,

XRCC1), the cohort with ALDH2 Lys=Lys and XRCC1

399Gln=Gln or Gln=Arg genotypes, plus low selenium intake

from the diet (<14.6 mg=day) and exposure to tobacco and

alcohol, had signiﬁcantly increased risk of esophageal squa-

mous cell carcinoma (72). The population cohort studied

(n¼633 in total) was from a selenium-deﬁcient region in

China (median selenium intake estimated to be 25.9 mg=day)

and where esophageal cancer has the highest worldwide in-

cidence rate (72). Nearly 60% of the patients investigated with

esophageal cancer had a selenium intake <14.6–22.1 mg=day,

and there was a lower risk of esophageal cancer in the highest

selenium intake group (43.2 mg=day) (72).

Genetic variants of the gene encoding manganese super-

oxide dismutase (SOD2) were linked with the association of

selenium and prostate cancer risk; men who had the AA ge-

notype and higher plasma selenium concentration (>139.8

ng=ml) had a lower risk of aggressive prostate cancer (RR:

0.60, 95% CI: 0.32–1.12), whereas men with the VV or VA

genotype and higher selenium concentration (>139.8 ng=ml)

had an increased risk (RR: 1.82, 95% CI: 1.27–2.61). The overall

suggestion from this cohort study with prostate cancer pa-

tients (n¼489) from the United States indicated that the as-

sociation between plasma selenium concentration and

prostate cancer risk may be modiﬁed by different SOD2 ge-

notype (81). Cooper et al. (89) showed that there was an in-

teraction between SOD2 and SEPP SNPs and prostate cancer

risk in a large (n¼4871 in total) population case–control study

in Sweden. Men who had the SOD2Ala16 þand were ho-

mozygous for SEPP1Ala234 had a signiﬁcantly higher risk of

prostate cancer and aggressive prostate cancer (OR: 1.43, 95%

CI: 1.17–1.76; OR: 1.60, 95% CI: 1.22–2.09) compared with

SOD2val16 homozygotes. This relationship between the

SOD2 and SEPP1 polymorphisms and prostate cancer risk

was more pronounced in smokers (89).

The SEPP1Ala234Thr and rs7579 polymorphisms may also

be linked to the relative abundance of the two isoforms (50

and 60 kDa forms) of selenoprotein P in plasma; the 60 kDa

form of selenoprotein P was signiﬁcantly reduced in the

plasma of colorectal cancer patients compared with controls

and this was linked to SEPP1 genotype (243). In a relatively

small case–control cohort study (n¼80 participants in total)

investigating the effect of GPX1Pro198Leu and Sep15

1125G=A polymorphisms on selenium status and gene ex-

pression in bladder cancer patients compared with healthy

controls, the GPX1 and SEP15 polymorphisms were not as-

sociated with the gene expression levels of GPX1,GPX3,

SEP15,orSEPP or with plasma selenium concentration, but in

patients with bladder cancer SEP15 and GPX3 were correlated

with grade of cancer. The expression levels of genes GPX1,

GPX3,SEP15, and SEPP1 were signiﬁcantly decreased (1.3–

2.0-fold) in leukocytes from bladder cancer patients compared

with the healthy controls (309). In a selenium supplementa-

tion trial, BRCA1 mutation carriers had increased levels of

DNA damage marker (8-oxodG) in leukocyte DNA compared

with the control group without the BRCA1 mutation, and

after supplementation with 300 mg=day sodium selenite, the

DNA damage marker level signiﬁcantly decreased (106).

Genetic variation in selenoprotein genes and other genes

may impact both the response to selenium and cancer

risk=outcome, which adds complexity to the relationship be-

tween selenium and cancer and requires further investigation

to pinpoint the key genetic associations and mechanisms of

effect.

C. Diabetes

The evidence supporting an effect of selenium on the risk of

diabetes is variable, occasionally conﬂicting, and limited to

very few human studies. Following a trial investigating the

effect of selenium supplementation (200 mg=day) on skin

cancer, subsequent analysis showed that there was an in-

creased risk of developing type 2 diabetes in the supple-

mented group (349). The participants in the trial were North

American and generally selenium replete. Supplementation

over a period of 7 years increased plasma selenium concen-

trations to *180–190 ng=ml (HR: 1.55, 95% CI: 1.03–2.33), and

it was observed that the risk for developing diabetes was

greatest in participants with the highest tertile of baseline

selenium status, >121.6 ng=ml (HR: 2.70, 95% CI: 1.30–5.61).

These ﬁndings suggest that the Upper Tolerable Intake Level

for selenium, currently set at 400 mg=day by the United States

DRI committee (274), may need to be revised, and that there

could be adverse effects associated with higher dietary intakes

that are not as overt as the typical toxicity signs associated

with selenosis (51).

Evidence from analysis of NHANES III (52) supports these

ﬁndings; the adjusted mean serum selenium concentrations

were slightly, but signiﬁcantly, higher in diabetics compared

with those without the disease; comparison of the highest

(>137.66 ng=ml) with the lowest (<111.62 ng=ml) quintile

gave an odds ratio of 1.57 (95% CI: 1.16–2.13). Conversely,

recent evidence from a European population suggests that

the incidence of diabetes was greater in men with lower me-

dian plasma selenium concentrations compared with higher

concentrations (71.06 ng=ml vs. 101.86 ng=ml) (4). This study,

conducted in an elderly French population, found a sex-

speciﬁc protective effect of higher selenium status at baseline

on later occurrence of dysglycemia; that is, risk of dysglyce-

mia was signiﬁcantly lower in men with plasma selenium in

the highest tertile (93.96–155.55 ng=ml) compared with those

in the lowest tertile (14.21–78.96 ng=ml) (HR: 0.48, 95% CI: 0.25–

0.92), but no signiﬁcant relationship was observed in women.

Cross-sectional case–control analyses have also given

mixed results. A number of studies have found a lower sele-

nium status in diabetic patients compared with controls (202,

259), which is in contrast to the ﬁndings from the NHANES III

analysis (52, 212). Analysis of the Health Professionals Fol-

low-up Study found the prevalence of diabetes to be greater in

men with the lowest tertile of toenail selenium (OR: 0.43, 95%

CI: 0.28–0.64) compared with the highest tertile (291). The

study also analyzed men with both diabetes and CVD com-

pared with controls, but no association was found. Due to the

global variations in selenium status these studies may not be

SELENIUM AND HUMAN HEALTH 1359

directly comparable, and the results may in fact indicate a U-

shaped risk curve, which could be further complicated by

other diseases associated with diabetes.

The mechanisms behind this potential U-shaped risk as-

sociation have not yet been clearly deﬁned. In its role as an

antioxidant, particularly within the GPxs, selenium is likely to

be important in reducing oxidative stress, an important risk

factor for developing diabetes. There are also plausible sug-

gestions that selenium can inﬂuence glucose metabolism.

However, at high intakes it is also conceivable that reactive

oxygen species could be generated or selenium may accu-

mulate in the organs associated with glucose metabolism

(51). In patients with diabetes, selenium supplementation

(960 mg=day) reduced NF-kB levels to those comparable with

nondiabetic controls (121). Animal model work has also

suggested a role for selenium supplementation in reducing

some biochemical effects of diabetes. Hwang et al. (176) found

that selenium supplementation of NOD (nonobese diabetic

mice) counteracted ER stress through stimulation of PERK-

eIF2 and IRE1-JNK pathways and also activating the insulin-

signalling pathway. The study also suggested that treatment

with selenium may inﬂuence aspects of other chronic diseases

associated with diabetes, for example, by decreasing the levels

of serum markers of liver damage. SelS was ﬁrst isolated (at

the time called Tanis) during work on diabetic rats and is

thought to be an important link in the relationship between

diabetes, inﬂammation, and CVD (387). Expression of SelS

was found to be signiﬁcantly lower in diabetic rats in a fed

state compared with normal control animals and appears to

be regulated by glucose. The importance of SelS in inﬂam-

matory responses is described further in section VII.D.

Whatever the mechanisms responsible, current evidence im-

plies that both low and high selenium intakes could inﬂuence

the risk of diabetes, and this relationship requires further in-

vestigation through good quality human studies.

D. Inﬂammation and inﬂammatory disorders

In addition to being an important antioxidant, selenium has

anti-inﬂammatory properties. The underlying mechanisms

have recently been reviewed elsewhere (104). In summary,

there are a number of ways in which selenium can inﬂuence

inﬂammatory responses, including the inhibition of the NF-

kB cascade, which induces the production of interleukins and

tumor necrosis factor-a(TNF-a) (209). Evidence also suggests

that SelS has a key role in inﬂammatory responses, ﬁrst

identiﬁed in diabetic rats (387). Serum amyloid A (SAA) is an

acute phase response protein produced in the liver, and SelS

has been identiﬁed as a potential receptor for the protein (387),

thus also establishing a link between selenium and CVD (as

SAA is incorporated into HDL cholesterol). Polymorphisms in

the SELS gene have been linked to variations in markers of

inﬂammation, with one particular variant 105G ?A

showing signiﬁcantly impaired expression of SelS (91).

However, a recent case–control study indicated that there is

no association between six polymorphisms in the SELS gene

and autoimmune inﬂammatory disorders, including arthritis

and diabetes (238). There is evidence to suggest a sex-speciﬁc

effect of selenium on inﬂammatory responses (324), which

may explain some of the variation in ﬁndings related to in-

ﬂammatory disorders. There is a degree of sexual dimorphism

in the distribution of selenium throughout the organs of the

body, which could impact on selenium status and prioritiza-

tion of certain systems or tissues in times of deﬁciency.

However, presently little consideration is given to the effect of

sex in either animal or human experimentation (324).

Chronic inﬂammatory disorders are normally associated

with a decrease in selenium status, and cross-sectional case–

control studies have suggested that patients with inﬂamma-

tory disorders such as cystic ﬁbrosis (247), acne (246), and

inﬂammatory bowel disease (268) may have a lower selenium

status than healthy controls. Therefore, supplementation with

selenium could possibly alleviate some of the symptoms of

such disorders through increasing antioxidant activity and

suppressing inﬂammatory conditions. Unlike the potential

preventative beneﬁts of selenium seen for other health issues,

most of the research surrounding inﬂammatory disorders has

been focused on supplementation as an alternative therapy, or

treatment, for patients.

A systematic review (6) of selenium supplementation for

chronic asthma patients found only one RCT of sufﬁcient

quality to assess the efﬁcacy of intervention. In this study

(151) signiﬁcant improvements were seen in the overall clin-

ical evaluation of patients in the supplemented group; how-

ever, these differences were not seen in the individual

parameters measured. All other assessed studies were either

not randomized or before–after trials, and therefore did not

meet the inclusion criteria for the review. The authors there-

fore concluded that although there was some indication of a

positive effect of selenium supplementation, high-quality

evidence is currently lacking. A more recent larger RCT (333)

concluded that selenium supplementation did not result in

any signiﬁcant improvements in either lung function or

asthma-related quality-of-life scores.

Other studies have indicated a varied response to supple-

mentation for asthma patients. One hypothesis for the varia-

tion in intervention results is that although selenium may

have important antioxidant properties, it can also enhance the

immune reactions responsible for the allergic responses of the

disorder (167). Mouse model work has suggested that low

and high selenium status may produce smaller allergic re-

sponses than a moderate selenium status (166). This may ex-

plain some of the variation in human trial results, assuming

that patients supplemented in the various studies had diverse

selenium status at baseline. However, a large European-wide

case–control analysis of selenium levels in asthma patients

and healthy matched controls revealed no association be-

tween status and risk of the disease (71). There are, of course,

other variables to consider, such as the speciﬁc type of asthma,

population characteristics, and concurrent use of asthma

drugs, which are likely to further complicate an already in-

tricate relationship.

Selenium has also been postulated as a potential therapy

for rheumatoid arthritis (RA) patients. Like many other in-

ﬂammatory disorders, selenium status appears to be lower in

RA patients than in controls [summarized in Tarp (363)]. A

recent systematic review of the use of antioxidants for treat-

ment of arthritis concluded that the ﬁve trials identiﬁed (for

selenium and RA) were generally of poor quality and that few

conclusions could be drawn on the efﬁcacy of supplementa-

tion. No meta-analysis was performed because in some in-

stances data reporting was incomplete, but most of the

included studies did not report any signiﬁcant effect of sele-

nium supplementation on clinical outcomes (75).

1360 FAIRWEATHER-TAIT ET AL.

Although there appears to be good evidence from case–

control studies suggesting lower selenium status in patients

with inﬂammatory conditions compared with healthy con-

trols, there is little supporting evidence from high-quality

RCTs for a therapeutic effect of selenium supplementation.

This could, in part, be explained by the dual functionality of

selenium, inﬂuencing both antioxidant and immune re-

sponses. Further high-quality interventions are required to

establish these relationships.

E. Fertility

The use of selenium supplements for fertility problems in

some domestic animal species prompted an investigation into

the relationship between selenium and impaired fertility in

both men and women, and reproductive outcomes. Much of

the current evidence has been focused on the role of selenium

in male spermatogenesis and semen quality (e.g., sperm

count, semen volume, motility, and morphology), but links

have also been made to female reproductive issues such as

pre-eclampsia and miscarriage (296). The evidence support-

ing a role for selenium in female fertility is limited, although

there are data to suggest that women with unexplained in-

fertility may have lower selenium levels in the follicular ﬂuid

than those with explained infertility (280). A study in which

couples were assessed over a period of 5 years found that the

pregnancy rate was greatest in the mid-range of selenium

status (50); however, status was only measured in the semen

of the men, and therefore these ﬁndings require cautious in-

terpretation as the exposure of both partners would not nec-

essarily be similar.

There is a larger body of evidence supporting a potential

role for selenium, and antioxidants in general, in postcon-

ception physiology and complicated pregnancies. Infants

born to mothers with the lowest selenium status in the early

stages of pregnancy have signiﬁcantly lower birthweights

than those born to mothers with higher selenium status (57).

Cross-sectional analysis suggests that women with pre-

eclampsia have both a signiﬁcantly lower selenium status in

the latter stages of pregnancy and lower levels of placental

GPx at delivery than healthy pregnant women (24). Pre-

eclampsia is characterized by an increase in the usual in-

ﬂammatory responses that occur during pregnancy. Subse-

quently, following the discovery that SelS is associated with

inﬂammatory responses (91), a retrospective genetic analysis

of a case–control study in Norway identiﬁed an increased risk

of pre-eclampsia in women carrying the allele associated with

impaired SelS expression (254). Miscarriage has also been

linked with selenium status; Barrington et al. (30) found that

women recently suffering a miscarriage in the ﬁrst trimester of

pregnancy had signiﬁcantly lower selenium status than

pregnant women at the same gestational age. A decrease in

antioxidant enzyme activity (particularly the GPxs) is attrib-

uted to the effect (428).

The relationship between selenium and male fertility has

been widely studied using animal models and cross-sectional

analyses of semen samples. However, the effect of dietary

supplementation on fertility measures has not been widely

studied through human interventions, and has thus far given

inconsistent results. Behne et al. (38) showed that the testis are

a primary target for selenium within the body (Fig. 4), and

during times of deﬁciency the supply of the micronutrient to

the male gonads appears to be prioritized. The selenium

content of the testis is high, and increases during puberty.

SePP is required to transport selenium, particularly to the

testis, where apoER2 is known to act as a receptor (273). In

Sepp1 knock-out mice the semen quality is severely compro-

mised, and wildtype mice fed low selenium diets show almost

identical problems, but these are reversed upon feeding a

high-selenium diet (270, 272).

The majority of selenium found within the testis is incor-

porated into the selenoprotein GPx4, which is expressed in

particularly large amounts and is now thought to have mul-

tiple roles within spermatogenesis. The selenium-containing

GPx enzymes are considered to have key antioxidant activi-

ties, scavenging and protecting cells from reactive oxygen

species. GPx4 fulﬁls this role within the testis, and is highly

expressed and active during the process of sperm maturation.

GPx4 also has a structural role within the mature spermato-

zoa, most of the selenium content of mature spermatozoa is

still present as GPx4; however, the activity of the enzyme is

negligible (374). During the ﬁnal phases of sperm maturation,

GPx4 forms interlinking structures and comprises >50% of

the mitochondrial containing capsule of mature spermatozoa,

a unique example of a GPx enzyme forming a keratin-like

structure and subsequently losing its activity (374). The po-

sition of the capsule, in the mid-piece of the spermatozoa, is

likely to explain the structural defects commonly seen in

selenium-deﬁcient animals, particularly the brittle and weak

connection between the head and tail regions (411). Two re-

cent animal studies that used spermatocyte-speciﬁc GPx4

knockouts or mice lacking expression of mitochondrial GPx4

both found that these mice were infertile, characterized by a

reduced number of spermatozoa plus increased abnormalities

(178, 321). Other selenoproteins present in the testis include

selenoproteins V, W, K, 15ka, and S, but the speciﬁc function

of these within the testis remains unknown (59).

Three different measures of selenium content in semen can

be made: the selenium concentration in the semen as a whole,

the concentration in the seminal plasma, and the concentra-

tion in the sperm. The choice of compartment is critical in

assessment of selenium concentration. Sperm selenium con-

tent is well regulated and does not appear to be heavily

inﬂuenced by dietary intake. Seminal plasma, however, is

largely composed of secretions from other glands (notably the

prostate) and therefore may not accurately reﬂect the sele-

nium present within the testis. Semen selenium takes both

measures into account, but it is, to a certain extent, dependent

upon sperm density (37).

Semen selenium values are typically about a third of the

value of blood plasma selenium (312) and extremes of semen

concentration have been associated with reduced semen

quality, particularly motility (50). Many cross-sectional ana-

lyses have been conducted to attempt to establish a relation-

ship between infertility and selenium content of semen.

Takasaki et al. (358) found no signiﬁcant difference between

the selenium concentration in whole semen or seminal plasma

of fertile and infertile men, although the sperm selenium

content was signiﬁcantly higher in the infertile group. The

exact proportion of semen selenium that is contributed by

sperm appears to vary, and not only according to the sperm

count. Behne et al. (37) found a correlation between the sperm

count of men seeking treatment for infertility and the contri-

bution of sperm selenium to whole semen concentrations, but

SELENIUM AND HUMAN HEALTH 1361

the proportion ranged from 0% to 41% and was not in

agreement with previous studies that suggested a value of

around 15% regardless of sperm count (50).

Since the discovery of the importance of the GPxs to male

fertility, particularly GPx4, a number of cross-sectional ana-

lyses of their relevance to measures of male fertility have been

conducted. Alkan et al. (5) reported that levels of GPx in the

seminal plasma of infertile men were lower than those of

fertile men, which in turn led to higher levels of reactive ox-

ygen species. GPx4 expression is signiﬁcantly lower in the

spermatozoa of some men with reduced fertility, but this only

appears to account for about a quarter of infertile men (180). A

comparison of the rescued GPx4 activity of specimens from

fertile and infertile men found the range of activity to be sig-

niﬁcantly lower in the latter (131).

Relatively few intervention studies have been conducted,

and these have yielded mixed results. Scott et al. (330)

showed that supplementation with selenium (100 mg=day, as

L-selenomethionine) improved motility after 3 months. How-

ever, the patients recruited for the trial had a low initial sele-

nium status and had low motility levels at onset of treatment.

An earlier study ad ministering 200 mg=day as either selenium-

enriched yeast or sodium selenite showed no signiﬁcant effect

on semen quality measurements in either group (184). A con-

trolled feeding trial, in which men were given either high

(297 mg=day) or low (13 mg=day) selenium-containing diets for

99 days, found no changes in sperm selenium or androgen

levels throughout the trial (156). However, there was a sig-

niﬁcant decrease in the fraction of motile sperm in the high-

selenium group, and an overall decrease in sperm count in both

groups. It was hypothesized that the latter could be a result of

seasonal ﬂuctuations in sperm production. Selenium supple-

mentation with selenium-enriched yeast (247 mg=day) also re-

sulted in no signiﬁcant changes in testosterone levels or ratios

in a small group of healthy adult males (108).

In one of the largest intervention trials to date, Safarinejad

and Safarinejad (313) conducted a 22 factorial trial to study

the effects of selenium and N-acetyl-cysteine (NAC) on a

group of 468 infertile men. A dose of 100 mg of selenium=day

was administered to one group for 26 weeks, which resulted

in an increase in testosterone and all semen quality parame-

ters. Similar patterns were seen in the NAC group and the size

of effect was increased in the group receiving both types of

supplement. The authors suggest that the positive effects seen

in this trial may have been a result of the larger study groups,

the population setting (with selenium status likely to be in-

ﬂuential), the form of selenium administered, and the speciﬁc

targeting of their study to a group of infertile men with con-

ditions most likely to respond to supplementation. A further

intervention trial by Hawkes et al. (154) supplemented healthy

men with 300 mg=day selenium-enriched yeast for 48 weeks

and found no effect on testosterone levels or semen quality

measures. However, semen volume and sperm selenium de-

creased, and velocity and normal morphology increased in

both the supplemented and placebo groups. The study also

conﬁrmed that sperm selenium levels are almost entirely

unaffected by recent dietary intakes, as the concentration in

the supplemented group did not alter despite large signiﬁcant

increases in blood selenium levels.

In addition to selenium supplementation trials, a number of

studies have assessed combinations of micronutrients as a

therapy for infertility in male patients. Keske-Ammar et al.

(197) compared a combination of selenium (as ‘‘Bio-selenium,’’

225 mg=day) and vitamin E with a control of B vitamins (a

standard therapy) in infertile men. Although a signiﬁcant

improvement was seen in mobility after 3 months in the vi-

tamin E-selenium group, less than half of the originally re-

cruited patients completed the study. A small study (n¼9)

supplementing infertile men with a combination of selenium

(100 mg=day organic selenium) and vitamin E reported sig-

niﬁcant improvements in motility, normal morphology, and

percentage of live spermatozoa after a treatment period

compared with a baseline control period (381).

The disparity in results from intervention and observa-

tional studies makes it difﬁcult to disentangle selenium–

semen quality relationships. The considerable natural variation

in semen parameters, even within deﬁned fertility categories,

makes large sample sizes imperative. Further, the selenium

status of the population, form of selenium administered, and

duration of intervention all varied in the few intervention

trials conducted. Duration could be particularly important if

seasonal variations can account for large differences in semen

measures, as suggested by Hawkes et al. (156). Few studies

have actually looked at reproductive outcomes associated

with semen parameters and selenium intake. One interven-

tion trial reported a paternity rate of 11% in the supplemented

group (330), and a cohort followed up reproductive outcomes

for up to 5 years, reporting that pregnancy rate was highest in

the mid-ranges of semen selenium (50). It is clear, however,

that much is still unanswered regarding the inﬂuence of se-

lenium on male fertility and, in particular, actual reproductive

outcomes. Further high-quality interventions are required to

establish whether selenium has any discernable therapeutic

effects for male infertility, and if so in which populations

and circumstances. Evidence to date suggests that high die-

tary intakes (although below the upper safety limits) may

be as detrimental as deﬁciency to male fertility, and there-

fore determining the optimal range for health is all the more

pertinent.

F. Genetics of selenoproteins

Theoretically, there are three broad routes by which sele-

noprotein function can differ between individuals: ﬁrst, dif-

ferent dietary intakes affect selenoprotein synthesis and

activity; second, genetic variants in a selenoprotein gene

(mutations or SNPs) lead to altered protein function or reg-

ulation; third, a combination of dietary intake and genetic

variants affect selenoprotein function. It is well established

that selenoprotein synthesis varies with dietary intake and

that there is a hierarchy in sensitivity to selenium intake (39,

42). In addition, a small number of mutations have been

identiﬁed in selenium-related genes that lead to clinical dis-

ease. For example, a mutation in the gene encoding SECIS

Binding Protein 2, SBP2, causes an amino acid change that

results in altered selenocysteine incorporation into seleno-

proteins, and as a result impaired thyroid hormone action due

to low deiodinase expression (103). Recently, newly identiﬁed

nonsense mutations in this gene have been shown to lead to a

complex syndrome that includes myopathic, thyroid, and

neurological features (122). In addition, a congenital muscular

dystrophy has been associated with a rare mutation in the

region of the selenoprotein N gene predicted to correspond to

the SECIS within the 30UTR (7). In these cases the effect of the

1362 FAIRWEATHER-TAIT ET AL.

rare mutation is independent of selenium intake—they give

rise to genetic diseases. In contrast, links between common

SNPs, alone or in combination with sub-optimal dietary se-

lenium, and risk of multifactorial diseases such as cancer and

heart disease remain to be established. However, over the past

few years a number of SNPs in selenoprotein or selenium-

related genes have been shown to have functional conse-

quences and thus to be worthy of study in relation to disease

risk.

Selenocysteine incorporation occurs during translation by a

mechanism that requires a speciﬁc RNA stem-loop structure

(SECIS) in the 30untranslated region (30UTR) of the mRNAs

(39, 160); therefore, it is important to consider SNPs seleno-

protein gene regions corresponding to 30UTR sequences and

not only those in promoter or coding regions. Indeed in se-

lenoprotein genes SNPs identiﬁed as being functional have

been found in coding, promoter, and 30UTR regions.

The ﬁrst coding region SNP identiﬁed in a selenoprotein

gene was rs1050450, which causes a Pro to Leu amino acid

change in GPx1 and which alters enzyme thermal stability

and enzyme activity (133). The variant has been found to alter

the relationship between plasma selenium and blood cell

GPx1 activity (185). More recently, a coding region SNP in the

SEPP1 gene (rs3877899) was identiﬁed (240), and this is pre-

dicted to cause a Thr to Ala change in the amino acid se-

quence. The SNP apparently alters SEPP function since it

leads to altered responses of blood cell GPx1, GPx4, and TR1

to selenium supplementation and also affects the proportion

of SePP isoforms in plasma (240, 243).

Reporter genes have proved useful in assessing the func-

tionality of promoter region polymorphisms in the seleno-

protein genes. For example, the promoter region of the SePP1

gene contains a TC repeat sequence, and a SNP in this se-

quence has been found to cause lower promoter activity when

linked to a reporter gene and expressed in a liver cell line (11).

More recently, eight linked variants have been identiﬁed in

the promoter region of the GPx3 gene; reporter studies have

suggested differences in promoter activity between the two

haplotypes, suggesting that there are functional variants

within these groups (383). In addition, a SNP has been found

in the promoter region of the Selenoprotein S gene at position

105, and this variant has been found to alter both the levels

of markers of inﬂammation such as TNF-aand interleukin 1b

and the response to endoplasmic reticulum-related stress (91).

Reporter genes have also proved useful in exploring the

functionality of SNPs in gene regions corresponding to the

30UTR of selenoprotein mRNAs. Approximately 10 years ago

two SNPs, a C=T substitution at position 811 (rs5845) and a

G=A at position 1125 (rs5859), were found in the region of the

Sep15 gene that corresponds to the 30UTR of the mRNA, and

expression studies using the sequences linked to a reporter

gene showed that the combination of the variants inﬂuenced

read-through at a UGA codon (172). In addition, a variant in

the 30UTR region of the GPX4 gene (rs713041) has also been

found to determine selenoprotein deiodinase reporter gene

activity in transfected Caco-2 cells; the two allelic variants of this

rs713041 SNP in GPx4 promote reporter activity to differing

extents in selenium-deﬁcient and selenium-supplemented con-

ditions (46). The C variant promotes reporter gene activity to a

greater extent and this would be expected to result from

greater selenocysteine incorporation into the deiodinase re-

porter. In addition, in vitro RNA–protein binding assays show

that transcripts corresponding to the T and C variants differ in

their ability to form RNA–protein complexes (241), with the C

variant having the stronger binding properties. Further, data

from a selenium supplementation trial showed that this SNP

affected responses of GPx4, GPx1, and GPx3 protein expres-

sion or activity in response to selenium supplementation or

withdrawal (241). In addition, a G=A variant has been found

at position 25191 in the 30UTR region of the SEPP1 gene

(rs7579) and on the basis of results from a human selenium

supplementation trial the SNP appears to be functional.

Rs7579 was found to modulate both plasma and lymphocyte

GPx activities, plasma concentrations of SePP post-

supplementation, and the proportion of SEPP isoforms found

in plasma (240).

The allele frequencies of a limited number of these SNPs

have been assessed in disease association studies [reviewed in

Hesketh (160) and Rayman (301)] and although the cohorts

analyzed have been relatively small the analyses have led to

suggestions that some of the variants may be associated with

disease risk. Variants in the family of GPx gene family have

been linked to cancer risk. The Leu variant of GPx1 (rs

1050450) has been reported to increase susceptibility to lung,

breast, and bladder cancer, possibly when combined with the

inﬂuence of either a second SNP in the gene encoding the

antioxidant defense protein manganese superoxide dismutase

or environmental factors such as alcohol consumption and

smoking (90, 171, 177, 293, 295). These studies suggest that

this allele, in combination with increased cell stress, affects

disease susceptibility.

To date, studies of the association of rs713041 (a T=C SNP in

the 30UTR of GPX4) have produced contradictory results with

one small UK study indicating that the T variant is associated

with a lower risk of colon cancer (44), but a recent larger study

in a Czech population showing that the T variant is associated

with a higher risk of colorectal cancer (CRC) (242). In addition,

results from a large association study suggest a link between

genotype at this SNP and susceptibility to breast cancer (373).

Other variants have been reported in the GPx4 gene, but there

was no clear relationship between any of these variants and

sperm viability or fertility. SNPs in the promoter region of the

GPx3 gene fall into two haplotype groups, and the group that

showed a lower activity in reporter gene assays was also

present at higher frequency in children and young adults with

arterial ischemic stroke (383).

Since SePP has a key role in selenium transport, it might be

expected that variants in this gene would inﬂuence risk of

diseases in which selenium intake has been implicated as a

determining factor. However, the evidence for such associa-

tions is limited. Initial studies suggested that neither the TC

promoter polymorphism nor the Ala-Thr SNP in SEPP1

(rs3877899) show altered allele frequencies in colorectal can-

cer patients (11, 12). However, a more recent study has

studied different SNPs in the SEPP1 gene and reported that a

combination of several SNPs in SEPP1 promoter modify risk

of colorectal adenoma (286). Recent studies have suggested

that rs7579 is associated with altered risk of CRC and

rs3877899. In combination with the rare allele for the man-

ganese superoxide dismutase SNP rs4880 affects risk of

prostate cancer in smokers (89).

An association between the combined rs5845 and rs5859

variants in Sep15 and breast cancer risk has been reported;

in addition, the genotype for rs5859 has been observed to

SELENIUM AND HUMAN HEALTH 1363

inﬂuence lung cancer risk in smokers (186). Two small asso-

ciation studies have showed no evidence that the 105G ?A

SNP in the promoter of SelS affects risk of ulcerative colitis or

other autoimmune inﬂammatory diseases (331). However, a

recent study in a Japanese population has suggested the

variant affects the risk of gastric cancer (338). In addition, a

recent association study has linked another variant in SelS (rs

34713741) to CRC risk (242).

In summary, genetic variants in regions of selenoprotein

genes corresponding to promoter, coding region, or 30UTR

have been identiﬁed and shown to cause functional changes.

To date, disease association studies of these SNPs have been

inconclusive and there is a need to carry out more extensive

studies of larger cohorts so as to incorporate analysis of an

appropriate range of SNPs to assess variation across the se-

lenoprotein pathway as a whole, and in combination with

selenium status=intake. Results of the small association

studies carried out to date suggest that such future extensive

studies will be important, especially when they consider in-

teractions between different variants and also take environ-

mental and dietary factors into account.

VIII. Selenium in Critical Illness

Selenium is generally accepted as an essential component

of total parenteral nutrition since in its absence deﬁciency

symptoms are observed (198, 292), and it has been shown to

have a positive effect on immune function in patients on home

parenteral nutrition for short-bowel syndrome (285).

Critically ill patients, including those with burns (40), have

reduced plasma GPx activity and selenium concentrations

(236, 237), in particular selenoprotein P (129). The magnitude

of the decrease in plasma selenium appears to reﬂect the se-

verity of the disease (15) and the concentration continues to

fall over time for patients in intensive care (152). There is an

accompanying increase in urinary selenium excretion (201)

although these losses are not enough to account for the re-

duction in plasma selenium concentrations, which must re-

ﬂect the redistribution of body selenium. In the light of these

observations it has been suggested that there is a higher de-

mand for selenium in critical illness, and recommendations

made for selenium to be included in parenteral nutrition

and=or for selenium to be administered intravenously (25, 335).

The reason for the transfer of selenium from plasma into

other body compartments is not known, and the underlying

mechanisms have yet to be elucidated. In critical illness, TSH,

thyroxine, and thyroxintriodothyronine (T3) are low and re-

verse T3 is elevated (195). Although the etiology and conse-

quences of changes in thyroid hormones are unclear, it is

likely to be a direct effect of cytokines rather than selenium

insufﬁciency per se (142). The hierarchy in synthesis of sele-

noproteins when selenium supply is inadequate gives pref-

erence to the three iodothyronine deiodinases involved in

thyroid metabolism (45). Further, selenium supplementation

has no effect on thyroid hormone levels in critically ill patients

(16).

Excessive oxidative stress plays a key role in the develop-

ment of complications of critical illness, such as systemic

inﬂammatory response syndrome (SIRS). Several selenopro-

teins are enzymes involved in antioxidant defences and redox

regulation, such as the GPxs, thioredoxin reductases, and

methionine sulfoxide reductase. Sepsis is an important cause

of mortality in intensive care unit patients; infection and

endotoxemia provoke a cascade of localized and systemic

responses, including increased free radical production, cyto-

kines, and lipid peroxidation (139). It has been proposed that

low GPx activity in critically ill patients and low total, but

increased glutathione disulﬁde levels, plus increased free

radicals in body compartments may contribute to multiorgan

failure (149). Selenium supplementation (158–454 mg=d) was

found to increase plasma selenium and GPx activity in se-

verely septic patients in intensive care, but thyroid function

tests, C-reactive protein, and F2 isoprostanes were unaffected

(250). An intriguing hypothesis to explain the observed re-

distribution of selenium in septic shock and SIRS is that se-

lenoprotein P binds strongly to the endothelium and hence

the fall in plasma concentration, which is particularly notable

just before death (129).

High-dose selenium supplementation has been reported to

decrease mortality in septic shock, especially when using a

bolus administration, whereas studies using a continuous

administration fail to ﬁnd any beneﬁt. In septic shock patients

given high-dose selenium administration by continuous in-

fusion (selenium as sodium selenite (4000 mg on the ﬁrst day,

1000 mg=day for the 9 following days) or placebo), there was

no difference in mortality rates or adverse events rates. Con-

versely, when patients with severe SIRS, sepsis, and septic

shock were given 1000 mg of selenium as sodium-selenite as a

30-min bolus injection, followed by 14 daily continuous in-

fusions of 1000 mg intravenously, or placebo, mortality rate

was reduced (14).

Heyland et al. (161) undertook a systematic review to in-

vestigate whether antioxidant supplementation (including

selenium) improved the survival of critically ill patients. Sub-

group analysis of seven studies showed a trend [RR: 0.59, 95%

CI: 0.32, 1.08 p¼0.09] toward lower mortality with high

dose (500–1000 mg=d) selenium supplements, either alone or

in combination with other antioxidants, but not with lower

doses (<500 mg=d); there was no effect of selenium on infec-

tious complications. A Cochrane Review on the impact of

selenium supplementation in critically ill adults was pub-

lished in 2004 and updated in 2007 (27). Ten randomized trials

involving 1172 patients were included, but they were re-

ported to be generally poor quality (inadequate size and=or

methodology). The administration of intravenous sodium

selenite was not demonstrated to result in a signiﬁcant re-

duction in mortality of intensive care patients. There was also

no effect on the development of infection, or number of days

on a ventilator, length of intensive care unit stay, length of

hospital stay, or quality of life. Since these systematic reviews

were published, the results of a trial examining the inﬂuence

of early antioxidant supplementation (selenium, zinc, vitamin

C, and thiamine) on clinical outcome of critically ill patients in

intensive care with conditions characterized by oxidative

stress, namely, cardiac valve or coronary bypass surgery with

postoperative complications, major trauma, and severe sub-

arachnoid hemorrhage, have been published (41). Plasma

selenium increased and C-reactive protein decreased faster in

the test versus the placebo group, but infectious complications

did not differ and length of stay in hospital was only reduced

in the trauma group.

In conclusion, despite the well-documented fall in circu-

lating selenium in critical illness, there is limited evidence

for any meaningful improvement in the outcome that can be

1364 FAIRWEATHER-TAIT ET AL.

attributed to selenium supplementation. A large trial (SIG-

NET) in critical care patients has recently been completed to

determine whether selenium and glutamine offer any poten-

tial to enhance host defence and thereby reduce infections and

mortality (13). Another trial (CRISIS) is currently underway,

investigating the prophylactic effect of enteral supplementa-

tion with zinc, selenium, and glutamine on nosocomial in-

fections and sepsis in critically ill children (78). When the

results of these trials are published, it will hopefully be pos-

sible to develop a transparent and robust policy for selenium

administration in critical illness.

IX. Dietary Reference Intakes

The range of intake between which selenium deﬁciency

and toxicity occurs is relatively narrow, with current estima-

tes suggesting that intakes below 30 mg=day are inadequate

and those exceeding 900 mg=day are potentially harmful (409,

420). Globally, dietary intakes traverse both of these guide-

lines due to the inﬂuence of geochemistry on the quantity of

selenium in foods. The best known examples of the inﬂuence

of local geochemistry on selenium intakes are within China,

where there are areas with extremely low and high selenium

consumption. Much of the data pertaining to the risks of ex-

cessive and deﬁcient intakes have been derived from these

areas.

The methodology and terminology of DRIs can be con-

fusing. Essentially, DRIs encapsulate a range of different

values recommended by expert bodies, although even the

term DRI is not exclusive, with dietary reference values and

nutrient intake values having similar deﬁnitions. Although

there have been attempts to align the terminology (199), at

present it is as diverse as the values themselves. Each set of

DRIs typically includes values equivalent to an estimated

average requirement (EAR), the mean intake level that would

meet the needs of half the population, and a recommended

dietary allowance (RDA), the intake level at which the needs

of 97.5% of the population are met (2 SDs above the EAR; Fig.

11). In addition, many bodies have issued advice on the tol-

erable upper intake level, the highest daily intake level that

poses no adverse effects to health and normally includes the

application of an uncertainty factor; some have also desig-

nated a lower level of intake, normally deﬁned as the mini-

mum intake required to maintain proper function or prevent

deﬁciency symptoms.

Not only do current dietary recommendations aim to pre-

vent overt deﬁciency, but also, in most cases, the DRIs have

been set to achieve an optimum status. For selenium, the most

commonly used marker for deriving current recommenda-

tions is the optimization of plasma GPx3 activity. Despite this,

DRIs for selenium are diverse (Fig. 12). This variation is lar-

gely due to the selection of articles from which to derive an

evidence base, the use of varying average body weights, and

the interpolation techniques applied. The DRIs for adults

published by a selection of countries and expert bodies are

shown in Table 1. Some of the recommendations, notably the

UK (93) and the European Food Safety Authority (EFSA) (329)

DRIs, are almost 20 years old, and since then further data from

studies have become available. However, when the Nordic

Nutrition Council and the World Health Organization (WHO)

updated their recommendations in 2004 (265, 410), they con-

cluded that there was no signiﬁcant new evidence to incor-

porate into their decisions and the reference values were left

unchanged, despite nearly a decade elapsing since the pre-

vious reports. Two of the most recently published recom-

mendations, WHO (410) and Australia and New Zealand

(AU=NZ) (26), are quite different, with the Recommended

Dietary Intake (RDI, RDA equivalent) of AU=NZ more than

twice the value of the equivalent Recommended Nutrient

Intake (RNI) set by WHO. The AU=NZ recommendations are

in fact more in line with those published by the UK back in

1991 (Table 1).

The choice of data for determining recommendations and

its interpretation are often speciﬁc to the country or the

committee setting the DRIs. The UK panel chose to set rec-

ommendations based on assessments of intake and status

data from dietary surveys within its own country. From these

data they concluded that, at the time of review, the whole

blood selenium concentrations within the population were

just over the 100 mg=l value suggested for optimization of GPx

activity (367); therefore, the average diet consumed by UK

residents was adequate to meet requirements. The Reference

Nutrient Intake (RNI, RDA equivalent) value was calculated

using the current intakes and set at an equivalent to 1 mg=kg

per day (93), but there were insufﬁcient data to derive an EAR.

In comparison, WHO recommendations were set on the basis

of two-thirds maximal plasma GPx3 activity rather than full

saturation (the end point used by most expert bodies) because

they saw no obvious health beneﬁt of maximal saturation.

Further, the average body weight used by the committee was

FIG. 11. (A) Theoretical dose–response curves used in the

derivation of Dietary Reference Intakes. (B) Theoretical distri-

bution graph for determining recommended dietary allow-

ances from estimated average requirements. EAR, estimated

average requirement; RDA, recommended dietary allowance;

UL, tolerable upper intake level.

SELENIUM AND HUMAN HEALTH 1365

65 kg for men, signiﬁcantly less than in many Western coun-

tries, to better reﬂect the needs of populations in developing

countries (410). WHO set their recommendations using data

from a trial in which severely depleted individuals were

supplemented with varying amounts of selenium over time

(423).

Several other DRI committees have also used data from the

trials conducted in China by Yang et al. (423), including EFSA

(329), the Nordic Nutrition Council (265), and the Institute of

Medicine (IOM) (274). The latter, however, averaged the

suggested requirement of 41 mg=day from the Yang trial (423)

(interpolated to 52 mg=day for American males) with a study

from New Zealand (99) that suggested a ﬁgure of 38 mg=day to

arrive at their EAR of 45 mg=day for adults. The panel re-

viewing the literature for the AU=NZ DRIs in 2005 (26) also

used evidence from the Dufﬁeld et al. (99) study in which New

Zealanders with low blood selenium concentrations were

selected for a supplementation trial where various doses of

selenomethionine (up to 40 mg=day) were provided, on top of

a habitual dietary intake just under 30 mg=day, for 20 weeks.

Plasma GPx3 activity only reached a plateau in the 40mg=day

supplement group, suggesting an intake of around 70 mg=day

is necessary for deﬁcient populations. However, the panel

also used evidence from a more recent trial that was con-

ducted in China and involved groups supplemented with

either selenomethionine or selenite up to doses of 66 mg=day,

plus a habitual average intake estimated as 10 mg=day, also for

20 weeks (414). GPx3 activity reached a plateau in the sele-

nomethionine group at a supplemental intake of 37 mg=day

and in the selenite group at 66 mg=day.

Many countries and bodies have chosen not to distinguish

recommended intakes for men and women, selecting instead

just one value for adults. The IOM concludes that although

Keshan disease has been recorded in women of reproductive

age, this was only an issue in extremely deﬁcient populations

and not currently of concern, even in China, given recent

improved intakes. The DRIs, however, are calculated on a

basis of average male body weight and therefore are more

than adequate to meet female needs (274). The majority of

differences in the gender-speciﬁc recommendations are as a

result of calculations made on average body weights. The

Japanese recommendations have assigned different values for

the Tolerable Upper Intake Level for each gender (Table 1),

which is not the practice of the majority of panels as the value

already incorporates an uncertainty factor (249). None of the

recommendations discriminate between different forms of

selenium, although this might be of relevance for upper limits.

DRI panels tend to set requirements for children and ado-

lescents by extrapolating data from the adult values on the

basis of metabolic body weight. Although far from ideal, there

is currently very limited evidence for setting EARs for these

population groups. Infants under the age of 1 year are not

covered by this method of estimation. Instead, an adequate

intake is set which is based on observations and evidence

from the literature of intakes that appear to be adequate to

meet the population needs. These estimations are usually

based on average measurements from human milk, which are

assumed to be adequate during the ﬁrst year of life.

The process of setting DRIs using data from trials conducted

in populations exposed to very different selenium intakes

could potentially be misleading. There is evidence to suggest

that there is a signiﬁcant adaptation to usual intakes within a

FIG. 12. Current diversity in selenium recommendations

by sex. Compiled using the EURRECA Nutri-RecQuest da-

tabase (80). Where recommendations are given as ranges, the

midpoint has been used. Recommendations for males (M)

and females (F) are shaded as dark gray or light gray bars,

respectively.

Table 1. Current Dietary Reference Intakes for Adults (mg Selenium=Day) of Selected Countries and Bodies

Country or body Year EAR

RDA

UK (93) 1991 Not derived for selenium 60 (F), 75 (M) 450 40

USA and Canada (274) 2000 45 55 400 —

Nordic (265) 2004 30 (F), 35 (M) 40 (F), 50 (M) — 20

WHO=FAO (410) 2004 20 (F), 27 (M) 26 (F), 34 (M) 400 —

EFSA (EU) (329) 1993 40 55 450 20

AU=NZ (26) 2005 50 (F), 60 (M) 60 (F), 70 (M) 400 —

Japan (249) 2005 20 (F), 25–30 (M) 25 (F), 30–35 (M) 350 (F), 450 (M) —

EAR, estimated average requirement (USA, UK, AU=NZ, and Japan); equivalent to AR, average requirement (EFSA, Nordic); ANR,

average normative requirement (WHO).

RDA, recommended dietary allowance (USA, Japan); equivalent to RNI, reference nutrient intake (UK); PRI, population reference intake

(EFSA); RNI, recommended nutrient intake (WHO=FAO); RDI, recommended dietary intake (AU=NZ); RI, recommended intake (Nordic).

UL, tolerable upper intake level (USA, Japan, WHO=FAO); equivalent to UL, upper level of intake (AU=NZ); maximum safe intake (UK, EFSA).

LI, lower level of intake (Nordic); equivalent to LRNI, lower reference nutrient intake (UK); LTI, lowest threshold intake (EFSA).

EFSA, European Food Safety Authority.

1366 FAIRWEATHER-TAIT ET AL.

population, and therefore historical intakes will affect the se-

lenium balance of an individual. This theory is supported by

trials in American men (219) in whom an intake of 80mg=day

was necessary to balance losses. Conversely, Luo et al. (233)

conducted a similar study in Chinese men and estimated the

ﬁgure to be 7.4 mg=day. The wide variation in these ﬁgures can

partly be attributed to differences in body weight of the sub-

jects, but also the difference in selenium body pool size.

The choice of plasma GPx3 as a biomarker for use in setting

dietary reference values is subject to debate. The two trials that

served as the basis for the AU=NZ recommendations (99, 414)

both reported that plasma selenoprotein P did not plateau in

any of their intervention groups, suggesting that it reaches a

maximum at intakes in excess of 70 mg=day. The Nordic Nu-

trition Council conceded that although intakes of 30–40 mg=day

appear adequate to optimize plasma GPx3, other GPxs may

require considerably higher intakes to reach a plateau (265).

The choice of biomarker has a signiﬁcant impact on the refer-

ence value that is derived, as does the cut-off point chosen. A

recent systematic review of selenium biomarkers concluded

that for most measures of selenium status there are insufﬁcient

data to determine the conditions for which different biomark-

ers are useful (23). There is also currently some debate as to

whether recommendations should be set to prevent overt de-

ﬁciency symptoms or to maximize optimal health. This dis-

cussion is further fuelled byevidence that suggests that intakes

higher than current recommendations may reduce the risk of

certain chronic diseases, such as cancer and CVD (see Section

VII.A, B). Currently, although many DRI expert bodies ac-

knowledge these relationships, the general conclusion is that

the evidence is not sufﬁcient to use for deriving DRI values.

In a recent risk modeling exercise, Renwick et al. (308)

compared the data used for setting the current DRIs with

other potential, but less substantiated, health effects. In the

model, the range of intake that provided a very low (<0.001%)

risk of deﬁciency or toxicity, according to data used by DRI

committees, was 90–500 mg=day. The potential complications

(Fig. 13) of using alternative health end-points was illustrated

by the addition of lines modeled for an anticancer effect [using

data from Clark et al. (86)] and an increased prothrombin time

effect [using data from Yang et al. (419)]. This eliminates the

safe range, and results in an overlap for beneﬁcial and adverse

effects, thereby highlighting the complications of including

risk–beneﬁt assessment as part of the DRI process.

A further consideration that is pertinent to DRIs is sele-

nium bioavailability. Although the bioavailability of sele-

nium compounds is generally high (compared with iron, for

example), there are marked differences in the absorption of

the organic and inorganic forms (117). The bioavailability of

different species of selenium from varying food sources is not

well deﬁned and requires further research. In addition, the

quantity of selenium within speciﬁc foods, even those grown

in the same region, can vary considerably, and therefore a

larger error factor is sometimes applied to selenium require-

ments to counteract inconsistencies in intake.

The EURRECA Network of Excellence is a European

Commission Framework Programme 6 (FP6)–funded project

that aims to address some of the discrepancies currently evi-

dent in dietary recommendations throughout Europe. During

the ﬁrst stage of the research activities current data on the

recommendations set by panels were collated and trans-

formed into an online database (80), which will be a resource

to the wider community interested in DRIs. Further work is

planned to develop a series of instruments designed to revise

and standardize the way micronutrient reference values are

derived. In addition, it is hoped that the Network will identify

areas of research that are needed to progress DRI develop-

ment, and also address the concept of personalized nutrition.

The inﬂuence of genotype on nutrient requirements is still an

emerging ﬁeld, but evidence suggests that certain polymor-

phisms may alter the metabolism of dietary selenium (240,

241) (see section VII.F). One particular remit of the Network is

to pay special attention to vulnerable groups within popula-

tions. There is evidence to suggest that those on parenteral

nutrition, HIV-positive patients, alcoholics, and the chroni-

cally ill may all be at risk of poor selenium status. No DRI

panel has yet issued advice for speciﬁc population subgroups,

but it may be the ﬁrst step toward a more personalized approach,

and it is increasingly evident that the identiﬁcation of at risk

groups is extremely important for the development of public

health policies.

X. Conclusions and Perspectives

As outlined throughout this review a great deal of research

is needed to improve our understanding of selenium metab-

olism, which is currently rather limited compared with many

other nutrients. The mechanisms of absorption have not yet

been identiﬁed, and various roles of selenium within the body

are awaiting characterization. Robust measures of status in

relation to short- and long-term exposure and biochemical,

functional, and health outcomes need to be developed. Ex-

isting possible relationships between blood selenium con-

centration and selenium function or health effects are

summarized (Fig. 14). However, the relationship between

selenium intake=status and risk of disease is complex, as ex-

empliﬁed by the observation that the effects of selenium

supplementation trials are cancer type speciﬁc (location of

tumor and grade=severity of disease) and speciﬁc to popula-

tions or individuals, being dependent on baseline selenium

FIG. 13. Risk modeling comparing the data used to set

the UL and RDA values with other potential effects asso-

ciated with dietary intake. Adapted with permission from

Renwick et al. (308).

SELENIUM AND HUMAN HEALTH 1367

status, intake, metabolism, and genotype. The potential for

some selenium species to inhibit certain types of cancer and

their possible role as an adjuvant in cancer therapy requires

further investigation. Greater understanding of the relation-

ship between selenium and health will be assisted by a more

complete knowledge about the functions of selenoproteins

and interactions with other metabolites, which can be

achieved using a systems biology approach. The impact of

genotype, in particular polymorphisms, is a key component of

personalized nutrition=medicine, which will aid preventive

medicine and therapeutic clinical practice. Gender is another

important parameter that is all too often ignored during the

design of trials and during the analyses. Finally, and most

urgently, in view of on-going activities in the United States

and Europe to update current dietary reference intakes, bio-

markers that can be used to derive selenium requirements are

needed to reﬁne current dietary recommendations and to

develop public health policies.

Acknowledgments

This review was carried out with partial ﬁnancial support

from the Commission of the European Communities, speciﬁc

RTD Programme ‘‘Quality of Life and Management of Living

Resources,’’ within the 6th Framework Programme (Contract

No. FP6-036196-2 EURRECA: EURopean micronutrient RE-

Commendations Aligned) (R.C. and R.H.). This review does

not necessarily reﬂect the views of the Commission and in no

way anticipates the future policy in this area. Other ﬁnancial

support was provided from the University of East Anglia

(SJF-T), the BBSRC (Agri-Food Committee Industry Partner-

ing Award, BB-G013969-1), and by Yara (UK) Ltd. ( M.R.B.).

We thank Dr N.Tejo Prakash from Thapar University, India,

for the photographs provided in this review.

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Address correspondence to:

Prof. Susan J. Fairweather-Tait

School of Medicine, Health Policy and Practice

University of East Anglia

Norwich, Norfolk NR4 7TJ

United Kingdom

E-mail: s.fairweather-tait@uea.ac.uk

Date of ﬁrst submission to ARS Central, April 30, 2010; date of

ﬁnal revised submission, August 20, 2010; date of acceptance,

September 2, 2010.

Abbreviations Used

AIDS ¼acquired immune deﬁciency syndrome

AKR ¼aldo-keto reductase

ALDH2 ¼aldehyde dehydrogenase 2

AP-1 ¼activator protein-1

ApoER2 ¼apolipoprotein E receptor 2

ASK1 ¼apoptosis signal-regulating kinase 1

CAD ¼coronary artery disease

CHD ¼coronary heart disease

CNS ¼central nervous system

CRC ¼colorectal cancer

CVB ¼Coxsackie virus B

CVD ¼cardiovascular disease

DIDS ¼diisothiocyano-2,20-disulphonic acid

stilbene

DIO ¼iodothyronine deiodinase

DIO ¼iodothyronine deiodinase gene

1382 FAIRWEATHER-TAIT ET AL.

Abbreviations Used (Cont.)

DRI ¼dietary reference intake

EAR ¼estimated average requirement

EEC ¼European Economic Community

EFSA ¼European Food Safety Authority

EU ¼European Union

EURRECA ¼European Micronutrient

Recommendations Aligned

GCS ¼g-glutamylcysteine synthetase

GI ¼gastrointestinal

GPx ¼glutathione peroxidase

GPX ¼glutathione peroxidase gene

GST ¼glutathione transferase

HIV ¼human immunodeﬁciency virus

HO ¼heme oxygenase

HR ¼hazard ratio

ICP-MS ¼inductively coupled plasma mass

spectrometry

IOM ¼Institute of Medicine

KBD ¼Kashin-Beck disease

LC ¼liquid chromatography

LI ¼lower level of intake

mnSOD ¼manganese superoxidase dismutase

NAC ¼N-acetyl cysteine

NDNS ¼National Diet and Nutrition Survey

NF-kB¼nuclear factor kappa B

NHANES ¼National Health and Nutrition

Examination Survey

NPC ¼Nutritional Prevention of Cancer trial

OA ¼osteoarthritis

OR ¼odds ratio

PIN ¼prostatic intraepithelial neoplasia

PSA ¼prostate-speciﬁc antigen

QR ¼quinone oxidoreductase

RA ¼rheumatoid arthritis

RCT ¼randomized controlled trial

RDA ¼recommended dietary allowance

RNI ¼recommended nutrient intake

ROS ¼reactive oxygen species

RR ¼relative risk

rT3 ¼3,30,50triiodothyronine

SBP2 ¼SECIS binding protein 2

SECIS ¼selenocysteine insertion sequence

SelH ¼selenoprotein H

SelM ¼selenoprotein M

SelR ¼selenoprotein R

SelS ¼selenoprotein S

SelT ¼selenoprotein T

SelW ¼selenoprotein W

SEP15 ¼15 kDa selenoprotein gene

SePP ¼selenoprotein P

SEPP ¼selenoprotein P gene

SEPS ¼selenoprotein S gene

SEPW ¼selenoprotein W gene

SFN ¼sulforaphane

SNP ¼single nucleotide polymorphism

SOD ¼superoxide dismutase

SOD2 ¼manganese superoxide dismutase

gene

T-2 ¼trichothecene mycotoxin

T3 ¼3,3,50tri-iodothyronine

T4 ¼tetra-iodothyronine or thyroxine

TNF-a¼tumor necrosis factor-a

Trx ¼thioredoxin

TXNRD ¼thioredoxin reductase

TXNRD ¼thiredoxin reductase gene

UGT ¼UDP-glucuronyltransferase

UL ¼tolerable upper intake level

WCRF ¼World Cancer Research Fund

WHO ¼World Health Organization

XMRV ¼Xenotropic murine leukemia

virus-related virus

XRCC1 ¼x-ray repair cross-complementing 1

SELENIUM AND HUMAN HEALTH 1383

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Full-text available

Apr 2025

Acrylamide, a harmful substance generated during the normal thermal treatment of foods, has been shown to adversely affect human health, particularly the vital intestinal barrier function. Meanwhile, natural polysaccharides are recognized to exert an important biofunction in the intestine by protecting barrier integrity. In this study, the non-starch, water-soluble, and nondigestive yam polysaccharide (YP) was extracted from fresh Chinese yam, while two selenylated derivatives with different extents of selenylation were prepared via the HNO3-Na2SeO3 reaction system, and designated as YPSe-I and YPSe-II, respectively. Their protective activities and the associated molecular mechanisms of these substances against acrylamide-induced damage in rat intestinal epithelial (IEC-6) cells were thereby investigated. The experimental results demonstrated that the selenium contents of YPSe-I and YPSe-II were 0.80 and 1.48 g/kg, respectively, whereas that of the original YP was merely 0.04 g/kg. In IEC-6 cells, in comparison with YP, both YPSe-I and YPSe-II showed higher efficacy than YP in alleviating acrylamide-induced cell toxicity through promoting cell viability, suppressing the release of lactate dehydrogenase, and decreasing the generation of intracellular reactive oxygen species. Both YPSe-I and YPSe-II could also manifest higher effectiveness than YP in maintaining cell barrier integrity against the acrylamide-induced barrier disruption. The mentioned barrier protection was achieved by increasing transepithelial electrical resistance, reducing paracellular permeability, facilitating the distribution and expression of F-actin between the cells, and up-regulating the production of three tight junctions, namely ZO-1, occludin, and claudin-1. Additionally, acrylamide was observed to trigger the activation of the MAPK signaling pathway, thereby leading to cell barrier dysfunction. In contrast, YPSe-I and particularly YPSe-II were capable of down-regulating two MAPK-related proteins, namely p-p38 and p-JNK, and thereby inhibiting the acrylamide-induced activation of the MAPK signaling pathway. Moreover, YPSe-II in the cells was consistently shown to provide greater barrier protection than YPSe-I. In conclusion, chemical selenylation of YP could cause higher activity in mitigating acrylamide-induced cytotoxicity and intestinal barrier dysfunction, while the efficacy of activity enhancement was positively affected by the selenylation extent.

Plant Growth Promotion and Selenium Accumulation in Zea Mays in Seleniferous Soils by Selenium Tolerant Bacteria

Article

Full-text available

Apr 2025
WATER AIR SOIL POLL

Selenium (Se) is an essential nutrient for both humans and livestock, but its toxicity becomes particularly evident in soils with naturally high Se concentrations. Conversely, Se deficiency in regions with low soil Se levels can lead to severe health issues. This study focused on the isolation of bacteria from seleniferous agricultural soils (Se content: 6.86 ± 0.12 mg/kg), screening their tolerance to Se, and evaluating their potential for promoting plant growth. Three bacterial isolates, Se3, Se38, and Se5 were selected as Se-tolerant and assessed for their effectiveness in enhancing maize growth and regulating Se uptake in seleniferous soils. These isolates exhibited high tolerance levels, withstanding up to 200 mM selenate and 150 mM selenite. These bacteria were identified as Proteus terrae (Se3), Corynebacterium glutamicum (Se38), and Halopseudomonas formosensis (Se5) based on their 16S rRNA sequence analysis. All three bacterial isolates exhibited plant growth-promoting traits, including indole acetic acid (IAA) production, phosphate solubilization, and siderophore production. Inoculation with Se3, Se38, and Se5 significantly enhanced maize growth by 26.8%, 19.6%, and 21.9%, respectively, compared to the control in seleniferous soil. Additionally, plants inoculated with these strains displayed higher root and shoot biomass than non-inoculated controls. Notably, Se3 inoculation resulted in the greatest reduction in Se uptake in maize tissues compared to Se38 and Se5. This study demonstrated that selenium-tolerant bacterial isolates, Proteus terrae, Halopseudomonas formosensis, and Corynebacterium glutamicum offer a dual benefit in seleniferous soils by enhancing plant growth and mitigating selenium toxicity. These bacteria exhibit high Se tolerance, promote maize growth, and significantly reduce Se uptake in plant tissues, making them valuable biofertilizers. Moreover, their ability to bioaccumulate or biosorb selenium and convert it into elemental selenium (Se⁰) presents an environmentally friendly solution for bioremediation of Se-contaminated soils. Ultimately, leveraging these Se-tolerant, plant growth-promoting bacteria could transform Se-affected areas into viable agricultural lands.

Beyond traditional methods: nanomaterials pave the way for precise nutrient detection in nutritionally fortified foods

Article

May 2025
CRIT REV FOOD SCI

Selenoprotein M Inhibits the Replication of Influenza A Virus by Regulating Reactive Oxygen Species Levels

Article

Apr 2025

Background: Influenza A virus (IAV) is the major pathogen responsible for influenza pandemics and can cause seasonal influenza outbreaks. In general, viral infection of host cells increases reactive oxygen species (ROS) levels, a process that triggers cell death, lung injury (LI), and other damage mechanisms. Methods: In our previous study, we revealed that selenoproteins may inhibit IAV replication at the cellular level. In this study, we determined the effect of selenoprotein M (SelM) on Nanoluc-IAV-PR8 replication through Nanoluc analysis. The mechanism through which selenoprotein inhibits the replication of the influenza virus was investigated using the SelM knockout cell line, nano-luciferase reporter assays, RNAi, qPCR, Western blot, and confocal microscopy. Results: Our experimental results show that SelM can effectively inhibit the replication of influenza A viruses and could potentially be used as a broad-spectrum inhibitor for IAV therapy in future clinical treatments. The increase in ROS levels induced by IAV infection was found to be inhibited by SelM, which possesses an important Sec functional site, thus weakening the ability of IAV to replicate in cells. Conclusions: The results of this study highlight SelM as a selenoprotein that can effectively inhibit IAV replication.

Protective effect and pathways of the selenylation-modified nondigestive longan (Dimocarpus longan Lour.) polysaccharides in IEC-6 cells with indomethacin injury

Article

May 2025

The Effect of Chokeberry Juice and Fiber Consumption on the Concentration of Antioxidant Minerals in Serum

Article

Apr 2025

Aronia is a fruit that has become increasingly popular in recent years. Numerous health-promoting effects resulting from consumption have been indicated, including the possibility of using aronia as a functional food in the prevention and support of therapy for various ailments. For the first time, we assessed the effects of the impact of a 90-day nutritional intervention on the level of selected minerals in the serum of women (n = 67) and men (n = 35). The consumption of 100 mL of juice for 60 days resulted in a significant increase in the levels of copper, manganese, and selenium. The addition of 10 g of aronia fiber resulted in a further increase in the concentration of these elements with antioxidant properties. An interesting observation is that the concentration of zinc decreased, which may indicate the operation of compensatory mechanisms. The above results indicate that regular consumption of aronia bio-products may have a beneficial effect on the concentration of microelements in the serum.

Bioactive Properties of Fermented Beverages: Wine and Beer

Article

Full-text available

Apr 2025

In recent years, consumer demand has been increasingly oriented to fermented foods and/or beverages with functional properties. The functional beverage industry focused on producing a product that combines a peculiar aromatic taste with healthy properties. Today’s consumers are trying to reduce alcohol, gluten, sugar, and carbohydrates in beer and wine without reducing their native taste. Wine and beer are among the world’s most consumed beverages, and several studies confirm that fermented beverages could be associated with beneficial properties for human health. All beneficial properties derive both from the fermentation process and also from the characteristics of the raw materials used in the two beverages. This review was conducted to highlight the importance of the fermentative microorganisms in wine and beer and their relationship with functional foods, underlining their involvement in human health.

New Glycoconjugates Containing Selenium and Polyphenols. Stereoselective Synthesis by Pummerer‐like Rearrangement.

Article

Full-text available

May 2025
EUR J ORG CHEM

In the last 20 years the exploitation of antioxidant activity of selenobased compounds has improved, just due to the use of Ebselen, a selenocompound, as a Glutathione peroxidase (GPx) mimic. However, their clinical use seems to be compromised by the low solubility in water. To deal with this problem, it is possible to take advantage of the new approach including selenosugars in which selenium replaces heterocyclic oxygen. In this frame, to optimize the antioxidant properties of selenosugars, the glycoconjugation with a polyphenolic unit, which is a molecule capable of inhibiting or disabling the action of free radicals, has been considered in this work. The Mitsunobu reaction mechanism links covalently the primary alcoholic function of selenobased glycosyl donors, coming from the commercially available d‐mannose, and phenolic moiety acceptors, to obtain the corresponding glycoconjugates, has been exploited affording the products in efficient yields. A density functional theory (DFT) theoretical study is carried out to help understand the possible influence of the seleno donor on the reactivity. Crucially, a new pathway based on Pummerer‐like rearrangement followed by a glycosylation, gave a selenosugar with selenium in the ring and bearing an acetal‐like functional group at C‐1. All compounds are characterized by nuclear magnetic resonance (NMR) spectroscopy confirming their structures and purity.

Essential and Non-Essential Metals and Metalloids and Their Role in Atherosclerosis

Article

Full-text available

Apr 2025

Peripheral arterial disease (PAD) is becoming more prevalent in the aging developed world and can have significant functional impacts on patients. There is a recent recognition that environmental toxicants such as circulating metals and metalloids may contribute to the pathogenesis of atherosclerotic disease, but the mechanisms are complex. While the broad toxic biologic effects of metals in human systems have been extensively reviewed, the role of non-essential exposure and essential metal aberrancy in PAD specifically is less frequently discussed. This review of the literature describes current scientific knowledge regarding the individual roles several major metals and metalloids play in atherogenesis and highlights areas where a dearth of data exist. The roles of lead (Pb), arsenic (As), cadmium (Cd), iron (Fe), copper (Cu), selenium (Se) are included. Contemporary outcomes of therapeutic trials aimed at chelation therapy of circulating metals to impact cardiovascular outcomes are also discussed. This review highlights the supported notion of differential metal presence within peripheral plaques themselves, although distinguishing their roles within these plaques requires further illumination.

Erythrocyte glutathione peroxidase activity in acne vulgaris and the effect of selenium and vitamin E treatment

Article

Jan 1984

The glutathione-peroxidase (GSH-Px) activity in erythrocytes was determined in 42 men with severe acne and 47 women with acne--26 of a moderate degree and 21 severe. The male acne patients had significantly lower GSH-Px levels than the controls. The women with acne did not differ significantly from the controls in this respect when patients and controls using oral contraceptives were excluded. Both the female controls and the women with acne using oral contraceptives had significantly higher GSH-Px values than the corresponding groups not using the pill. The pubertal acne girls had the same high GHSH-Px activity as women on oral contraceptives. In an open trial 29 patients were given 0.2 mg of selenium (as Na2Se O3) + 10 mg of tocopheryl succinate for their acne twice daily for 6-12 weeks. A good result was obtained, especially in patients with pustular acne and low GSH-Px activity, and the beneficial effect was usually paralleled by a slow rise of the GSH-Px activity. Some 6-8 weeks after withdrawal of the treatment the GSH-Px values had returned to the pretreatment levels.

Selenium and Lung Cancer: A Quantitative Analysis of Heterogeneity in the Current Epidemiological Literature

Article

May 2004

While numerous laboratory investigations have shown that selenium may have anticarcinogenic activity, the epidemiological data have been inconsistent. In this report, meta-analysis was used to quantitatively summarize the existing epidemiological evidence on selenium and lung cancer and identify sources of heterogeneity among studies. When all studies were combined, the summary relative risk (RR) for subjects with higher selenium exposures was 0.74 [95% confidence interval (CI) 0.57–0.97]. In subgroup analyses based on the average selenium level in the study population, the summary RR for areas where selenium levels were low was 0.72 (95% CI 0.45–1.16), while the RR for areas where selenium levels were higher was 0.86 (95% CI 0.61–1.22). In both studies in high selenium areas where RRs were markedly below 1.0, protective effects were only found when subjects in the lowest category of selenium exposure were used as referents. No clear protective effects were seen when highly exposed subjects were compared with those in the middle exposure categories. The summary RR was lower in studies assessing selenium exposure using toenails (RR 0.46, 95% CI 0.24–0.87) than in studies using serum selenium (RR 0.80, 95% CI 0.58–1.10) or studies assessing dietary intake (RR 1.00, 95% CI 0.77–1.30). Overall, these results suggest that selenium may have some protective effect against lung cancer in populations where average selenium levels are low. The evidence for these findings is greater in studies of toenail selenium than in studies involving other measures of exposure.

Coxsackievirus B3 infection and Keshan disease

Article

Aug 2002

To study the relationship between the infection of enteroviruses and the etiology of keshan disease, we examined the 30 blood samples from the latent-chronic KD patients from Mianning, Xider, Derchang county of Sichuan Province with LDE-PCR (long distance enterovirus-specific RT PCR), two sensitive and specific ELISAs (one for CVB1-6 IgM and the other for CVB1-6 IgG), and three-primer RT PCR specific for CVB3. Results show that: 1) The infection rate of enteroviruses in the samples from the latent-chronic KD patients is higher than from the control group (80% VS 0%, P < 0.01); 2) The CVB1-6 antibody positive rate in latent-chronic KD is higher than that of the control group (IgM, 33% VS 0%, P < 0.01; IgG, 23% VS 0%, P < 0.01); 3) 16.6% (4/24) of enteroviruses positive samples or 40% (4/10) of CVB1-6 IgM antibody positive samples can be identified as CVB3. So, the infection of enter viruses maybe involves in the cause and development of latent-chronic keshan disease, and at least we conclude that the mutation of CVB3 is not the only cause of KD.

Endemic selenium intoxication of humans in China

Article

May 1983

An endemic disease was discovered in 1961 in parts of the population of Enshi County, Hubei Province of the People's Republic of China. During the years of the highest prevalence, from 1961 to 1964, the morbidity was almost 50% in the 248 inhabitants of the five most heavily affected villages; its cause was determined to be selenium intoxication. The most common sign of the poisoning was loss of hair and nails. In areas of high incidence, lesions of the skin, nervous system, and possibly teeth may have been involved. A case is reported of a middle-aged, female hemiplegic, whose illness and death apparently were related to selenosis. Daily dietary intakes of selenium, estimated after the peak prevalence had subsided, averaged 4.99 (range 3.20 to 6.69) mg and hair and blood selenium levels averaged 32.2 and 3.2 µg/ml, respectively. Up to l000× differences occurred when selenium contents of vegetables, cereals, scalp hair, blood, and urine from the selenosis areas were compared with those from Keshan disease (selenium deficiency) areas. The ultimate environmental source of selenium was a stony coal of very high selenium content (average more than 300 µg/g; one sample exceeded 80,000 µg/g). Selenium from the coal entered the soil by weathering and was available for uptake by crops because of the traditional use of lime as fertilizer in that region. This particular outbreak of human selenosis was due to a drought that caused failure of the rice crop, forcing the villagers to eat more high-selenium vegetables and maize and fewer protein foods.

The role of the selenoprotein S (SELS) gene -105G>A promoter polymorphism in inflammatory bowel disease and regulation of SELS gene expression in intestinal inflammation

Article

Aug 2007

Background/aim: Recently, a -105G>A promoter polymorphism coding for selenoprotein S (SELS) has been shown to increase proinflammatory cytokine expression (Nature Genetics 2005; 37:1234–41). We therefore analyzed SELS expression and potential phenotypic consequences of the -105G>A polymorphism in patients with inflammatory bowel disease (IBD). Methods: SELS mRNA was measured by quantitative PCR in intestinal epithelial cells (IEC) after stimulation with proinflammatory cytokines and in human colonic biopsies of IBD patients as well as in the TNFdeltaARE mouse model of ileitis. Genomic DNA from 563 individuals (Crohn's disease (CD): n=205; ulcerative colitis (UC): n=154; controls: n=204) was analyzed for the presence of the SELS -105G>A polymorphism and the three NOD2/CARD15 variants p.Arg702Trp, p.Gly908Arg, and p.Leu1007fsX1008. Results: SELS mRNA expression was increased in IEC after stimulation with proinflammatory cytokines, while its expression was not significantly altered in murine ileitis and in inflamed colonic lesions in IBD patients compared to unflamed tissue taken from the same patients. The SELS -105G>A polymorphism was observed with similar frequencies in IBD patients and controls and was not associated with a certain disease phenotype or serum TNF-alpha and CRP levels in these patients. Medium serum TNF-alpha was 1.27 pg/ml in IBD patients, while none of the controls had TNF-a concentrations above the detection threshold (p<0.0001). Conclusion: SELS mRNA expression is up-regulated by proinflammatory cytokines in IECs but the SELS -105G>A polymorphism is not associated with IBD susceptibility and does not contribute to a certain disease phenotype or increased TNF-alpha levels in IBD patients.

Mechanisms in occurrence and prevalence of Kashin-Beck disease (KBD)

Article

Jan 1998

J.B. Yang

Semen selenium and human fertility**Supported by the Medical Research Council (MRC) of Canada, Fonds de Recherches en Santé du Québec (FRSQ), and Programme de Formation de Chercheurs et d’Action Concertée (FCAC), Province of Quebec.

Article

Dec 1984
FERTIL STERIL

Selenium (Se) was measured in the semen of 125 men from couples consulting for infertility. A mean concentration of 71.3 ± 29.7 ng/ml of semen was found, with a range of 7 to 230 ng/ml. More than 85% of the Se is in the seminal plasma. There was a significant positive correlation between sperm count and semen Se. Sperm motility was maximal at semen Se levels ranging between 50 and 69 ng/ml; above and below this range, motility was decreased and the incidence of asthenospermia was high. This result suggests an optimal range for semen Se. A follow-up of 4.5 to 5 years after the initial assay of Se revealed that low semen Se levels (≤ 35 ng/ml) were associated with male infertility. A Se level between ~ 40 and 70 ng/ml was optimal for reproductive performance (high pregnancy rate and low abortion rate). Semen Se levels ≥ 80 ng/ml were associated with a high abortion rate and signs of ovarian dysfunction in the partner (both partners usually have the same diet and environmental exposure). These results attest to the role of Se in human reproduction, a well-established fact in several animal species. The semen Se level appears to be a useful indicator of Se status versus reproductive function. Further studies are warranted concerning the general aspects of metabolism and mechanism of action of Se in infertile couples before any therapeutic modification of intake of this element can be contemplated.

International harmonization of approaches for developing nutrient-based dietary standards - Introduction

Article

Mar 2007

Selenium accumulation in plant foods

Article

Jun 2005

John W Finley

Selenium (Se) is an essential nutrient, and Se deficiency is associated with disease conditions and general impairment of the immune system. Supplementation of Se to humans already consuming the RDA may help to prevent certain cancers. A convincing argument can be made for augmenting the food supply with Se, and Se-enhanced plants may be the best means of accomplishing this. Plants accumulate varying amounts of Se in different chemical forms; some plants accumulate Se in direct relationship to the amount available from the soil, whereas others (Seaccumulators) may accumulate Se in concentrations many orders of magnitude above that in the soil. There are many different chemical forms of Se in plants, and the form partially dictates the metabolism of Se by the animal that consumes the plant. The Se content and the chemical form of Se within plants may be altered by manipulation of plant genetics or by agricultural production conditions. However, attempts to maximize Se in plants may have unintended consequences and must be carefully monitored.

Effect of selenium on lesion of articular cartilage fed on T-2 toxin in chinese experimental mini-pig

Article

Jan 1998

T-2 toxin (1.5mg/kg feed) and sodium selenite (200ng/kg feed) were added Se-deficient feed containing selenium 35ng/kg for Chinese minipigs in a period of 105 days. Pathological observations and biochemical analyses were carried out on the articular cartilage of those minipigs. The results showed that there was obvious zonal and patchy chondronecrosis in the deep layer of articular cartilage in the T-2 toxin group, which was similar to the chondronecrotic lesions in the articular cartilage of human Kashin-Beck Disease. In addition, proteoglycans in the T-2 toxin group decreased compared with the control, however, such changes were not found in se-deficient group. Selenium could alleviate the severity of the lesion and ameliorate the metabolism of proteoglycans to some extent. These findings suggest that T-2 toxin has significant toxic effects on articular cartilage and selenium has some protective effects.

Selenium in Human Health and Disease

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