Endocrine disruptors and obesity

Abstract

The increasing incidence of obesity is a serious global public health challenge. Although the obesity epidemic is largely fueled by poor nutrition and lack of exercise, certain chemicals have been shown to potentially have a role in its aetiology. A substantial body of evidence suggests that a subclass of endocrine-disrupting chemicals (EDCs), which interfere with endocrine signalling, can disrupt hormonally regulated metabolic processes, especially if exposure occurs during early development. These chemicals, so-called 'obesogens' might predispose some individuals to gain weight despite their efforts to limit caloric intake and increase levels of physical activity. This Review discusses the role of EDCs in the obesity epidemic, the latest research on the obesogen concept, epidemiological and experimental findings on obesogens, and their modes of action. The research reviewed here provides knowledge that health scientists can use to inform their research and decision-making processes.

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1
Division of Extramural
Research and Training,
Population Health
Branch, National
Institute of
Environmental
Sciences (J.J.H., T.T.S.),
Division of the National
Toxicology Program,
National Institute of
Environmental Health
Sciences/National
Institutes of Health
(R.N.), POBox12233,
Research Triangle Park,
NC 27709, USA.
Correspondence to:
J.J.H.
heindelj@niehs.nih.gov
Endocrine disruptors and obesity
Jerrold J. Heindel, Retha Newbold and Thaddeus T. Schug
Abstract | The increasing incidence of obesity is a serious global public health challenge. Although the obesity
epidemic is largely fueled by poor nutrition and lack of exercise, certain chemicals have been shown to
potentially have a role in its aetiology. A substantial body of evidence suggests that a subclass of endocrine-
disrupting chemicals (EDCs), which interfere with endocrine signalling, can disrupt hormonally regulated
metabolic processes, especially if exposure occurs during early development. These chemicals, so-called
‘obesogens’ might predispose some individuals to gain weight despite their efforts to limit caloric intake
and increase levels of physical activity. This Review discusses the role of EDCs in the obesity epidemic, the
latest research on the obesogen concept, epidemiological and experimental findings on obesogens, and their
modes of action. The research reviewed here provides knowledge that health scientists can use to inform
theirresearch and decision-making processes.
Heindel, J.J. etal. Nat. Rev. Endocrinol. advance online publication 22 September 2015; doi:10.1038/nrendo.2015.163
Introduction
The prevalence of obesity in humans is increasing in
both developed and developing countries.1 Obesity is
rapidly becoming a worldwide public health problem
despite food shortages in many parts of the world.
In 2010, the World Health Organization estimated
that >700 million people worldwide have obesity and
~2 billion people are overweight.2 The prevalence of
childhood obesity is also increasing and is a strong risk
factor for adult obesity.3 Furthermore, an overwhel-
ming majority of individuals with obesity have multi-
ple comorbidities that result in poor health. Some of
these comorbidities include type2 diabetes mellitus,
gall bladder disease, sleep apnoea, high blood pressure,
insulin resistance, inflammation, breath lessness, the
metabolic syndrome, nonalcoholic fatty liver disease and
gestational diabetes mellitus.2,4 Individuals with obesity
also have an increased risk of coronary heart disease
and stroke, osteoarthritis and gout, impaired fertility,
cancers, cataracts and back problems.5 Obesity is, thus,
an issue of considerable concern, and the prevention of
childhood obesity is an essential step in controlling the
development of the disease.
The endocrine system controls body growth, weight
and metabolic processes by producing hormones and
growth factors that function through a series of tightly
integrated signalling pathways. Hormones regulate sig-
nalling pathways in the gastrointestinal system, pan creas,
muscle, liver, adipose tissue, immune system and brain,
which, in turn, regulate the number and content of fat
cells, as well as appetite and satiety.6–10 Adipose tissue
functions as an endocrine organ that produces and
responds to hormones and adipokines. As hor mones reg-
ulate the physiology of these systems, their action can be
disrupted by chemicals in the environ ment that mimic or
block normal endocrine functions. This Review focuses
on developmental exposures to endocrine-disrupting
chemicals (EDCs) and their sub sequent effects on weight
gain. We emphasize long-term weight gain, not inutero
exposures that result in low birth weight, as this factor is
associated with compensatory growth (as stated by the
Barker hypothesis11).
EDCs and obesogens
As obesity is a multifactorial and complex endocrine
disease, its aetiology involves interactions between
genes and the environment. Poor nutrition and lack of
exercise are important factors in the burgeoning obesity
epidemic, but other factors evidently have important
roles,12 including the built environment, stress, air pollu-
tion, and first and secondhand exposure to cigarette
smoke.13 Interestingly, the current increase in obesity
and other metabolic diseases correlates with substan-
tial increases in environmental chemical production
and exposures over the past few decades.14,15 EDCs are
exogenous chemicals capable of mimicking or blocking
the action of hormones by binding to or interfering with
their receptors. This interference disrupts signalling pro-
cesses throughout the body, which can lead to a variety
of diseases of the endocrine system.13,16 EDCs can also
function indirectly by disrupting hormone levels or by
altering hormonal transport mechanisms.
A subclass of EDCs have been identified that can
disrupt sensitive metabolic processes if exposure occurs
during early development, which leads to obesity, type2
diabetes mellitus and the metabolic syndrome.13 These
chemicals, so-called ‘obesogens’, are thought to predis-
pose individuals to weight gain owing to changes in
meta bolic ‘set-points’, particularly if exposure occurs
during sensitive periods of early life.17–19 For example,
Competing interests
The authors declare no competing interests.
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the pharmaceutical diethylstilbestrol is a model EDC that
causes obesity in animals when, even low-level, exposure
occurs during sensitive periods of development.20 Some
EDCs function by increasing the number of adipo cytes
and/or the storage of fat in existing adipocytes.21 EDCs
can also indirectly promote obesity by shifting the energy
balance in favour of fat storage in adipocytes and by
altering the body’s basal metabolic rate.21
Developmental origins of health and disease
A growing body of research has shown that many adult
diseases might originate during fetal and early childhood
development. This concept—the developmental origins
of health and disease (DOHaD)—proposes that early life
exposures to environmental chemicals or poor nutrition
can alter developmental pathways in ways that lead to
diseases and/or dysfunctions later in life.22 These early-
life periods are particularly vulnerable to environmental
chemicals as a consequence of incomplete development
or partial functioning of protective mechanisms, such
as DNA repair, immunity, xenobiotic metabolism and
the blood–brain barrier, in the fetus or neonate. In addi-
tion, the developmental period is a ‘plastic’ phase that is
sensi tive to altered programming of cell and tissue differ-
entiation by environmental stressors, and which can
cause changes in gene expression and protein levels due
to alterations in the levels or actions of hormones and
growth factors. For example, small changes in nutrient
availability at critical time points can result in casca ding
effects on adipose tissue development and metabolic pro-
gramming during early periods of growth.11 Importantly,
in epidemiological and animal studies, maternal, pater-
nal and inutero nutritional factors have been shown to
have important roles in determining birth weight and
susceptibility to long-term obesity.23,24
The concept of disruption of developmental program-
ming also includes non-nutritional early-life exposures
that have been shown to alter the body’s physiology.22
Prenatal exposure to chemicals in the environment can
modify normal cellular and tissue development and
function, even at the level of stem cell development.
For instance, inutero exposures to certain obesogens
have been shown to cause multipotent stem cells to pre-
maturely differentiate into lipid-filled mature adipo-
cytes.25 The DOHaD concept, therefore, provides a
framework to assess the effects of obesogenic chemicals
on long-term health and provides a common mechanism
Key points
■Obesity is an increasing global public health problem
■Obesity is a disease of the endocrine system, which involves many tissues and
metabolic processes
■The rapid growth of the obesity epidemic over the past few decades suggests
that environmental factors might have a role in the aetiology of the disease
■Obesity probably has its origins during development, when susceptibility to
weight gain and alterations in metabolism develop
■Obesogens are a subclass of endocrine-disrupting chemicals (EDCs) that might
predispose individuals to the development of obesity
■The obesogen hypothesis provides a means for the prevention of obesity by
reducing exposure to EDCs during early development
for chemical and nutritional stressors that ultimately
leads to obesity.22
Obesogen action during development
Almost 90% of individuals who lose a considerable
amount of weight regain that weight within 1year.26
Animproved understanding of the physiological factors
that dictate metabolic ‘set points’ and the propensity for
retaining weight is, therefore, critical. One aspect to con-
sider is that the endocrine system, which controls eating
behaviour, is extremely sensitive to perturbation by
EDCs. Early in life, EDCs can affect fetal adipose tissue
byincreasing the number and size of adipocytes.21 Fatcells
are generated from mesen chymal stem cells,which are
also capable of differentiating into bonecells, cartilage
cells and cells of other tissues.27 Obesogenic chemicals
can artificially direct mesen chymal stem cells to differ-
entiate into adipocytes, and promote the accumulation
of triglycerides in mature adipo cytes (Figure1).21 These
effects can lead to alterations in the ‘set point’ for gaining
weight and thus contribute both to weight gain and the
problems associated with weightloss.
EDCs can also cause changes in the hypothalamus—
the region of the brain that has a particularly important
role in eating behaviour.13 Disruptions in hypo thalamic
programming might result in altered metabolic ‘set
points’ in adolescents and adult individuals. These
adjustments might manifest and explain differences
between the eating behaviour of lean individuals and
those with obesity. Exposure to EDCs can also alter
the organization and function of dopaminergic path-
ways throughout the developing brain, which results
in lifelong behavioural effects.28 For example, early-life
exposure to bisphenolA has been shown to alter both
presynaptic and postsynaptic dopamine activity in
brain regions associated with addictive and impulsive
behaviour.29 Thus, obsessive eating patterns observed in
adult individuals with obesity might be, in part, due to
chemically-induced alterations in neural programming
early in life.
Epigenetic changes probably have an important role in
the mechanism by which obesogens exert their effects.
Epigenetic events (that is, DNA methylation and acety-
lation, ubiqui tination or other histone modifications) lead
to heritable patterns of gene expression during develop-
ment and are, therefore, important in the formation of
normal tissue and organs.30–32 As the epigenome cycles
through a series of precisely timed events during gamete
develop ment, fertilization and fetal development, the
system is particularly vulnerable to interference from
EDCs.33 Exposure to environmental stressors during
development can lead to epigenetic changes that persist
throughout life. Although a causal link between epi-
genetic changes and increased susceptibility to obesity
has not been established, epigenetic modifications along
with other programming changes represent a plausible
mechanism that links genes, environmental stressors and
susceptibility to obesity (Figure2).34–36 Some research
suggests that changes to our epigenome can be permanent
and inherited by subsequent generations.25,28,37–41
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Obesogenic chemicals
A variety of prescription drugs have adverse effects that
result in weight gain, such as thiazolinediones (anti-
diabetic drugs), tricyclic antidepressants, selective
5-hydroxytryptamine uptake inhibitors and atypical
anti psychotic drugs,42–44 which provides a proof-of-
principle that chemicals with similar structures and
modes of action might have a role in the obesity epi-
demic. Animal studies indicate that EDCs such as tri-
butyltin, estrogenic chemicals such as bisphenolA,
and chemicals acting via other mechanisms such as
lead, perfluor octanoic acid, phthalates, polychlorinated
bi phenyls, some pesti cides, dichlorodiphenyltrichloro-
ethane (DDT) and tobacco smoke, can lead to weight
gain later in life (Table1).25,37,41,45
Importantly, weight gain can be a poor proxy for
increased fat content as infiltrating adipose tissue can
replace bone, muscle or other tissues without a signi-
ficant gain in weight. Studies that measure the size of
fat depots or assess adipocyte number and size more
effectively reflect the percentage of fat in an individual
than those that just measure weight gain. Exposure to
environmental chemicals during development probably
increases susceptibility to weight gain; however, the full
spectrum of symptoms associated with obesity might not
be apparent unless a secondary challenge occurs later in
life, such as a high-fat diet or other stressors.
Cigarette smoke
Epidemiological data strongly support a positive and
probable causal association between maternal smoking
and increased risk of obesity or overweight in offspring.
This conclusion is based on the very consistent pattern
of overweight and/or obesity observed in children
whose mother smoked during pregnancy along with
findings of obese offspring from laboratory animals
exposed to nicotine during pregnancy.41 Approximately
20 epidemio logical studies have examined the effects of
maternal smoking during pregnancy on body weight
of offspring during childhood or adulthood. These
studies show a consistent association between mater-
nal smoking during pregnancy, low birth weight, and
increased risk of overweight and/or obesity in offspring.
This literature was evaluated in two meta-analyses which
indicated a 50–64% increase in obesity due to smoking
duringpregnancy.46,47
Polycyclic aromatic hydrocarbons and air pollution
Polycyclic aromatic hydrocarbons (PAHs) are a family of
environmental chemicals that occur in oil, coal and tar
deposits, and are produced as byproducts of fuel burning
(both fossil fuel and biomass), including ciga rette smoke
and diesel exhaust. Benzo(a)pyrene is a PAH that has
been shown to inhibit lipolysis and cause increased fat
accumulation in adult mice.48 Air pollution can result in
low birth weight and preterm birth, factors that can lead
to weight gain later in life.49,50 Forexample, in a study
of pregnant women who wore personal air monitors
during the second trimester, prenatal expo sure to PAHs
was associated with increased body size of their children
at age 5 and 7years.51 Additionally, air pollution near
roads can contribute to obesity late in life if the expo-
sure occurs during fetal development or childhood.52,53
Longitudinal epidemiological studies that encompass
the prenatal period through to adulthood are needed to
determine the lifelong effects of exposure to PAHs.
Animals exposed to diesel exhaust inute ro and a
high-fat diet as an adult showed increased suscepti-
bility to diet-induced weight gain and neuroinflamma-
tion later in life.54 Similarly, early-life exposure to air
pollution parti culates (particulate matter [PM]2.5 for
3–10weeks) in mice led to increased visceral obesity,
insulin resistance and inflammation.55 Also, mice fed
a high-fat diet for 10weeks who were then exposed to
PM2.5 as adults for 24weeks had increased visceral
obesity, insulin resistance and inflammation.56 These
results indicate an inter action between air pollution, diet
and metabolic program ming, particularly during periods
of development. Although these select studies indicate
that exposure to various components of air pollu tion
might have a role insuscepti bility to obesity, addi-
tional research is neededin both animals models and in
humans to accurately define the levels of air pollutants
that causeobesity.
Figure 1 | Potential mechanism by which environmental chemicals cause obesity in
animals and in humans. Several EDCs and obesogens such as organotins and the
fungicide triflumizole are known to activate PPAR-γ, which leads to weight gain
invivo and reprogramming of mesenchymal stem cell fate to favour formation of
adipogenic cells at the expense of the osteogenic fate. Triflumizole also functions
via PPAR-γ to induce adipogenesis in mesenchymal stem cells and preadipocytes
invitro through a PPAR-γ-dependent mechanism and promotes increased white
adipose tissue depot size and altered stem cell programming invivo.
Abbreviations: EDC, endocrine-disrupting chemical; PPAR-γ, peroxisome
proliferator-activated receptorγ.
Nature Reviews | Endocrinology
EDCs
Obesogens
Obesity
(animals and
humans)
PPAR-γ
activation
Increased
number and
size of adipocytes
Alterations to
stem cells
Increased
risk of
obesity
Nature Reviews | Endocrinology
Obesogens
Changes in
metabolic
set-points
■ Nuclear
receptor
activation
■ Epigenetic
regulation
■ DNA methylation
■ Histone
modications
■ Hormone
regulation
■ Metabolic
signalling
pathways
■ Cellular
differentiation/
migration
Figure 2 | Potential mechanisms of obesogen action that alter metabolic set-points
and increase the risk of obesity. If these programming events occur early in
embryonic development, they can lead to persistent changes in hormone
signalling. Numerous obesogens have been shown to act through activation of
fat-regulating nuclear receptors or other receptors that regulate key metabolic
signalling processes. Other obesogens act via unidentified pathways such as
those that result in various epigenetic changes, and which can have
transgenerational effects on a variety of health endpoints, including obesity
inoffspring.
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Tributyltin
Tributyltin is an organotin that is used as a fungicide and
as a heat stabilizer in polyvinyl chloride. This obesogenic
chemical has been found in house dust and in human
liver and blood, although data on human exposures are
limited.57 Tribuyltin functions as an agonist of retinoic
acid X receptor and peroxisome proliferator-activated
receptorγ (PPAR-γ) owing to its ability to bind and
induce transcriptional activation of these receptors.37
Several laboratories have shown that tributyltin stimu-
lates adipogenesis in 3T3 L-1 preadipocytes at nanomolar
concentrations,37,58,59 and drives adipogenesis in human
and mouse mesenchymal stem cells.60–62 Mesenchymal
stem cells from tributyltin-treated animals have an
increased propensity to develop into adipose tissue and
a decreased commitment to develop into bone.63 Prenatal
exposure to tributyltin results in increased lipid accu-
mulation in adipose tissue and liver and reduced muscle
mass in neonatal mice, effects that persists into adult-
hood and even into future generations.64,65 Tributyltin
has also been shown to enhance weight gain in mice
exposed during puberty and earlyadulthood.66
BisphenolA
BisphenolA is a high production chemical that is
widely used in polycarbonate plastics, can linings
and cash register receipts. The chemical structure of
bisphenolA enables it to fit into the binding site ofthe
estrogen receptor, which enables the compound to
activate both nuclear and cell membrane-localized
estrogenreceptors.67
Studies in rodents and humans have yielded con-
flicting results with regard to inutero and/or neo natal
bis phenolA exposure and increased weight gain in
young and adult mice.68–70 In a systematic review of
cross-sectional studies limited associations were found
between adult exposure to bisphenolA and obesity.68,71
Investigators in other studies have reported mixed
associ ations between concurrent bisphenolA exposure
(as measured by spot urine samples) and weight gainin
children.72–74 Although not examining weight gain,
inone study increased placental levels of bisphenolA
were associ ated with low birth weight;75 results from
another study showed that maternal exposure to bis-
phenolA correlated with reductions in the birth weight
ofoffspring.76
Considerable limitations exist in the epidemio logical
studies conducted, so far, on bisphenolA exposure and
metabolic outcomes. Most of these human studies have
been cross-sectional in design, which provide only
suggestive results and cannot address the temporality
of exposure and disease.71 The potential exists for mis-
classifying exposure to chemicals such as bisphenolA,
as they do not persist long-term invivo. Owing to the
short biological half-life of bisphenolA, urinary concen-
trations usually reflect exposures over the past 6–12 h.
Therefore, a single spot urine sample will not accurately
measure long-term or episodic exposure over weeks,
months or years.77 Additional large prospective cohort
studies are needed to confirm and validate findings from
cross-sectional human studies.
Several animal studies have demonstrated that expo-
sure to bisphenolA can disrupt multiple metabolic path-
ways and sites of action, which suggests that exposure
to environmentally relevant doses of this compound
can increase body weight.78–81 Although many of these
effects are thought to be mediated through estrogen
receptors,82,83 evidence also suggests that bisphenolA
and its derivatives act as obesogens by inducing adipo-
cyte differentiation and the expression of genes involved
in adipogenesis via various mechanisms.84,85
Laboratory studies in bisphenolA-exposed animals
have focused attention on the neurological effects of
weight gain. BisphenolA-exposed female mice fed a
high-fat diet consumed more food and gained more
weight than control animals on the same diet.81 The
Table 1 | Environmental chemicals associated with obesogenic properties
Chemical Source/commercial use Potential mechanism
Cigarette smoke First-hand and
second-handsmoke
Prenatal nicotine exposure alters neurological
developmentand exposures ↑ rates of preterm
andlow-weight births41,46,47
Air pollution
Polycyclic aromatic hydrocarbons
Incomplete combustion
offossilfuels
↑ Accumulation of visceral fat55
Inammation56
Tributyltin Fungicide in paints and
componentsof polyvinyl chlorides
Activation of peroxisome proliferator-activated
receptorγ37,58,59 and increased fat cell differentiation60–63
BisphenolA Plastics and epoxy resins Estrogenic82,83
Inhibition of proliferation of neural progenitor cells86
Flame retardants Chemicals applied to furniture
andelectronics
↑ Rate of adipogenesis105
↑ Glucose intolerance106
Polychlorinated biphenyls Coolants, plasticizers and
ameretardants
Altered thyroid function96,101
Altered metabolism112
Bioaccumulation in fat cells109
Phthalates Plasticizers, adhesives and
personal care products
↑ Rate of adipocyte differentiation117,120–122
Peruorooctanoic acid
Peruorooctanoate sulphonate
Components of lubricants,
nonstickcoatings and
stain-resistant compounds
↑ Serum levels of insulin126
↑ Serum levels of leptin126
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results from this study suggest that early-life exposure
to bisphenolA might lead to sexually dimorphic altera-
tions in hypothalamic energy balance circuitry, which
results in increased susceptibility to developing diet-
induced obesity and metabolic impairment.81 Similarly,
inv itro exposure to bisphenolA increased proliferation
of neural progenitor cells and altered neurogenesis;
some of the changes in gene expression were similar to
those occurring in the offspring of obese dams, which
have been related to hyperphagia.86 However, several
other studies in both animals and humans have failed
to find direct associations between bisphenolA expo-
sure and weight gain, which suggests a need for addi-
tional research to delineate the effects of bisphenolAon
metabolic systems.87–89 Interestingly, bisphenolA glucur-
onide, the major metabolite of bisphenolA, and com-
monly thought to be inactive, induces adipogenesis
but has no estrogenic activity.90 However, additional
research is needed to define the metabolic properties of
bisphenolA in both humans and animal models.
The costs associated with obesity due to bisphenolA
exposure have been estimated.91,92 BisphenolA exposure
has been predicted to contribute to 12,404 cases of child-
hood obesity and 33,863 cases of coronary heart disease
with an estimated societal cost of $2.98 billion in 2008.91
A separate expert panel used a weight-of-evidence
approach applied by the Intergovernmental Panel on
Climate Change93 to estimate bisphenolA exposures and
calculated that prenatal exposure to bisphenolA had a
20–60% probability of causing 42,400 cases of childhood
obesity in the European Union, with associated lifetime
costs of 1.54 billion euros.92
Flame retardants
Flame retardants are chemicals applied to a variety of
materials, including furniture, electronics and con-
struction materials, to reduce their flammability or
delay their combustion. Polybrominated biphenyls and
polybrominated diphenylethers are widely used as flame
retardants and, although a subset are banned accord-
ing to the Stockholm Convention, some have been
detected at biologically active levels in blood in children
and in the majority of the population of the USA.94,95
Flame retardants have been associated with a variety of
adverse health outcomes, including obesity and altered
or inappro priate thyroid function.96–99 In several studies,
prenatal and/or childhood exposure to polybrominated
diphenylethers is associated with low birth weight and
altered thyroid function in offspring.100–102 In a longi-
tudinal birth cohort study of children of Hispanic origin
in California, USA, inutero and childhood exposure to
polybrominated diphenylethers was associated with
increased BMI in boys at 7years of age but not in girls.103
This finding suggests that time after exposure and sex
might have a role in development of the disease. The
congener BDE-47 stimulated adipogenesis in a 3T3-L1
adipogenic screen104 and increased weight gain in rats
exposed inutero.105
The Firemaster®550 flame retardant (Chemtura, USA)
mixture came to market as the use of polybrominated
diphenylethers was being phased out. This mixture is
now the second most commonly invivo-detected flame
retardant sold in the USA. Evaluation of the toxi city
of Firemaster®550 in pregnant rats found elevated
expression of phenotypic biomarkers associ ated with
the meta bolic syndrome in offspring.106 Effects noted
included early female puberty, weight gain (which
became evident before puberty and continued into
adulthood), male cardiac hypertrophy, glucose intol-
erance, and increased serum levels of thyroxine, as
well as reduced hepatic carboxy lesterase activity in the
dams.106 Subsequent studies reported that the obeso-
genic effects of Firemaster®550 might be mediated by
binding to and activation of PPAR-γ, similar to those
oforganotins.107,108
Polychlorinated biphenyls
Polychlorinated biphenyls are a major component of
the highly persistent organic pollutants found in our
environ ment. These agents are man-made synthetic
chemical mixtures, which were widely used in industry
until the late 1970s, after which time they were banned
in the USA and many other developed countries.
Exposure to polychlorinated biphenyls remains ubiqui-
tous because of improper disposal and bioaccumulation
in the environ ment. In some studies, these lipophilic
pollutants have been shown to accumulate at high levels
in adipose tissue and might be a contributing factor in
the obesity epidemic.41,109 The NHANES 1999–2002
survey110 showed an association between waist circum-
ference and BMI in individuals with detectable levels of
persistent organic pollutants, which suggests a contri-
bution to the ongoing obesity epidemic. Data support-
ing the association between polychlorinated biphenyls
and metabolic disease continues to be reported, with
two studies in the past few years reporting that early-
life exposure to polychlorinated biphenyls is closely
associated with childhood obesity.111,112
Phthalates
Phthalates are diesters of phthalic acid and are a class of
chemicals that are commonly used to impart flexibility
in plastic products (plasticizers) including polyvinyl
chloride, and as a carrier for fragrances in cosmetics.
These compounds are also found in a variety of house-
hold and personal care products, including food pack-
aging and medical devices.113,114 Phthalates easily leach
from these products and, thus, are found in indoor air
and house dust; human exposure to phthalates has been
welldocumented.115
Diethylhexylphthalate, or its metabolite monohexyl-
phthalate, has been linked with obesity in animal
models.116,117 Prenatal and neonatal exposure to diethyl-
hexylphthalate in pregnant mice led to increased body
weight, numbers and size of adipocytes, and activa-
tion of PPAR-γ in male offspring, which suggests a
sex ually dimorphic effect.117 Using a different mouse
strain, exposure to diethylhexylphthalate inutero and
through out lactation led to increased weight gain,
which per sisted into adulthood.118 Both of these studies
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reported nonmonotonic dose responses, with lower
doses (0.05and 0.5 mg/kg/day) resulting in weight gain,
but no effect at the higher dose of 500 mg/kg/day. These
inviv o results were confirmed in the 3T3-L1 preadipo-
cyte cell line.119 Monohexylphthalate or diethylhexyl-
phthalate induced the expression of PPAR-γ, expression
of its target genes and the differentiation of these cells
into adipocytes.117,120–122 When diethylhexylphthalate
was administered to adult mice for 8weeks, all doses
(0.5, 5 and 500 mg/kg/day) resulted in increased food
intake, increased plasma levels of leptin, decreased
adipo nectin expression in adipose tissue, weight gain
and adipo cyte hypertrophy.118 These data indicate that
phthal ates have the ability to increase adipose tissue
mass both during development and in adulthood,
although the mechanism and sensitivity in these periods
are probablydifferent.
Perfluorinated chemicals
The perfluorinated chemicals, perfluorooctanoic acid
and perfluorooctane sulphonate, which persist in the
environment, are used to repel grease and oil, are found
in Teflon™ (DuPont, USA), Scotchguard™ (3M Company,
USA) and in carpets and clothing to repel staining,
and have been linked to obesity.123 Human and animal
studies on the metabolic effects of these compounds are
incon clusive. In one study in humans, perfluoro octanoic
acid concentrations over the first 3years oflife were
compared with BMI in adulthood; no risk of becom-
ing overweight was demonstrated.124 A separate study
in a Danish cohort measured perfluoro octanoic acid
concentrations at gestational week30 and showed a
positive associ ation with BMI and waist circumfer-
ence at 20years of age in female individuals but not in
male individuals.125 Differences in study design prob-
ably account for the different results. Young adult mice
exposed inute ro to perfluorooctanoic acid were over-
weight and had increased serum levels of insulin and
leptin.126 However, in a different mouse model bred for
intestinal neoplasia, neither perfluoro octanoic acid nor
perfluorooctane sulphonate (0.01, 0.1 or 3 mg/kg/day
given on gestational day17) led to weight gain in off-
spring at 10weeks and 20weeks of age.127 Currently,
insufficient data exists to determine if perfluoro octanoic
acid and/or perfluorooctane sulphonate should be
classified as obesogens.
Transgenerational obesogenic transmission
In the past decade, a considerable body of evidence has
shown that chemical exposures occurring during certain
periods of fetal development can generate phenotypes
that persist through multiple generations.128 These
pheno typic changes probably do not have a genetic
origin as low-dose exposure to EDCs typically does
not damage DNA but, rather, causes alterations in the
epigenetic profile that can be passed on to subsequent
generations.31,45,129 For example, exposure to pesticides,
fungicides, jet fuel, plastics and air pollution have been
linked to reproductive diseases in the F3 generation of
mice.130 Maternal exposure to bisphenolA has been
linked to behavioural changes in offspring through
four generations, which is probably due to epigenetic
modification of imprinted genes.131
A preponderance of data supporting the concept of
transgenerational inheritance of obesity is beginning to
emerge in the literature. For instance, mice prenatally
exposed to tributyltin have increased adipose depots
and adipocyte size, as well as fatty liver through three
generations.45 Transgenerational inheritance of obesity
resulting from exposure to DDT,132 a mixture of bis-
phenolA and di-(2-ethylhexyl)-phthalate, and a hydro-
carbon mixture (jet propellant8; commonly known
as JP-8) has also been demonstrated.133,134 However,
in other studies no trans generational transmission
of obesity after exposure to dioxin, vinclozolin or a
mixture of permethrin and N,N-diethyl-meta-toluamide
that indicates chemical selec tivity of effects on meta-
bolic processes135 and specificity of chemical-induced
transgenerational effects has been found. Although
the mechanism of transgenerational inheritance is far
from understood, transmission of epi genetic infor-
mation is probably involved.136–138 Indeed, the global
demethyl ation that is required to maintain the germ-
line epi genetic programme and thus reset the gamete
epi genome for pluripotency is incomplete during this
period of development.139 Some loci in the germline of
humans and mice are resistant to DNA demethylation,
thereby providing the potential for transgenerational
epi genetic inheritance.140 In summary, early-life expo-
sure to at least some obesogens might exert permanent
and transgenerational effects.
Ideal conditions for obesity
We propose that the convergence of early nutrition and
exposure to obesogens during development (inutero and
in first few years of life) in association with over-nutrition
and decreased physical activity later in life, creates ideal
conditions that drive the worldwide obesity epidemic.141
Continued exposure to obesogens through out life
exacer bates the problem by interfering with the endo-
crine system, which controls metabolism. This problem
burgeons as infants born to parents with obesity also
have an increased risk of being obese. Dealing withthe
obesity epidemic will require additional research in
theunderstanding of how nutritional and environmental
chemical exposures affect the basic mechanisms under-
lying the development and function of adipose tissue, as
well as eating behaviours. The implications of the obesity
epidemic are vast, and new research into the metabolic
effects of chemical exposures during development offers
a window on prevention and/or intervention.
Conclusions
Although the obesogen hypothesis is less than 10years
old, the obesogenic properties of ~20environmental
chemicals are already known. Given the difficulty in
treating obesity, the obesogen hypothesis opens the door
to reducing the incidence of this global health problem
by focusing on its prevention through reducing early-life
chemical exposures.
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Author contributions
J.J.H., R.N. and T.T.S. researched data for the ar ticle,
provided substantial contributions to discussions of
content, wrote the article and reviewed and/or edited
the manuscript before submission.
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