Soy as an Endocrine Disruptor: Cause for Caution?

Abstract

Endocrine disrupting compounds (EDCs) alter the function of the endocrine system and consequently cause adverse health effects. Phytoestrogens, natural plant compounds abundantly found in soy and soy products, behave as weak estrogen mimics or as antiestrogens. They are considered to be EDCs, and have some beneficial effects on health, including reducing the risk of breast cancer and improving metabolic parameters. However, the supporting evidence that consumption of phytoestrogens is beneficial is indirect and inconsistent. Lifetime exposure to estrogenic substances, especially during critical periods of development, has been associated with formation of malignancies and several anomalies of the reproductive systems. Phytoestrogen consumption in infants, through soy-based formulas, is of particular concern. Prospective epidemiological studies for the evaluation of the effect of phytoestrogens alone, and in combination with other estrogenic chemicals, are lacking, yet possible adverse effects should not be taken lightly.

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© Freund Publishing House Ltd., London Journal of Pediatric Endocrinology & Metabolism, 23, 855-861 (2010)
VOLUME 23, NO. 9, 2010 855
Soy as an Endocrine Disruptor: Cause for Caution?
Bar-El Dadon S and Reifen R
School of Nutritional Sciences, The Robert H. Smith Faculty of Agriculture, Food and Environment,
The Hebrew University of Jerusalem, Rehovot, Israel
ABSTRACT
Endocrine disrupting compounds (EDCs) alter
the function of the endocrine system and
consequently cause adverse health effects.
Phytoestrogens, natural plant compounds
abundantly found in soy and soy products,
behave as weak estrogen mimics or as anti-
estrogens. They are considered to be EDCs,
and have some beneficial effects on health,
including reducing the risk of breast cancer
and improving metabolic parameters. How-
ever, the supporting evidence that con-
sumption of phytoestrogens is beneficial is
indirect and inconsistent. Lifetime exposure to
estrogenic substances, especially during
critical periods of development, has been
associated with formation of malignancies and
several anomalies of the reproductive systems.
Phytoestrogen consumption in infants, through
soy-based formulas, is of particular concern.
Prospective epidemiological studies for the
evaluation of the effect of phytoestrogens
alone, and in combination with other estro-
genic chemicals, are lacking, yet possible
adverse effects should not be taken lightly.
INTRODUCTION
Endocrine disrupting compounds (EDCs) are
chemicals with the potential to elicit negative
effects on the endocrine systems of humans and
wildlife. They include a broad class of chemicals
such as natural estrogens/androgens, synthetic
estrogens/androgens, and industrial chemicals1.
Synthetic chemicals are not the only exogenous
agents that have caused health concerns because
Corresponding author:
Ram Reifen MD MSc
reifen@agri.huji.ac.il
of their hormone-like activity. Of particular
interest are the phytoestrogens, which are defined
as any plant compounds structurally and/or
functionally similar to ovarian and placental
estrogens and their active metabolites2. These
compounds can be found in blood and urine
samples of virtually every person and animal on
this planet, often in high concentrations. The
main phytoestrogens derived from the diet are
genistein, daidzein and glycitein, which are
isoflavones. Soy is considered to be the richest
source of plant estrogens. Soybeans are
ubiquitously used in the food industry, including
milk formula substitutes, and have become
increasingly popular over the past 20 years.
Studies have shown that there is a large
variability in isoflavone content and composition
in soybeans, depending on the variety of soy
grown, as well as environmental conditions3. The
metabolism of isoflavones is rather complex. The
two major isoflavones, genistein and daidzein, are
present in soy as glycosides, which are bio-
logically inactive4. Once ingested, isoflavone
glycosides are hydrolyzed in the intestinal wall,
resulting in the conversion to their corresponding
bioactive aglycones. Isoflavones are similar in
their spatial conformation to mammalian
estrogens, bind to estrogen receptors and affect
estrogen-regulated gene products5. They have
traditionally been considered to be weak estro-
gens5. However, isoflavones have the potential to
exert physiologic effects in humans consuming
soy foods, since serum isoflavone levels are 100-
1000 times higher than endogenous estrogen
levels6. In addition, several phytoestrogens,
mostly genistein and its analogs, possess binding
affinities for the ER far greater than many of the
EDCs of concern7,1, such as bisphenol A, and
diethylstilbestrol (DES). Hence, from a potency
standpoint, the phytoestrogens exert a far greater
impact on human exposure to exogenous
estrogens than do the synthetic chemicals. This

856 S. BAR-EL DADON AND R. REIFEN
JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM
denotes that the estrogenic activities derived from
phytoestrogens cannot be neglected.
This review summarizes the health-effect of
different exposures to phytoestrogens as a class of
EDCs.
OBESITY AND METABOLISM
A number of clinical and epidemiological
studies have evaluated the effects of soy and its
isoflavones on human metabolism, among which
some suggest that soy protein or isoflavones
consumption is associated with lower risk of
diabetes and a reduction in plasma concentration
of total and LDL cholesterol8,9. However, a
significant number of studies reported an absence
of beneficial effects of soy on classical metabolic
parameters such as body weight, serum lipid
profiles, fat mass, blood glucose and insulin
profiles10,11. These discrepancies make it difficult
to draw firm conclusions regarding the beneficial
effect of soy on glucose and lipid metabolism. As
in humans, reports in rodents also indicate that
the effect of soy isoflavones is not always
towards an improvement in metabolic parameters,
but rather differs, depending on the tissue
investigated, and the dose and timing of exposure.
For example, neonatal exposure to genistein
caused a significant increase in body weight in
mice at 4 months of age12. Dang et al. suggest
that genistein affects adipogenesis of mouse
progenitor cells in a biphasic way; an inhibition
of adipogenesis at low concentrations and stimu-
lation of adipogenesis at high concentrations13.
Overall, the effects of soy isoflavones are com-
plex and their mechanism of action is yet to be
clarified, and though positive dietary trends for
the use of soy have been demonstrated in several
studies, it still cannot be considered a substitute
for pharmacological therapy for people with
hypercholesterolemia. Taking into account also
the inconsistency in the results, any discussion
regarding its beneficial effect should be handled
with caution.
REPRODUCTION
It has long been known that grazing on clover-
rich pastures high in phytoestrogens precursors
causes infertility in sheep14. More recently,
considerable evidence from laboratory animal
studies exists of the adverse effects of exposure
of males and females to estrogen disruptors,
including genistein, during critical periods of
development.
A study by Eustache et al. provides evidence
that lifelong exposure to low-dose genistein
and/or vinclozolin results in reproductive devel-
opmental anomalies, alterations in sperm
production and quality, and fertility disorders15.
This study contrasts previous reports based on
short windows of exposure to these compounds,
showing only mild or no reproductive alterations.
You et al.16 reported that exposure to either
genistein or methoxychlor (MXC) resulted in
extensive developmental alterations in both male
and female reproductive tracts. In addition, in
utero and lactational exposure to maternally
dosed genistein and MXC affects development in
male rats at the prepubertal stage17. Exposure to
high-dosage of these compounds, particularly to a
combination of the two, also caused marked
feminization of the adult male mammary gland,
well recognizable through morphological evalua-
tion and detection of milk protein expression18.
Neonatal exposure of mice to genistein at
environmentally relevant doses caused abnormal
estrous cyclicity, altered ovarian function, early
reproductive senescence, subfertility/infertility19.
Although genistein was administered as s.c
injections in this study, its circulating serum
levels were similar to the range of those found in
infants consuming soy-based formulas20. Similar
doses were used in another study, in which
neonatal rat pups were orally treated with
genistein, also showing adverse effects, including
multiple ovarian follicles in the ovary and
reduced female fertility21. Early developmental
stages were not the only sensitive stages to
exposure of phytoestrogens. Studies conducted on
adult male rats have also shown that acute
exposure to a diet of high phytoestrogen content
transiently reduces their fecundity22.
Studies using other phytoestrogens including
daidzein23 have also demonstrated disruptions in
reproduction, supporting the concept that phyto-
estrogens, although weaker than 17β-estradiol,

SOY AS ENDOCRINE DISRUPTOR: CAUSE FOR CAUTION? 857
VOLUME 23, NO. 9, 2010
can cause adverse effects on the developing
reproductive tract.
In human trials, Chavarro et al. found an
inverse association between consumption of soy
foods and sperm concentration which was more
pronounced at the higher end of the sperm
concentration distribution and among overweight
or obese men24. Studies have also shown
prolongation of the menstrual cycle in healthy
premenopausal women given soy protein daily
containing 45 mg of isoflavones, attributed to
prolongation of the follicular phase due to
suppression of the normal midcycle surge in FSH
and LH 25. It was also found that vegetarian diets
containing high levels of soy during pregnancy
have been associated with increased incidence of
hypospadias in the male offspring26.
These observations, together with the in-
creasing incidence of testicular dysgenesis syn-
drome (hypospadias, cryptorchidism, poor semen
quality and testicular cancer)27 in the last decade,
may propose a link between exposure to EDCs, as
phytoestrogens, during critical periods of repro-
ductive development and disorders of impaired
masculinization in males. Overall, it is evident
that an exposure to various estrogenic compounds
during critical periods of development can have
adverse consequences on reproductive systems,
both in rodents and humans. Therefore, an
extensive use of soy and its products, especially
in infants' formulas, should be of great concern.
PRECOCIOUS PUBERTY
Over the past decades, the age of onset of
puberty has tended to decrease. This phenomenon
could be partially attributed to the presence of
environmental factors, such as dietary phyto-
estrogens. Several studies have noted that
pubertal onset may be hastened, delayed, or
unchanged by early exposure to phytoestrogens,
an effect to which females seem to be particularly
susceptible, and that it is dependent upon
compound, dose, and timing of exposure. For
instance, gestational and lactational exposure to a
mixture of isoflavones hastened the onset of
puberty in female mice, while males were
unaffected28. Postnatal exposure to genistein and
coumestrol hastened the onset of puberty in
female rats23,29. Treatment with genistein during
gestation and lactation reduced anogenital
distance (AGD) and body mass during pre-
pubertal development and increased the
expression of defensive behaviors in adult male
mice30. It is important to mention that the
abnormal development of AGD induced by
genistein showed a non-linear dose response;
genistein at low-dose exerted a greater effect than
the high dose. This non-monotonic pattern has
been reported in other studies of endocrine
disrupting chemicals, such as bisphenol A and
diethylstilbestrol (31), and it is proposed that high
doses of EDCs can induce toxicity, whereas low
doses often show increased bioactivity32. These
data suggest that puberty is a sensitive endpoint
upon which perinatal phytoestrogens may exert
their effects with a relatively long latency.
CANCER
The anti-carcinogenic potential of phyto-
estrogens on the risk for various cancers,
especially of the breast, has been evaluated in
several studies. Despite this, no clear consensus
has emerged regarding the preventive action of
phytoestrogens against cancer. Experimental
studies support the human observations that
timing of exposure may be a critical factor in
determining the effects of phytoestrogens. For
example, isoflavones found in soy products have
been generally thought to confer reduced breast
cancer risk33. However, experimental evidence
from other studies in rats and mice provides
support for the view that phytoestrogens may
negatively affect breast cells. Genistein
administration in rats during gestation resulted in
a dose-dependent increase in mammary tumor
susceptibility in the F1 animal34, and a significant
increase in mammary tumor weight and volume,
and lung metastases were observed in female rats
receiving soy-isoflavones35. Genistein at low
concentration stimulated cell growth in mammary
epithelia cells (MCF-7)36. Dietary genistein
stimulated growth of estrogen-dependent breast-
cancer tumors37,38, and also negated the inhibitory
effect of tamoxifen on growth of estrogen-

858 S. BAR-EL DADON AND R. REIFEN
JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM
dependent human breast cancer (MCF-7) cells
implanted in athymic mice39. A recent study by
Taxvig et al. found that a mixture of phyto-
estrogens increased estradiol production and
decreased testosterone production in H295R
human adrenal corticocarcinoma cells, indicating
an induced aromatase activity40. In addition,
various mixtures of phytoestrogens significantly
stimulated MCF-7 human breast adenocarcinoma
cell growth and induced aromatase activity in
JEG-3 choriocarcinoma cells. Overall, their
results indicate that nutrition-relevant concentra-
tions of phytoestrogens possess various endocrine
disrupting effects. In humans, findings from
epidemiological studies of isoflavone intake and
breast cancer risk are equivocal. However, most
studies suggest that soy consumption is not
associated with a reduced breast cancer risk41-43.
Moreover, soy supplementation might also
increase the proliferation rate of cells in breast
biopsies of premenopausal women44. Overall,
epidemiologic and clinical data support the view
that lifetime exposure to estrogens has significant
influence on increased breast cancer risk45. As for
phytoestrogens, studies suggest that both
proliferative and antiproliferative effects are
observed, depending on tumor cell type, dose,
timing of phytoestrogen exposure, and phyto-
estrogen given. This may be because phyto-
estrogens can act via multiple mechanisms of
action, both estrogen-receptor mediated and non-
receptor mediated, and compounds like genistein
have been shown to possess both estrogenic and
antiestrogenic properties. This raises the question
of whether foods rich in phytoestrogens may have
complex actions in such diseases as breast cancer,
exerting both preventive and promoting effects
and perhaps depending on whether or not the
tumor is estrogen dependent. Thus, caution is
necessary in promoting the beneficial effects of
phytoestrogens, in particular with respect to
breast cancer.
THE PERINATAL PERIOD
The most disquieting aspect of misuse of soy
is in the perinatal period, mostly in infant foods.
Approximately one million American infants
ingest large doses of phytoestrogens in soy-based
formula every year. Total isoflavone concentra-
tions in soy-based infant formulas were found to
be much higher than the isoflavone concen-
trations in human breast milk and cow's milk-
based infant formulas, which were negligible46,47.
Circulating plasma concentrations of isoflavones
in 4-month-old infants fed exclusively soy-based
formula were found to be 13,000 to 22,000 times
higher than plasma estradiol concentration in
early life48. Therefore it is hard to believe that
soy-derived isoflavones, circulating at these
enormous concentrations, are biologically inert in
infants. To date, there is very little research on the
effects of soy consumption by infants. Therefore,
it is only logical to take a precautionary approach
in cases where there are potential adverse effects
due to soy consumption.
Data on the effect of exposure to
phytoestrogens on puberty in humans is in-
sufficient. A recent study by Zung et al. reports a
higher prevalence of breast buds during the
second year of life in female infants fed with soy-
based formulas, possibly due to the estrogenic
effect of the isoflavones in soy49. Similar studies
in neonates and children are lacking.
The relationship between early life exposures
to EDCs and functioning in adult life is poorly
understood. The period of highest susceptibility
to adverse effects from environmental exposure is
in utero. Other important critical development
stages include lactation, adolescence and
senescence. The critical period represents a
developmental window during which endocrine
signals can program genes, which regulate the
functioning of a tissue. If proper programming
fails to occur during this time, structural or
functional abnormalities can result. Therefore, it
is essential to study exposure at each stage rather
than to extrapolate risk associated with
developmental exposure based on data from
adults.
GEOGRAPHY AND SOY
The difference in cancer risk in Asian vs.
Western populations should also be addressed.
Asian men consume 5–10 times more

SOY AS ENDOCRINE DISRUPTOR: CAUSE FOR CAUTION? 859
VOLUME 23, NO. 9, 2010
phytoestrogens than Western men, and exhibit
low rates of incidence and mortality of breast,
prostate and colorectal cancers33,50. Some studies
suggest that lifestyle and diets are the two main
causes of these differences. However, there may
be other factors that could make Western men
more susceptible to phytoestrogens. The long
term exposure of the east Asian population to
soy-based foods has probably resulted in an array
of adaptations at the population level, namely in
different allelic repertoire compared with
European or North American human populations.
Such likely adaptations could be reduced
sensitivity to different phytochemicals, and
different patterns of receptors to phytochemicals,
governed by the respective alleles.
SUMMARY
Human exposure to environmental estrogens
has increased tremendously over the past 20
years. Estrogenic compounds are abundant in
both agricultural and industrial products as well
as increased consumption of nutritional
supplements containing soya.
Several studies, mostly in animals, denote that
soy products, and specifically through phyto-
estrogens, have a beneficial effect on health,
including breast cancer and improved metabolic
parameters. However, data from human studies
do not support these findings, and often
contradict them, indicating that phytoestrogens
could potentially be hazardous to human health.
Phytoestrogens, as an endocrinal disruptor,
probably have a much broader impact which goes
beyond identifying the effects of one substance.
One should consider the possible additive,
antagonistic or synergistic activity of simul-
taneous exposure to various agents, as industrial
contaminants and pharmaceutical estrogens,
which may synergistically affect health.
The putative physiological effects of phyto-
estrogens have created a market that has been
utilized by the food industry as a cheap ingredient
in an array of products. The public perceives soy
as a natural product and hence has a positive
attitude towards it and is unaware of the potential
cellular and molecular targets common with
synthetic EDCs, which have been proved to be of
concern. Future efforts in the study of
phytoestrogens need more focus on timing,
frequency and duration of exposure to these
compounds. Studies undertaken in uncontrolled
situations or done retrospectively should be
replaced with prospective controlled studies.
Until the effect of soy is thoroughly investigated,
soy should be consumed with caution, especially
during the perinatal period but also in the adult
population.
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