494 | AUGUST 2013 | VOLUME 9
Although genome-wide association studies
have identified numerous loci associated
with obesity, their total contribution to vari-
ation in BMI and body weight is estimated
to be <2%, suggesting that environmental
influences such as exposure to obesogens
during critical periods of development
are more important than genetic factors.1
Obesogens are chemicals that promote
obesity by increasing the number of fat cells
or promoting the storage of fat into exist-
ing cells. Obesogens can act indirectly by
changing the basal metabolic rate, shift-
ing the energy balance to favour increased
calorie storage, or altering hormonal
control of appetite and satiety.2–7 Several
obesogenic chemicals have been identified.
Estrogenic compounds such as diethyl-
stilbestrol8 and bisphenol A,9,10 organotins
such as tributyltin (Box 1),11 and perfluoro-
octanoates12 are obesogenic in animals.
Exposure to phthalates is correlated with
increased waist diameter,13,14 and high levels
of several persistent organic pollutants (for
example, polybrominated diphenylethers)
have been linked with obesity in humans.15
In this Perspectives, we examine the
growing evidence linking an increased intake
of fructose, especially during fetal develop-
ment, the neonatal period and infancy,
with altered metabolism and early obesity.
Furthermore, we discuss the evidence to
suggest that dietary fructose exposure has
increased in the past two gener ations and
that high fructose exposure during critical
developmental periods might have a key role
in the development of adult obesity.
Dietary sugars and obesity
Strong and consistent evidence supports a
link between high intakes of dietary sugars
and obesity in children.16–19 However, most
of these studies have not differentiated
between the effects of different sugars.
The limited number of studies that have
been conducted in infants and young chil-
dren suggest that this strong association is
present even in early life. In a retrospective
cohort study, analysis of data from 10,904
children aged 2–3 years showed that those
who consumed sugar-sweetened bever-
ages (SSB; defined as any drink sweetened
with glucose, sucrose, fructose or high-
fructose corn syrup [HFCS]) had a twofold
increased probability of becoming over-
weight compared with children who did
not consume such beverages.20 Our research
group examined 1,483 Hispanic children
from low-income families and showed
that any consumption of SSB at 2–4 years
was strongly associated with obesity.21
Consumption of SSB was defined as high
(≥2 servings daily), medium (1 serving
daily) or none. We found striking differ-
ences in the prevalence of obesity (defined
as a BMI >95th percentile for age). In chil-
dren who were not breastfed at all or were
breastfed for <1 year, SSB consumption had
a strong effect: the prevalence of obesity was
~23% among toddlers with high consump-
tion of SSB, versus ~14% in children who
did not consume any SSB. When breast-
feeding was sustained for >12 months, SSB
c onsumption had no effect on obesity.
Considerably more data are available for
children aged >4 years. A meta-analysis of
12 studies in children and adolescents, pub-
lished in 2008, found a near-zero effect of
SSB consumption on obesity,22 although
this conclusion was later challenged by
another group that reanalysed the same
data and found a clear association between
SSB consumption and obesity.23 In a longi-
tudinal study, 196 prepubertal girls, aged
8–12 years, were followed up until 4 years
after menarche.16 Among all the categories
of energy-dense food and drink consid-
ered (baked goods, ice cream, chips, sugar-
sweetened soda and candy), consumption of
SSB was the only factor that was linked to
BMI z-score over the 10-year study period.
The percentage of body fat, however, was not
associated with consumption of any type (or
with overall consumption) of energy-dense
foods or drinks.16
Increased fructose consumption
In determining the potential link between
dietary sugar intake and obesity, it is
The obesogenic effect of high fructose
exposure during early development
Michael I. Goran, Kelly Dumke, Sebastien G. Bouret, Brandon Kayser,
Ryan W. Walker and Bruce Blumberg
Abstract | Obesogens are compounds that disrupt the function and development
of adipose tissue or the normal metabolism of lipids, leading to an increased risk of
obesity and associated diseases. Evidence for the adverse effects of industrial and
agricultural obesogens, such as tributyltin, bisphenol A and other organic pollutants
is well-established. Current evidence suggests that high maternal consumption of fat
promotes obesity and increased metabolic risk in offspring, but less is known about
the effects of other potential nutrient obesogens. Widespread increase in dietary
fructose consumption over the past 30 years is associated with chronic metabolic and
endocrine disorders and alterations in feeding behaviour that promote obesity. In this
Perspectives, we examine the evidence linking high intakes of fructose with altered
metabolism and early obesity. We review the evidence suggesting that high fructose
exposure during critical periods of development of the fetus, neonate and infant can act
as an obesogen by affecting lifelong neuroendocrine function, appetite control, feeding
behaviour, adipogenesis, fat distribution and metabolic systems. These changes
ultimately favour the long-term development of obesity and associated metabolic risk.
Goran, M. I. et al. Nat. Rev. Endocrinol. 9, 494–500 (2013); published online 4 June 2013;
B. Blumberg declares that he is a named inventor
on the following US patents: 5,861,274;
6,200,802; 6,815,168; and 7,250,273. See the
article online for full details of the relationship.
The other authors declare no competing interests.
© 2013 Macmillan Publishers Limited. All rights reserved
NATURE REVIEWS | ENDOCRINOLOGY
VOLUME 9 | AUGUST 2013 | 495
important to appreciate the shifts in dietary
sugar consumption. A study conducted in
2–18-year-old individuals, using National
Health and Nutrition Examination Survey
data, showed that nearly 40% of their total
energy consumption consisted of calories
from solid fats and added sugars. About
half of this 40% came from six sources:
soda, fruit drinks, dairy desserts, grain des-
serts, pizza and whole milk.24 These epi-
demiological observations are of particular
concern given the increasing use of HFCS
in commercial food and beverage produc-
tion. HFCS is a highly processed sweetener
derived from maize, in which the glucose
from cornstarch is chemically converted
to fructose.25 HFCS was introduced into
the US food supply in the 1970s, and its
consumption increased dramatically over
the ensuing years, plateauing around the
year 2000. This shift probably accounts
for the reported increase of 10–20% in the
amount of fructose consumed by children
between 1977 and 2004.26 In an ecological
analysis that looked at changes in diet and
in the prevalence of type 2 diabetes melli-
tus (T2DM) in the USA between 1900 and
1997, increased consumption of HFCS
from the 1970s onwards was identified as
the primary nutritional factor associated
with the increase in prevalence of T2DM.27
Our research group published an updated
global ecological analysis in 2013, which
showed that countries including HFCS in
their food supply had a 20% higher national
preva lence of T2DM than countries that did
not include HFCS in the food supply.28
A major difference between HFCS and
sucrose is that HFCS is composed of free
fructose and free glucose mono saccharides,
whereas in sucrose, a glycosidic bond joins
the fructose and glucose molecules. An
important remaining question is whether
the presence or absence of this glycosidic
bond influences the subsequent diges-
tion and metabolism of these sugars; for
example, free fructose might be more
rapidly metabolized than the fructose con-
tained in sucrose. In fact, one study showed
that the consumption of free fructose had
more detrimental effects (on fasting glucose
levels, weight gain and fat mass) than the
consumption of sucrose.29 Perhaps even
more importantly, the actual levels of fruc-
tose in foods and beverages made with
HFCS are not entirely clear. A common
assumption is that sucrose and HFCS
contain similar amounts of free fructose
because they have a similar fructose:glucose
ratio (50:50 in sucrose versus 55:40 in
HFCS-55, the most commonly used form
of HFCS).30 However, 55% of HFCS-55
consists of fructose, another 40% is glucose
and the remaining 5% is other sugars, pre-
dominantly maltose and maltotriose. Thus,
HFCS-55 contains 10% more fructose than
sucrose does, and foods and beverages
made with HFCS-55 contain 10% more
fructose than they would if they were made
Moreover, HFCS can be blended to
increase the fructose content. In a study
from 2011, our group measured the sugar
composition of popular SSBs and found
that in most beverages fructose accounted
for >55% of the sugar content, and reached
65% in the three most popular carbonated
beverages.31 A HFCS fructose:glucose ratio
of 65:35 (approaching 2:1) is equivalent to
these drinks containing 30% more fructose
than if they were made with sucrose alone.
Our initial analysis was limited to popular
beverages and we have not yet investigated
the possibility that higher than expected
levels of fructose also occur in other pro-
cessed foods made with HFCS, including
breads, yogurts, cookies, breakfast cereals
and other beverages (such as fruit juices)
that contain naturally high levels of fruc-
tose. Thus, with the ubiquitous presence of
HFCS in our food supply and the increased
consumption of fruit juices by infants and
children, along with the unknown fructose
content of commercially prepared foods and
beverages, the actual level of fructose con-
sumption in the population might be higher
than predicted on the basis of common
assumptions regarding HFCS composi-
tion. However, even given these limitations,
the most recent data available (1977–2004)
on population levels of fructose consump-
tion indicate that infants and children have
the highest levels of fructose consumption
when normalized to body weight.26
Obesogenic effects of fructose
Feeding studies in humans
A growing body of evidence supports
the hypothesis that the adverse effects of
sugar intake on obesity and metabolic risk
are largely driven by fructose rather than
glucose.32–36 For example, several studies
show that fructose (owing to its high lipo-
genic potential) is a major contributor to
excess liver fat deposition. In one study, 47
overweight persons were randomly assigned
to drink 1 litre daily of cola, milk (contain-
ing the same amount of calories as the cola),
sugar-free cola or water.37 The total fat mass
was not altered across the groups after
6 months, but the cola group had a signifi-
cant increase in liver fat (~35%) as well as
increased visceral adipose tissue (~25%)
and triglycerides (32%). In a crossover
study, 16 boys who had at least one parent
with T2DM and eight boys matched for age,
BMI and total body fat received 7 days of
two different diets: an isocaloric diet con-
taining 55% carbohydrate, 30% fat, and 15%
protein, or a hypercaloric diet (the same
diet supplemented with fructose to achieve
a 35% increase in daily energy intake).38
Compared with the isocaloric diet, the
high-fructose diet increased liver fat by 76%
Box 1 | Obesogenic effects of organotins
The organotins tributyltin and triphenyltin are the only obesogens with a known pathway of
action. Both compounds are nanomolar-affinity ligands for two nuclear receptors that are
critical for adipocyte development: 9-cis retinoic acid receptor α (RXR-α) and peroxisome
proliferator activated receptor γ (PPAR-γ).11,93 Current evidence suggests that these compounds
act as obesogens through altering the regulation of adipose tissue development, and that the
effects of these changes are inheritable.
Effects of tributyltin in mice
Promotion of adipocytogenesis in mouse 3T3-L1 preadipocytes11,93 and human and mouse
multipotent MSCs, via a PPAR-γ-dependent pathway94,95
Prenatal exposure (a single maternal oral dose) resulted in increased fat deposition in offspring
at birth, increased adipose depot size in adults and increased expression of adipogenic markers94
Prenatal exposure also influenced the differentiation of MSCs toward the development of new
fat cells at the expense of bone11,94
The effects of prenatal exposure on fat mass, adipocyte size and multipotent MSC gene
expression profiles were heritable through at least three generations, suggesting that the
effects are permanent96
Sources of human organotin exposure97,98
Dietary (seafood and shellfish)
Fungicides and miticides (on food crops, in wood treatments, industrial water systems and textiles)
Leaching from organotin-stabilized plastics (including water pipes and food wrapping*)
*Tributyltin is a contaminant in plastics rather than an intentionally added component. Abbreviation: MSCs,
mesenchymal stem cells.
© 2013 Macmillan Publishers Limited. All rights reserved
496 | AUGUST 2013 | VOLUME 9
in controls and by 79% in the boys whose
parents had T2DM.38 The increase in liver
fat was similar in T2DM offspring and con-
trols, hence independent of T2DM status.
Persons with overweight or obesity who
consumed beverages sweetened with either
glucose or fructose for 10 weeks, in amounts
supplying 25% of their daily energy require-
ments, have been examined under closely
controlled conditions.39 Despite similar
weight gain in the two groups, the fructose
group had significant increases in visceral
adipose tissue mass (14% versus 3%) and
in hepatic de novo lipogenesis (75% versus
27%). The adverse effects of fructose have
also been suggested to relate to the meta-
bolic effects of uric acid, a by-product of
fructose metabolism in the liver.40 A study
in 2,727 teenagers showed that individuals
who consumed high amounts of HFCS-rich
beverages had significantly elevated levels of
circulating uric acid compared with those
who did not drink such beverages.41
Despite numerous findings support-
ing an obesogenic role for HFCS, other
researchers have disputed the view that
consumption of fructose is more meta-
bolically damaging than glucose, and
have suggested that the published studies
involved supra physiological levels of fruc-
tose ingestion.42–44 In 2012, however, a study
in healthy men showed that consumption
of moderate amounts of fructose over
3 weeks had worse adverse effects on insulin
sensitivity than c onsumption of equivalent
amounts of glucose.45
Feeding studies in rodents
Rigorous pair-feeding studies in rodent
models have also demonstrated that excess
fructose consumption induces metabolic
changes independent of increased adiposity.
Compared to rats fed a high-starch diet, rats
fed a diet containing 68% of total calories as
sucrose develop hepatic insulin resistance
after as little as 1 week, and muscle insulin
resistance by 2 weeks, as assessed by the
These impairments in insulin sensitiv-
ity were accompanied by hypertriglyceri-
daemia and increased hepatic triglyceride
content.46 Other studies showed that the
fructose moiety, rather than the glucose,
confers this sucrose-induced insulin resis-
tance.47 Diets containing 68% of calories
as sucrose far exceed the levels that occur
human consumption, but rodent chow
containing only 18% of calories as sucrose
also induces insulin resistance, primarily in
However, not all studies in rodents have
demonstrated deleterious effects of excess
fructose consumption. For example, in
one study, neither high sucrose49 nor high
fructose50 consumption led to increases in
body weight, total body fat or regional adi-
posity, nor did high sucrose consumption
cause insulin resistance in weaned male51
or in adult female rats.52 Ad libitum access
to fructose-containing diets does not neces-
sarily increase body weight in rodents, but
it consistently increases fat mass. Mature
male rats gained more weight when given
solutions composed of 32% fructose or 32%
sucrose than when given a solution of
32% glucose, although all three solutions
increased retroperitoneal fat pad weights
compared to controls fed the same chow
and given plain water.53 Weanling rats, on
the other hand, failed to gain more weight
when given a 32% sucrose solution, despite
an energy intake greater than age-matched
controls given water.54 However, sucrose
feeding did increase fat mass in young rats
by postnatal day 46 and, by postnatal day 70,
had resulted in approximately 50% greater
wet-carcass fat mass compared to control
rats on a standard diet.55
The effects of HFCS or HFCS-like solu-
tions (that is, solutions with a high fructose
content or high levels of free monosaccha-
rides, respectively) have also been compared
to the effects of sucrose. When mice were
given solutions containing 15% of fructose,
sucrose-sweetened soda or artificially sweet-
ened diet soda, the fructose solution was the
only one that resulted in increased body-
weight and hepatic steatosis.56 In another
study, dark-cycle ad libitum access to HFCS-
sweetened water for 8 weeks increased body
weight of male rats, whereas identical access
to a sucrose solution did not increase body
weight above that of control animals fed the
same chow and plain water.57 Unfortunately,
differences in body composition were not
assessed in this study.
Effects of fructose in the brain
Evidence from both human studies and
animal models also support the notion that
fructose and glucose have different effects
in the brain, such that consumption of fruc-
tose promotes food intake and obesity. In
a well-controlled human study, changes in
appetite- related hormone levels over 24 h
were examined in response to meals con-
taining either glucose or fructose.58 Levels
of insulin and leptin were significantly
lower after the fructose meal than after the
glucose meal, and fructose failed to suppress
post-meal ghrelin levels as effectively as
glucose, which suggests that consumption
of fructose could disrupt energy balance
signalling to the brain and result in excess
energy consumption and obesity.58
One study compared the effects of fruc-
tose and glucose in the human brain using
functional MRI.59 This study showed that
in nine healthy, lean adults, fructose and
glucose had similar effects on hypo thalamic
activity, whereas the cortical response
was increased in response to glucose and
decreased in response to fructose.59 In this
study, however, the doses of glucose and
fructose were relatively small (~20–25 g,
depending on body weight), and the sugar
solution was infused intravenously. In
another imaging study, regional cerebral
blood flow (a marker of neuronal activation)
was assessed in response to oral consump-
tion of either fructose or glucose.60 In a ran-
domized, blinded, crossover imaging study,
20 healthy, nonobese, primarily white vol-
unteers underwent MRI and blood sampling
60 min after ingestion of a drink containing
75 g of either fructose or glucose. Neuronal
activation was significantly increased in
the hypothalamus, orbitofrontal cortex and
ventral striatum after ingestion of fructose,
compared to activation levels after glucose
ingestion. This study provides further evi-
dence that fructose and glucose have dif-
ferential effects on brain regions involved in
In animal studies, direct administra-
tion of either fructose or glucose into the
brain has opposing effects on obesity and
food intake regulation.61 Essentially, these
studies show that fructose metabolism in
the brain is poorly controlled and rapidly
depletes hypothalamic ATP, whereas
glucose metabo lism is closely regulated
and increases ATP levels in the hypothala-
mus. Consequently, ingestion of fructose
leads to a reduction in malonyl coenzyme
A in the brain, a factor known to contrib-
ute to increased food intake.61 In another
study, rats fed a very high fructose diet for
6 months demon strated leptin resistance
and reduced hypothalamic phosphory-
lation of STAT3 (a downstream component
of the leptin receptor signalling cascade).
The leptin-resistant animals gained more
weight and had greater fat pad weights than
control animals when they were switched to
a high-fat diet for 2 weeks.50
Fructose-mediated induction of leptin
resistance would be particularly relevant
during both the fetal and neonatal period;
our group has shown that leptin is a key
© 2013 Macmillan Publishers Limited. All rights reserved
NATURE REVIEWS | ENDOCRINOLOGY
VOLUME 9 | AUGUST 2013 | 497
neurotrophic factor for the developing
hypothalamus.62 Leptin resistance during
this critical period could impair energy
balance throughout life.63,64
The role of maternal nutrition
Growing evidence supports a link between
maternal nutrition and obesity in offspring.
Studies in pregnant female primates indi-
cate that maternal nutrition during critical
developmental periods in gestation might
alter the development of fetal metabolic
systems.65 Fetuses from lean and obese
mothers (both fed a high-fat diet) had a
threefold increase in liver triglyceride levels,
increased hepatic oxidative stress, increased
serum triglycerides and a twofold increase
in body fat, consistent with the develop-
ment of nonalcoholic fatty liver disease.65
These adverse effects of excess maternal fat
consumption during pregnancy might be
due to the fact that fetuses of most species
lack white adipose tissue until late in preg-
nancy (in humans, typically until the third
trimester). White adipose tissue is criti-
cal for the storage of excess lipids, and the
results of studies of maternal obesity and
hyperglycaemia in humans suggest that
this fetal lack of structurally or function-
ally sufficient adipose tissue depots leads
to ectopic lipid storage under conditions of
high maternal fat consumption.66,67 In turn,
this excess lipid storage induces whole-
body insulin resistance and susceptibility
to fatty liver disease in adulthood.66,67 Other
studies in humans suggest that altered
maternal nutrition during critical develop-
mental periods, including pregnancy and
lactation, might predispose offspring to
long-term metabolic, neuroendocrine and
Fructose exposure during development
The deleterious effects of excess fructose
consumption in adults are well researched,
but limited data are available on the long-
term effects of high fructose exposure
during gestation, lactation and infancy.
These periods are, however, critically impor-
tant in determining an individual’s lifelong
health. Emerging research suggests that
fructose consumption by both mothers and
their offspring during these stages of early
life can lead to persistent neuroendocrine
and metabolic dysfunction.
Appetite, energy balance and metabolism
are regulated by the central nervous system
and the important components include
neurons located in the arcuate nucleus of the
hypothalamus. The hypothalamus primarily
regulates the homeostatic drive to eat,
whereas other regions (such as the ventral
striatum, insula, amygdala and hippo-
campus) include a behavioural pathway
that controls the hedonic drive to eat.70
The regions that control homeostatic and
hedonic feeding are tightly interconnected
and form an integrated network that dictates
overall feeding behaviour. This network is
activated during hunger, and its activity nor-
mally decreases in response to food intake.70
The hypothalamus undergoes tremendous
growth from early gestation, which con-
tinues during the postnatal period. These
developmental windows represent periods
of vulnerability during which alterations in
the environment can perturb hypothalamic
development and subsequent function.
Fructose exposure during critical develop-
ment periods has been examined by feeding
lactating rats either tap water or a 10%
fructose solution in addition to their chow,
starting on postnatal day 1.71 The offspring
of fructose-fed rats showed increased body
weight, decreased hypothalamic sensitivity
to exogenous leptin, increased food intake,
insulin resistance and increased retro-
peritoneal adipose tissue (with an increase
in both fat mass and adipo cyte size).71
Additional studies have further elucidated
the effects of the fructose moiety during
these critical develop ment periods by
compara tive analyses of experiments using
different sugar concen trations. In one study,
female rats were fed ad libitum diets con-
taining either 40% fructose or 50% sucrose
during gestation and lactation.72 Control
animals received the same ad libitum diet
without additional sugars. During gesta-
tion, the fructose-fed rats developed elevated
levels of circulating glucose and triglycerides,
and their offspring were hyperglycaemic at
birth.72 Further investigation revealed that
only the fructose-fed rats and their offspring
had hyperglycaemia during pregnancy and
after birth, respectively,72 suggesting that a
possible mechanism underlying the develop-
ment of hyperglycaemia in these two groups
might be the increased concentration of the
fructose moiety in the 40% fructose diet. In
another study, female rats were randomly
assigned to 8 weeks of deionized distilled
water or deionized distilled water sweet-
ened with 13% of glucose, sucrose, fructose
or HFCS-55.73 The 13% value was selected
to reflect the concentrations of these sugars
typically found in the human diet. No differ-
ence was found in energy intake between
the rats given plain water and those given
sweetened water. However, the type of sugar
influenced body fat mass, as only HFCS-55
Additional studies in rats fed a diet con-
taining either 10% fructose or 10% glucose
showed that fructose-fed dams ate more food
and drank less water than dams fed glucose.74
Moreover, the offspring of fructose- fed dams
had almost double the fasting insulin levels
at weaning compared with the offspring of
glucose-fed dams.74 However, in another
study, the offspring of fructose-fed dams
showed increased plasma leptin and plasma
glucose levels but had no change in insulin
levels.75 Furthermore, one study has exam-
ined the effect of a diet containing fructose
on successive generations. Female rats were
weaned onto a diet containing either starch
(no fructose) or sucrose (50% fructose
and 50% glucose), and the same diet was
maintained through successive generations
bred from these dams. The first-generation
offspring born to sucrose-fed dams were
heavier, had more body fat and higher cir-
culating glucose and t riglyceride levels than
rats born to starch-fed dams.76
Other studies have focused on under-
standing the effect of maternal nutrition
on the development of taste preferences
(termed nutrient conditioning) in their off-
spring. Human studies showed that mater-
nal intakes of protein, fat and carbohydrates
during pregnancy were associated with
their children’s intakes of these nutrients at
10 years of age.77 Rodent studies show that
a preference for sweet flavours can develop
before weaning, suggesting that nutrient
conditioning is transmitted through breast
milk.78 Furthermore, 10-week old rat pups
whose dams were fed a diet containing high
levels of fat, sugar and salt (as found in ‘junk
food’) during gestation and lactation showed
a greater preference for fatty, sugary and
salty foods than pups whose mothers were
fed a balanced chow diet.79 Further experi-
ments revealed that offspring of dams fed
the junk-food diet during gestation and lac-
tation developed more obesity, greater eleva-
tions in glucose and insulin levels and had
an increased risk of fatty liver disease, as well
as signs of steatosis and liver damage, when
given free access to the same junk-food diet,
compared with rats whose mothers had a
normal chow diet.80
Potential obesogenic mechanisms
In this Perspectives, we propose a novel
hypothesis that high levels of fructose in
beverages, fruit juices, infant food and pro-
cessed foods can act as an obesogen when
ingested during critical perinatal periods
© 2013 Macmillan Publishers Limited. All rights reserved
498 | AUGUST 2013 | VOLUME 9
of adipose tissue and brain development.
Several potential mechanisms could explain
the adverse effects of high fructose exposure
during these periods. From an evolution-
ary perspective, infants would not typi-
cally be exposed to high levels of fructose,
given that the main sugar in breast-milk is
lactose (a disaccharide consisting of glucose
bound to galactose). Although 30 or more
oligosaccharides are also present in breast-
milk, fructose is not a natural component of
human breast-milk.81 However, no study has
yet investigated whether fructose is present
in human breast-milk from mothers who
eat high levels of this sugar. Under normal
conditions, the abundance of mRNAs
encoding the sugar transporters SLC5A1,
GLUT-2 and GLUT-5 is developmentally
modulated, with higher levels in adult than
in fetal intestines. Moreover, immunohisto-
chemical analysis showed that the fructose
transporter GLUT-5 was expressed on the
luminal surface of mature enterocytes in
adult intestine, whereas in fetal intestine,
expression of GLUT-5 occurred only along
the inter cellular junctions in developing
villi.82 These observations suggest that the
mechanism of fructose absorption may
not be fully or even partially function-
ing during gestation and early life. Lack of
functional fructose transport could be pro-
tective, because an infant might not have the
ability to absorb dietary fructose. However,
in rat models, a high-fructose diet,83 as well
as hyper glycaemia and T2DM, upregu-
late expression of Slc2a5 (which encodes
GLUT-5) in the intestine.84,85 Whether this
upregulation of GLUT-5 occurs during
fetal development or infancy is unknown,
but fructose does cross the placenta, and
infants can be exposed to fructose either by
direct consumption or through breast-milk.
Studies in humans revealed a higher fructose
concentration in fetal blood than in mater-
nal blood, showing that the human placenta
actively transfers fructose to the fetal circu-
lation.86,87 Thus, fetal and infantile exposure
to fructose, through placental transmission,
breast feeding or direct consumption, is pos-
sible and would have detrimental metabolic
effects on the fetal and infant metabolism.
We hypothesize that fructose directly
p romotes adipogenesis during critical
periods of adipose tissue development.
A study from 2012 showed that fructose
induced adipocyte differentiation in 3T3–L1
preadipocytes, and that Slc2a5–/– mice (which
lack uptake of fructose) had a dramatic
reduction in epididymal fat mass compared
with wild-type controls.88 In our opinion,
a high fructose intake during develop ment
could also promote obesity by disrupt-
ing neuroendocrine signalling between
adipose tissue and the hypothalamus. The
arcuate nucleus of the hypothalamus con-
tains neurons that respond to various circu-
lating factors, including glucose, insulin
and leptin.89 By acting on the arcuate
nucleus, leptin conveys the level of adiposity
to the brain, thereby regulating both energy
expenditure and food intake.90 Our research
group has shown that leptin acts as a critical
growth factor connecting the arcuate nucleus
to other hypothalamic nuclei during brain
development in mice.62 However, as fructose
does not stimulate leptin release, an imbal-
ance in fetal exposure to fructose and glucose
could potentially limit the effects of leptin on
these important brain development path-
ways. Indeed, other studies have shown that
prenatal or early-life overnutrition leads to
hypothalamic leptin insensitivity, impaired
signalling via phosphorylated STAT3 and
obesity in adulthood.91,92 Collectively, the
evidence supports the concept that expo-
sure to high levels of fructose during criti-
cal periods of development could promote
obesity by several mechanisms: direct effects
of fructose on adipose tissue; direct or
in direct actions of fructose on the develop-
ing hypothalamus; and by disrupting neuro-
endocrine signalling between adipose tissue
and the h ypothalamus (Figure 1).
Evidence from human and animal studies
suggests that the link between dietary
sugars and obesity is probably driven by
the metabolic effects of fructose. Fructose
has a unique metabolic fate that favours the
development of obesity and, so far, no data
suggest that the developing fetus, neonate
or infant would be protected from these
well-known adverse effects. Thus, exposure
to fructose, which is not a natural com-
ponent of an infant’s diet, in conjunction
with the active transport of fructose across
the placental barrier, probably increases the
propensity of fructose to cause metabolic
and developmental dysfunction. Further
investigations are required to determine the
effects of high levels of fructose consump-
tion during critical periods of gestation,
l actation and infancy.
Department of Preventive Medicine and
Childhood Obesity Research Centre, University
of Southern California, 2250 Alcazar Street,
Los Angeles, CA 90089, USA (M. I. Goran,
K. Dumke, B. Kayser, R. W. Walker).
The Saban Research Institute, Developmental
Neuroscience Program, Children’s Hospital
of Los Angeles, 4650 Sunset Boulevard,
MS#135, Los Angeles, CA 90027, USA
(S. G. Bouret). Departments of Developmental
& Cell Biology and Pharmaceutical Sciences,
2011 Biological Sciences 3, University of
California at Irvine, Irvine, CA 92697, USA
Correspondence to: M. I. Goran
High fructose intake
and/or breast feeding
in regulation of
and fat mass
Figure 1 | Links between obesity and fructose exposure during critical developmental periods.
High levels of exposure to fructose during gestation and infancy influence the development of
adipose tissue, hypothalamic signalling and appetite regulation. In turn, these changes promote
long-term obesity, metabolic dysfunction and disease.
© 2013 Macmillan Publishers Limited. All rights reserved
NATURE REVIEWS | ENDOCRINOLOGY
VOLUME 9 | AUGUST 2013 | 499
1. Loos, R. J. Recent progress in the genetics of
common obesity. Br. J. Clin. Pharmacol. 68,
Blumberg, B. Obesogens, stem cells and the
maternal programming of obesity. J. Dev. Orig.
Health Dis. 2, 3–8 (2011).
Janesick, A. & Blumberg, B. in Obesity before
birth Vol. 30 Ch. 19 (ed. Lustig, R. H.) 383–399
Janesick, A. & Blumberg, B. Endocrine
disrupting chemicals and the developmental
programming of adipogenesis and obesity. Birth
Defects Res. C. Embryo Today 93, 34–50 (2011).
La Merrill, M. & Birnbaum, L. S. Childhood
obesity and environmental chemicals. Mt Sinai
J. Med. 78, 2–48 (2011).
Heindel, J. J. in Obesity before birth Vol. 30
Ch. 17 (ed. Lustig, R. H.) 355–366
Newbold, R. R. in Obesity before birth Vol. 30
Ch. 18 (ed. Lustig, R. H.) 367–382
Newbold, R. R., Padilla-Banks, E. &
Jefferson, W. N. Environmental oestrogens and
obesity. Mol. Cell. Endocrinol. 304, 84–89 (2009).
Rubin, B. S., Murray, M. K., Damassa, D. A.,
King, J. C. & Soto, A. M. Perinatal exposure to
low doses of bisphenol A affects body weight,
patterns of estrous cyclicity, and plasma LH
levels. Environ. Health Perspect. 109, 675–80
10. Rubin, B. S. Bisphenol A: an endocrine disruptor
with widespread exposure and multiple effects.
J. Steroid Biochem. Mol. Biol. 127, 27–34 (2011).
11. Grün, F. et al. Endocrine-disrupting organotin
compounds are potent inducers of
adipogenesis in vertebrates. Mol. Endocrinol.
20, 2141–2155 (2006).
12. Hines, E. P . et al. Phenotypic dichotomy
following developmental exposure to
perfluorooctanoic acid (PFOA) in female CD-1
mice: low doses induce elevated serum leptin
and insulin, and overweight in mid-life. Mol. Cell.
Endocrinol. 304, 97–105 (2009).
13. Stahlhut, R. W., van Wijgaarden, E., Dye, T. D.,
Cook, S. & Swan, S. H. Concentrations of
urinary phthalate metabolites are associated
with increased waist circumference and insulin
resistance in adult U.S. males. Environ. Health
Perspect. 115, 876–882 (2007).
14. Hatch, E. E. et al. Association of urinary
phthalate metabolite concentrations with body
mass index and waist circumference: a cross-
sectional study of NHANES data, 1999–2002.
Environ. Health 7, 27 (2008).
15. Tang-Peronard, J. L., Andersen, H. R.,
Jensen, T. K. & Heitmann, B. L. Endocrine-
disrupting chemicals and obesity development
in humans: a review. Obes. Rev. 12, 622–636
16. Phillips, S. M. et al. Energy-dense snack food
intake in adolescence: longitudinal relationship
to weight and fatness. Obes. Res. 12, 461–472
17. Ludwig, D. S., Peterson, K. E. &
Gortmaker, S. L. Relation between
consumption of sugar-sweetened drinks and
childhood obesity: a prospective, observational
analysis. Lancet 357, 505–508 (2001).
18. Berkey, C. S., Rockett, H. R., Field, A. E.,
Gillman, M. W. & Colditz, G. A. Sugar-added
beverages and adolescent weight change.
Obes. Res. 12, 778–788 (2004).
19. Kant, A. K. Reported consumption of
low-nutrient-density foods by American children
and adolescents: nutritional and health
correlates, NHANES III, 1988 to 1994. Arch.
Paediatr. Adolesc. Med. 157, 789–796 (2003).
20. Welsh, J. A. et al. Overweight among low-income
preschool children associated with the
consumption of sweet drinks: Missouri, 1999–
2002. Paediatrics 115, e223–e229 (2005).
21. Davis, J. N., Whalley, S. & Goran, M. I. Effects of
breastfeeding and low sugar sweetened
beverage intake on obesity prevalence in
Hispanic toddlers. Am. J. Clin. Nutr. 95, 3–8
22. Forshee, R. A., Anderson, P . A. & Storey, M. L.
Sugar-sweetened beverages and body mass
index in children and adolescents: a meta-
analysis. Am. J. Clin. Nutr. 87, 1662–1671
23. Malik, V. S., Willett, W. C. & Hu, F. B. Sugar-
sweetened beverages and BMI in children and
adolescents: reanalyses of a meta-analysis.
Am. J. Clin. Nutr. 89, 438–440 (2009).
24. Reedy, J. & Krebs-Smith, S. M. Dietary sources
of energy, solid fats, and added sugars among
children and adolescents in the United States.
J. Am. Diet. Assoc. 110, 1477–1484 (2010).
25. Marshall, R. O. & Kooi, E. R. Enzymatic
conversion of d-glucose to d-fructose. Science
125, 648–649 (1957).
26. Marriott, B. P ., Cole, N. & Lee, E. National
estimates of dietary fructose intake increased
from 1977 to 2004 in the United States.
J. Nutr. 139, 1228S–1235S (2009).
27. Gross, L. S., Li, L., Ford, E. S. & Liu, S.
Increased consumption of refined
carbohydrates and the epidemic of type 2
diabetes in the United States: an ecologic
assessment. Am. J. Clin. Nutr. 79, 774–779
28. Goran, M. I., Ulijaszek, S. J. & Ventura, E. E.
High fructose corn syrup and diabetes
prevalence: a global perspective. Glob. Public
Health 8, 55–64 (2013).
29. Le, M. T. et al. Effects of high-fructose corn
syrup and sucrose on the pharmacokinetics of
fructose and acute metabolic and
haemodynamic responses in healthy subjects.
Metabolism 61, 641–651 (2012).
30. Hanover, L. M. & White, J. S. Manufacturing,
composition, and applications of fructose.
Am. J. Clin. Nutr. 58, 724S–732S (1993).
31. Ventura, E. E., Davis, J. N. & Goran, M. I. Sugar
content of popular sweetened beverages based
on objective laboratory analysis: focus on
fructose content. Obesity (Silver Spring) 19,
32. Bray, G. A., Nielsen, S. J. & Popkin, B. M.
Consumption of high-fructose corn syrup in
beverages may play a role in the epidemic of
obesity. Am. J. Clin. Nutr. 79, 537–543 (2004).
33. Elliott, S. S., Keim, N. L., Stern, J. S., Teff, K.
& Havel, P . J. Fructose, weight gain, and the
insulin resistance syndrome. Am. J. Clin. Nutr.
76, 911–922 (2002).
34. Gaby, A. R. Adverse effects of dietary fructose.
Altern. Med. Rev. 10, 294–306 (2005).
35. Lim, J. S., Mietus-Snyder, M., Valente, A.,
Schwarz, J. M. & Lustig, R. H. The role of
fructose in the pathogenesis of NAFLD and the
metabolic syndrome. Nat. Rev. Gastroenterol.
Hepatol. 7, 251–264 (2010).
36. Lustig, R. H. Fructose: metabolic, hedonic, and
societal parallels with ethanol. J. Am. Diet.
Assoc. 110, 1307–1321 (2010).
37. Maersk, M. et al. Sucrose-sweetened
beverages increase fat storage in the liver,
muscle, and visceral fat depot: a 6-mo
randomized intervention study. Am. J. Clin. Nutr.
95, 283–289 (2012).
38. Le, K. A. et al. Fructose overconsumption
causes dyslipidemia and ectopic lipid
deposition in healthy subjects with and without
a family history of type 2 diabetes. Am. J. Clin.
Nutr. 89, 1760–1765 (2009).
39. Stanhope, K. L. et al. Consuming fructose-
sweetened, not glucose-sweetened, beverages
increases visceral adiposity and lipids and
decreases insulin sensitivity in overweight/
obese humans. J. Clin. Invest. 119, 1322–1334
40. Cox, C. L. et al. Consumption of fructose- but
not glucose-sweetened beverages for 10 weeks
increases circulating concentrations of uric
acid, retinol binding protein 4, and γ-glutamyl
transferase activity in overweight/obese
humans. Nutr. Metab. (Lond.) 9, 68 (2012).
41. Lin, W. T. et al. Effects on uric acid, body mass
index and blood pressure in adolescents of
consuming beverages sweetened with high-
fructose corn syrup. Int. J. Obes. (Lond.) 37,
42. Sievenpiper, J. L. et al. Effect of fructose on
body weight in controlled feeding trials:
a systematic review and meta-analysis.
Ann. Intern. Med. 156, 291–304 (2012).
43. Lowndes, J. et al. The effects of four hypocaloric
diets containing different levels of sucrose or
high fructose corn syrup on weight loss and
related parameters. Nutr. J. 11, 55 (2012).
44. Rippe, J. M. & Kris Etherton, P . M. Fructose,
sucrose, and high fructose corn syrup: modern
scientific findings and health implications.
Adv. Nutr. 3, 739–740 (2012).
45. Aeberli, I. et al. Moderate amounts of fructose
consumption impair insulin sensitivity in
healthy young men: a randomized controlled
trial. Diabetes Care 36, 150–156 (2013).
46. Pagliassotti, M. J., Prach, P . A.,
Koppenhafer, T. A. & Pan, D. A. Changes in
insulin action, triglycerides, and lipid
composition during sucrose feeding in rats.
Am. J. Physiol. 271, R1319–R1326 (1996).
47. Thresher, J. S., Podolin, D. A., Wei, Y.,
Mazzeo, R. S. & Pagliassotti, M. J. Comparison
of the effects of sucrose and fructose on
insulin action and glucose tolerance. Am. J.
Physiol. Regul. Integr. Comp. Physiol. 279,
48. Pagliassotti, M. J. & Prach, P . A. Quantity of
sucrose alters the tissue pattern and time
course of insulin resistance in young rats.
Am. J. Physiol. 269, R641–R646 (1995).
49. Pagliassotti, M. J., Shahrokhi, K. A. &
Moscarello, M. Involvement of liver and skeletal
muscle in sucrose-induced insulin resistance:
dose–response studies. Am. J. Physiol. 266,
50. Shapiro, A. et al. Fructose-induced leptin
resistance exacerbates weight gain in response
to subsequent high-fat feeding. Am. J. Physiol.
Regul. Integr. Comp. Physiol. 295,
51. Pagliassotti, M. J., Gayles, E. C., Podolin, D. A.,
Wei, Y. & Morin, C. L. Developmental stage
modifies diet-induced peripheral insulin
resistance in rats. Am. J. Physiol. Regul. Integr.
Comp. Physiol. 278, R66–R73 (2000).
52. Horton, T. J., Gayles, E. C., Prach, P . A.,
Koppenhafer, T. A. & Pagliassotti, M. J. Female
rats do not develop sucrose-induced insulin
resistance. Am. J. Physiol. 272, R1571–R1576
53. Kanarek, R. B. & Orthen-Gambill, N. Differential
effects of sucrose, fructose and glucose on
carbohydrate-induced obesity in rats. J. Nutr.
112, 1546–1554 (1982).
54. Hirsch, E., Dubose, C. & Jacobs, H. L.
Overeating, dietary selection patterns and
sucrose intake in growing rats. Physiol. Behav.
28, 819–828 (1982).
© 2013 Macmillan Publishers Limited. All rights reserved
500 | AUGUST 2013 | VOLUME 9
55. Kanarek, R. B. & Marks-Kaufman, R.
Developmental aspects of sucrose-induced
obesity in rats. Physiol. Behav. 23, 881–885
56. Jurgens, H. et al. Consuming fructose-
sweetened beverages increases body adiposity
in mice. Obes. Res. 13, 1146–1156 (2005).
57. Bocarsly, M. E., Powell, E. S., Avena, N. M. &
Hoebel, B. G. High-fructose corn syrup causes
characteristics of obesity in rats: increased
body weight, body fat and triglyceride levels.
Pharmacol. Biochem. Behav. 97, 101–106
58. Teff, K. L. et al. Dietary fructose reduces
circulating insulin and leptin, attenuates
postprandial suppression of ghrelin, and
increases triglycerides in women. J. Clin.
Endocrinol. Metab. 89, 2963–2972 (2004).
59. Purnell, J. Q. et al. Brain functional magnetic
resonance imaging response to glucose and
fructose infusions in humans. Diabetes Obes.
Metab. 13, 229–234 (2011).
60. Page, K. A. et al. Effects of fructose vs glucose
on regional cerebral blood flow in brain regions
involved with appetite and reward pathways.
JAMA 309, 63–70 (2013).
61. Cha, S. H., Wolfgang, M., Tokutake, Y.,
Chohnan, S. & Lane, M. D. Differential effects
of central fructose and glucose on hypothalamic
malonyl-CoA and food intake. Proc. Natl Acad.
Sci. USA 105, 16871–16875 (2008).
62. Bouret, S. G., Draper, S. J. & Simerly, R. B.
Trophic action of leptin on hypothalamic
neurons that regulate feeding. Science 304,
63. Bouret, S. G. Role of early hormonal and
nutritional experiences in shaping feeding
behaviour and hypothalamic development.
J. Nutr. 140, 653–657 (2010).
64. Bouret, S. G. & Simerly, R. B. Minireview: Leptin
and development of hypothalamic feeding
circuits. Endocrinology 145, 2621–2626 (2004).
65. McCurdy, C. E. et al. Maternal high-fat diet
triggers lipotoxicity in the fetal livers of
nonhuman primates. J. Clin. Invest. 119,
66. Lawlor, D. A. et al. Epidemiologic evidence for
the fetal overnutrition hypothesis: findings from
the mater-university study of pregnancy and its
outcomes. Am. J. Epidemiol. 165, 418–424
67. Knight, B. et al. The impact of maternal
glycaemia and obesity on early postnatal
growth in a nondiabetic Caucasian population.
Diabetes Care 30, 777–783 (2007).
68. Kral, J. G. et al. Large maternal weight loss
from obesity surgery prevents transmission of
obesity to children who were followed for 2 to
18 years. Paediatrics 118, e1644–e1649
69. Taylor, G. M., Alexander, F. E. & D’Souza, S. W.
Interactions between fetal HLA-DQ alleles and
maternal smoking influence birthweight.
Paediatr. Perinat. Epidemiol. 20, 438–448
70. Malik, S., McGlone, F., Bedrossian, D. &
Dagher, A. Ghrelin modulates brain activity in
areas that control appetitive behaviour.
Cell. Metab. 7, 400–409 (2008).
71. Alzamendi, A., Castrogiovanni, D.,
Gaillard, R. C., Spinedi, E. & Giovambattista, A.
Increased male offspring’s risk of metabolic-
neuroendocrine dysfunction and overweight
after fructose-rich diet intake by the lactating
mother. Endocrinology 151, 4214–4223
72. Jen, K. L. C., Rochon, C., Zhong, S. &
Whitcomb, L. Fructose and sucrose feeding
during pregnancy and lactation in rats changes
maternal and pup fuel metabolism. J. Nutr.
121, 1999–2005 (1991).
73. Light, H. R., Tsanzi, E., Gigliotti, J., Morgan, K. &
Tou, J. C. The type of caloric sweetener added
to water influences weight gain, fat mass, and
reproduction in growing Sprague-Dawley female
rats. Exp. Biol. Med. (Maywood) 234, 651–661
74. Rawana, S. et al. Low dose fructose ingestion
during gestation and lactation affects
carbohydrate metabolism in rat dams and their
offspring. J. Nutr. 123, 2158–2165 (1993).
75. Vickers, M. H., Clayton, Z. E., Yap, C. &
Sloboda, D. M. Maternal fructose Intake during
pregnancy and lactation alters placental growth
and leads to sex-specific changes in fetal and
neonatal endocrine function. Endocrinology
152, 1378–1387 (2011).
76. Ghusain-Choueiri, A. A. & Rath, E. A. Effect of
carbohydrate source on lipid metabolism in
lactating mice and on pup development. Br. J.
Nutr. 74, 821–831 (1995).
77. Brion, M. J. et al. Maternal macronutrient and
energy intakes in pregnancy and offspring
intake at 10 y: exploring parental comparisons
and prenatal effects. Am. J. Clin. Nutr. 91,
78. Myers, K. P . & Sclafani, A. Development of
learned flavour preferences. Dev. Psychobiol.
48, 380–388 (2006).
79. Bayol, S. A., Farrington, S. J. & Stickland, N. C.
A maternal ‘junk food’ diet in pregnancy and
lactation promotes an exacerbated taste for
‘junk food’ and a greater propensity for obesity
in rat offspring. Br. J. Nutr. 98, 843–851
80. Bayol, S. A., Simbi, B. H., Bertrand, J. A. &
Sticklandm, N. C. Offspring from mothers fed a
‘junk food’ diet in pregnancy and lactation
exhibit exacerbated adiposity that is more
pronounced in females. J. Physiol. 586,
81. Jenness, R. The composition of human milk.
Semin. Perinatol. 3, 225–239 (1979).
82. Davidson, N. O. et al. Human intestinal glucose
transporter expression and localization of
GLUT5. Am. J. Physiol. 262, C795–C800
83. Burant, C. F. & Saxena, M. Rapid reversible
substrate regulation of fructose transporter
expression in rat small intestine and kidney.
Am. J. Physiol. 267, G71–G79 (1994).
84. Douard, V., Choi, H. I., Elshenawy, S.,
Lagunoff, D. & Ferraris, R. P . Developmental
reprogramming of rat GLUT5 requires
glucocorticoid receptor translocation to the
nucleus. J. Physiol. 586, 3657–3673 (2008).
85. Douard, V. & Ferraris, R. P . Regulation of the
fructose transporter GLUT5 in health and
disease. Am. J. Physiol. Endocrinol. Metab. 295,
86. Holmberg, N. G., Kaplan, B., Karvonen, M. J.,
Lind, J. & Malm, M. Permeability of human
placenta to glucose, fructose, and xylose.
Acta Physiol. Scand. 36, 291–299 (1956).
87. Hagerman, D. D. & Villee, C. A. The transport of
fructose by human placenta. J. Clin. Invest. 31,
88. Du, L. & Heaney, A. P . Regulation of adipose
differentiation by fructose and Glut5.
Mol. Endocrinol. 26, 1773–1782 (2012).
89. Sandoval, D., Cota, D. & Seeley, R. J. The
integrative role of CNS fuel-sensing
mechanisms in energy balance and glucose
regulation. Annu. Rev. Physiol. 70, 513–535
90. Elmquist, J. K., Coppari, R., Balthasar, N.,
Ichinose, M. & Lowell, B. B. Identifying
hypothalamic pathways controlling food intake,
body weight, and glucose homeostasis.
J. Comp. Neurol. 493, 63–71 (2005).
91. Kirk, S. L. et al. Maternal obesity induced by
diet in rats permanently influences central
processes regulating food intake in offspring.
PLoS ONE 4, e5870 (2009).
92. Glavas, M. M. et al. Early overnutrition results
in early-onset arcuate leptin resistance and
increased sensitivity to high-fat diet.
Endocrinology 151, 1598–1610 (2010).
93. Kanayama, T., Kobayashi, N., Mamiya, S.,
Nakanishi, T. & Nishikawa, J. Organotin
compounds promote adipocyte differentiation
as agonists of the peroxisome proliferator-
activated receptor γ/retinoid X receptor
pathway. Mol. Pharmacol. 67, 766–774 (2005).
94. Kirchner, S., Kieu, T., Chow, C., Casey, S.
& Blumberg, B. Prenatal exposure to the
environmental obesogen tributyltin predisposes
multipotent stem cells to become adipocytes.
Mol. Endocrinol. 24, 526–539 (2010).
95. Li, X., Ycaza, J. & Blumberg, B. The
environmental obesogen tributyltin chloride
acts via peroxisome proliferator activated
receptor γ to induce adipogenesis in murine
3T3-L1 preadipocytes. J. Steroid Biochem.
Mol. Biol. 127, 9–15 (2011).
96. Chamorro-Garcia, R. et al. Transgenerational
inheritance of increased fat depot size, stem
cell reprogramming, and hepatic steatosis
elicited by prenatal obesogen tributyltin in
mice. Environ. Health Perspect. 121, 359–366
97. Grün, F. & Blumberg, B. Environmental
obesogens: organotins and endocrine
disruption via nuclear receptor signalling.
Endocrinology 147 (Suppl. 6), S50–S55
98. Golub, M. & Doherty, J. Triphenyltin as a
potential human endocrine disruptor. J. Toxicol.
Environ. Health B. Crit. Rev. 7, 281–295 (2004).
M. I. Goran, S. G. Bouret, B. Kayser, R. W. Walker
and B. Blumberg researched the data for the article.
All authors contributed to writing the manuscript,
provided substantial contributions to discussions
of its content, and reviewed and/or edited the
manuscript before submission.
© 2013 Macmillan Publishers Limited. All rights reserved