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Developmental exposure to endocrine-disrupting chemicals programs
for reproductive tract alterations and obesity later in life
1–4
Retha R Newbold
ABSTRACT
Many chemicals in the environment, especially those with estrogenic
activity, are able to disrupt the programming of endocrine signaling
pathways established during development; these chemicals are re-
ferred to as endocrine-disrupting chemicals. Altered programming
can result in numerous adverse consequences in estrogen-target tis-
sues, some of which may not be apparent until later in life. For ex-
ample, a wide variety of structural, functional, and cellular effects
have been identified in reproductive tract tissues. In addition to
well-documented reproductive changes, obesity and diabetes have
joined the list of adverse effects that have been associated with de-
velopmental exposure to environmental estrogens and other endo-
crine-disrupting chemicals. Obesity is a significant public health
problem reaching epidemic proportions worldwide. Experimental
animal studies document an association of developmental exposure
to environmental estrogens and obesity. For example, a murine model
of perinatal exposure to diethylstilbestrol has proven useful in study-
ing mechanisms involved in abnormal programming of differentiat-
ing estrogen-target tissues, including reproductive tract tissues and
adipocytes. Other environmental estrogens, including the environ-
mental contaminant bisphenol A, have also been linked to reproduc-
tive problems and obesity later in life. Epidemiology studies support
similar findings in humans, as do studies of cells in culture. Together,
these findings suggest new targets for abnormal programming by es-
trogenic chemicals and provide evidence supporting the scientific
concept termed the developmental origins of adult disease. Further-
more, the association of environmental estrogens with obesity and
diabetes expands the focus on these diseases from intervention or
treatment to include prevention or avoidance of chemical modifiers,
especially during critical windows of development. Am J Clin
Nutr 2011;94(suppl):1939S–42S.
INTRODUCTION
A complex series of events is involved in the development of
the mammalian fetus and neonate. Processes including cell di-
vision, proliferation, differentiation, and migration are all in-
volved and are closely regulated by hormonally active substances
that communicate information between specializing cells, tis-
sues, and organs. Although embryonic and fetal development was
once thought to occur by the “unfolding of a rigid genetic
program,” for which environmental factors played no significant
role (see reference 1 for a review), this strict interpretation of
developmental events has changed because numerous experi-
mental and epidemiologic studies point to the developmental
plasticity of the fetus and neonate. Mounting evidence suggests
that environmental factors, such as chemical toxicants, can
drastically alter developmental programming cues and result in
permanent long-term consequences (2). Research now focuses
on the role of environmental factors during critical windows of
perinatal growth and development and the mechanisms involved
(3). It has become obvious that the placenta is not impenetrable,
ie, it cannot completely protect the fetus from the outside world
and, in many cases, the fetus and neonate are more sensitive than
the adult to the same environmental insults. Reports identifying
a cocktail of environmental chemicals in amniotic fluid, cord
blood, and breast milk only serve to heighten concern for ex-
posures during development (see reference 4 for a review).
The term the fragile fetus was coined by Howard Bern in
1992 to denote the extreme vulnerability of the developing or-
ganism to perturbation by environmental chemicals, particularly
those with hormone-like activity (5). Bern pointed out that rapid
cell proliferation and cell differentiation coupled with complex
patterns of cell signaling contribute to its unique sensitivity and
therefore makes the fetus prone to chemical insult. Exposure to
environmental chemicals during development can result in death
in the most severe cases or in structural malformations and/or
functional alterations in the embryo or fetus. Unlike adult ex-
posures that can result in reversible alterations, exposure to
environmental chemicals or other factors during critical win-
dows of development can cause irreversible consequences.
Some of these consequences, such as birth defects, are seen
fairly immediately after exposure. For example, prenatal expo-
sure to thalidomide, which was used to treat maternal anxiety
and depression, resulted in limb deformities in the exposed
offspring; this chemical is probably the best known example of
a prenatal teratogen. Other consequences of developmental ex-
posure may not be seen until later in life: prenatal exposure to
1
From the National Institute of Environmental Health Sciences, National
Institutes of Health, Department of Health and Human Services, Research
Triangle Park, NC.
2
Presented at the conference “The Power of Programming: Developmen-
tal Origins of Health and Disease,” held in Munich, Germany, 6–8 May
2010.
3
Supported by the Intramural Research Program of the NIEHS/NIH. The
author is retired, but the research was conducted while she was employed by
the NIEHS.
4
Address correspondence to RR Newbold, 127 Radcliff Circle, Durham,
NC 27713. E-mail: newbold1@niehs.nih.gov.
Received August 3, 2010. Accepted for publication November 18, 2010.
First published online November 16, 2011; doi: 10.3945/ajcn.110.001057.
Am J Clin Nutr 2011;94(suppl):1939S–42S. Printed in USA. Ó2011 American Society for Nutrition 1939S
the potent synthetic estrogen diethylstilbestrol, which was pre-
scribed in the 1940s21970s to prevent miscarriage, is a well-
known example whereby a multitude of adverse consequences
were not seen until puberty or later in life (5–7). In fact, the full
extent of the consequences of this chemical exposure is still
unfolding as the diethylstilbestrol population ages, and it may
also include multigenerational effects (8–10). The concept that
developmental exposure to drugs and chemicals such as di-
ethylstilbestrol can cause permanent functional changes that are
not overtly toxic, such as ionizing radiation, or teratogenic ef-
fects, such as thalidomide, but still result in increased suscep-
tibility to disease or dysfunction later in life, even at low
environmental exposure levels, has greatly expanded the field of
“developmental toxicology.”
Interestingly, the concept that there is a developmental origin
of adult health and disease also has roots in epidemiology studies
that have examined maternal nutrition; an altered nutritional
status leading to low-birth-weight infants was shown to be as-
sociated with the latent appearance of disease in adult life, in-
cluding increased susceptibility to noncommunicable diseases,
coronary heart disease, obesity or overweight, type 2 diabetes,
osteoporosis, and metabolic dysfunction (11). Chronic stress was
also shown to be associated with similar latent responses; for
example, experimental studies using macaque monkeys showed
that early life stress resulted in obesity and increased incidences
of metabolic diseases later in life (12). Maternal smoking, another
example of a fetal stressor, was also shown to be linked to the
subsequent development of obesity and disease later in life (13).
These studies represent just a few examples that have led to
a substantial research effort focusing on perinatal influences and
subsequent chronic disease (14). These topics are covered in
detail in other articles in this supplement issue. Taken together,
epidemiologic studies describing an association of restricted fetal
nutrition with the subsequent development of obesity and met-
abolic diseases and experimental studies showing a correlation of
perinatal exposure to endocrine-disrupting chemicals (EDCs)
with multiple effects on reproductive tract tissues and obesity
provide an attractive framework for understanding delayed
functional effects of toxicant exposures. The mechanisms in-
volved in how environmental factors—eg, nutrition, stress, or
EDCs—can affect developmental events are not completely
understood but most likely involve numerous pathways including
the following: 1) changes in the neuroendocrine system,
whereby the developing nervous system communicates in-
formation from the environment to the developing endocrine
system; 2) epigenetic mechanisms, whereby environmental
signals alter the methylation or modify the histone patterns of
genes, causing their transcriptional activities to be altered; 3)
and/or direct effects on gene expression, particularly with regard
to hormonally active environmental agents (15).
EXPOSURE TO DIETHYLSTILBESTROL VERIFIES THE
DEVELOPMENTAL ORIGIN OF THE DISEASE OR
DYSFUNCTION CONCEPT
Diethylstilbestrol, a synthetic nonsteroidal chemical with es-
trogenic activity, is an EDC that was used in the 1950s–1960s as
a feed additive to enhance weight gain in cattle and poultry.
However, its notoriety was due to its widespread clinical use to
prevent miscarriage and other complications of pregnancy in the
1940s–1970s. In 1971, a hallmark report associated prenatal
diethylstilbestrol treatment with a rare form of reproductive tract
cancer, vaginal clear cell adenocarcinoma, which was detected in
a small number (,0.1%) of adolescent daughters of women who
had taken the drug while pregnant (16). Later, diethylstilbestrol
was also linked to more frequent benign reproductive tract
problems in .95% of the diethylstilbestrol-exposed daughters;
reproductive tract malformation and dysfunction, poor preg-
nancy outcome, and immune system disorders were just some of
the reported effects. Likewise, prenatally diethylstilbestrol-
exposed men experienced a range of reproductive tract abnor-
malities, including hypospadias, microphallus, retained testes,
and increased genital-urinary inflammation (see references 6,
17, and 18 for review and update). Although an increased in-
cidence in prostatic and testicular cancers was proposed, thus far
the diethylstilbestrol-exposed population has not reported an
increase in these diseases relative to unexposed men, but rig-
orous studies await a definitive conclusion.
Thus, diethylstilbestrol became a well-documented example of
the developmental origin of disease/dysfunction. It had the du-
bious distinction of being the first example of a human trans-
placental carcinogen; it was shown to cross the placenta and to
induce a direct carcinogenic effect on the developing fetus.
Diethylstilbestrol caused a major medical catastrophe that still
continues today. Although it is no longer prescribed to prevent
miscarriage, a major concern remains that as diethylstilbestrol-
exposed individuals age and reach the time when the incidence of
reproductive organ tumors normally increases, they will have
a much higher incidence of lesions than will unexposed indi-
viduals. For example, diethylstilbestrol-exposed women have
been reported to have a higher incidence of breast cancer as they
age than do unexposed individuals (19). Another concern is that
additional organ systems (eg, urinary, immune, cardiovascular,
brain/nervous, gastrointestinal, bone, and adipocytes) may be
affected. Furthermore, the possibility of multigenerational effects,
as suggested by experimental animal (8) and human studies (9, 10,
20), suggests that another generation may be at risk of developing
health problems associated with the diethylstilbestrol treatment of
their grandmothers. The diethylstilbestrol episode is a salient re-
minder of the potential toxicity that may be caused by EDCs if
exposure occurs during critical windows of susceptibility.
DEVELOPMENTAL EFFECTS OF DIETHYLSTILBESTROL
ON THE REPRODUCTIVE TRACT
Questions about the mechanisms involved in diethylstilbestrol-
induced abnormalities in humans prompted the development of
numerous experimental animal models to study the adverse
effects of estrogens and other EDCs on genital tract differenti-
ation. The perinatal (prenatal or neonatal) mouse model has been
particularly successful in duplicating and predicting many ad-
verse effects observed in humans with similar diethylstilbestrol
exposures (see reference 7 for a review). These murine models
have also been successfully used to study the molecular mech-
anisms involved in diethylstilbestrol-adverse effects (21–24).
In general, prenatal diethylstilbestrol treatment caused a high
incidence of malformation and a low, but significant, increase in
reproductive tract tumors; whereas, neonatal treatment causes
a low incidence of malformation, but a high incidence of re-
productive tract neoplasia. Predictably, it is apparent that the
1940S NEWBOLD
timing of exposure and the stage of tissue differentiation de-
termine the subsequent resulting abnormalities. Furthermore,
because many developmental events for the reproductive tract
that occur in the mouse during prenatal and neonatal life, happen
entirely prenatally in humans, the prenatal plus neonatal mouse
model can be useful in predicting what happens prenatally in
humans. In humans, the timing of exposure was also shown to be
an important factor for cancer risk in diethylstilbestrol daughters;
research showed that exposure early in pregnancy was associated
with a greater risk of vaginal cancer than was exposure later in
pregnancy (6, 18).
DEVELOPMENTAL EFFECTS OF DIETHYLSTILBESTROL
AND OTHER EDCs ON OBESITY
Obesity and overweight have dramatically increased in
prevalence in wealthy industrialized countries over the past 2 to 3
decades and also in poorer underdeveloped nations, where it often
coexists with undernutrition (25, 26). Obesity has now reached
epidemic proportions in the United States, although a recent
study found that its increase has stopped its upward spiral in the
past few years; however, there is no indication of any decreases in
prevalence (27). Common causes of obesity have usually been
attributed to high-calorie, high-fat diets and a lack of exercise
combined with a genetic predisposition for the disease. However,
the current alarming rise in obesity cannot be solely explained by
only these factors; an environmental component must be in-
volved. It has been suggested that exposure to EDCs during
critical stages of adipogenesis is contributing to the obesity
epidemic (28–32). The term obesogens has been coined for
environmental chemicals that stimulate fat accumulation, re-
ferring to the idea that they inappropriately regulate lipid me-
tabolism and adipogenesis to promote obesity (33).
Experimental animal studies support the idea of involvement
of EDCs in obesity; developmental exposure to numerous
chemicals—including diethylstilbestrol, other estrogens (32),
and other chemicals, such as tributyl tin (33)—has been asso-
ciated with obesity or overweight and adipogenesis. Recently,
there has been much interest in the chemical bisphenol A (BPA)
because of its high production volume and its potential for
widespread environmental contamination (34). Numerous studies
have now shown an association of BPA exposure with increased
body weight and adiposity (35–43). The later study suggests that
an increase in body weight is sex specific, but that timing and
dose may contribute to the complexity of these findings because
other investigators report effects in both males and females.
Interestingly, a recent article describes similar increases, as
previously reported, in the body weights of pups obtained from
moms fed BPA in their diets during pregnancy; the doses were
low and were considered “ecologically relevant” at 1 lg BPA/kg
diet (1 ppb) (44). However, unlike previous reports, the differ-
ences in body weight at weaning disappear as the mice age (44).
This is probably due to the palatability of the diet, which was
substituted at weaning because both control and BPA mice did
not continue to gain weight on the new diets.
In vitro studies with BPA provide additional evidence of a role
for this chemical in the development of obesity and further
suggest specific targets; BPA causes 3T3-L1 cells (mouse fi-
broblast cells that can differentiate into adipocytes) to increase
differentiation (45) and, in combination with insulin, accelerates
adipocyte formation (46, 47). Other in vitro studies have shown
that low doses of BPA, similar to diethylstilbestrol, impair cal-
cium signaling in pancreatic acells, disrupt bcell function, and
cause insulin resistance (48, 49). Low environmentally relevant
doses of BPA have also been reported to inhibit adiponectin and
stimulate the release of inflammatory adipokines, such as in-
terleukin-6 (IL-6) and tumor necrosis factor-a(TNF-a), from
human adipose tissue, which suggests that BPA is involved in
obesity and the related metabolic syndrome (50, 51). Further-
more, other studies have linked BPA exposure to disruption of
pancreatic bcell function and blood glucose homeostasis in
mice (52), which suggests changes indicative of the metabolic
syndrome.
Epidemiologic studies also support an association of BPA with
obesity. BPA was detected at higher concentrations in both
nonobese and obese women with polycystic ovarian syndrome
than in nonobese healthy women, which suggests the possible
involvement of BPA in polycystic ovarian syndrome and/or
obesity (53).
CONCLUSIONS
The data included in this article support the idea that de-
velopmental exposure to EDCs are contributing to disease and
dysfunction later in life; the adverse consequences from EDCs
that have been identified in various developing organ systems
include, but are not limited to, reproductive tract tissues and
adipocytes. Together, these data show the extreme sensitivity of
the developing organism and emphasize the need for identifi-
cation and avoidance of EDCs, especially during critical win-
dows of prenatal and neonatal development. Additional
mechanistic studies are essential to determine critical windows of
susceptibility for various target tissues, effects of dose, potential
additivity, or synergy of effects from mixtures of EDCs and
altered programming of developmental pathways so that future
generations can look forward to a healthy future.
The author declared that she had no conflicts of interest.
REFERENCES
1. Soto AM, Maffini MV, Sonnenschein C. Neoplasia as development
gone awry: the role of endocrine disruptors. Int J Androl 2008;31:
288–93.
2. Colborn T, Dumanoski D, Myers JP. Our stolen future. New York, NY:
Penguin Books USA, Inc, 1996.
3. Soto AM, Sonnenschein C. Environmental causes of cancer: endocrine
disruptors as carcinogens. Nat Rev Endocrinol 2010;6:363–70.
4. Needham LL, Calafat AM, Barr DB. Assessing developmental toxicant
exposures via biomonitoring. Basic Clin Pharmacol Toxicol 2008;102:
100–8.
5. Bern B. The fragile fetus. Princeton, NJ: Princeton Scientific Pub-
lishing Co, 1992.
6. NIH. DES research update. Bethesda, MD: NIH, 1999. (NIH publi-
cation no. 00-4722.)
7. Newbold RR. Lessons learned from perinatal exposure to di-
ethylstilbestrol. Toxicol Appl Pharmacol 2004;199:142–50.
8. Newbold RR, Padilla-Banks E, Jefferson WN. Adverse effects of the
model environmental estrogen diethylstilbestrol are transmitted to
subsequent generations. Endocrinology 2006;147:S11–7.
9. Brouwers MM, Feitz WF, Roelofs LA, Kiemeney LA, de Gier RP,
Roeleveld N. Hypospadias: a transgenerational effect of diethyl-
stilbestrol? Hum Reprod 2006;21:666–9.
10. Titus-Ernstoff L, Troisi R, Hatch EE, et al. Birth defects in the sons and
daughters of women who were exposed in utero to diethylstilbestrol
(DES). Int J Androl 2010;33:377–84.
DEVELOPMENTAL EXPOSURE TO EDCS 1941S
11. Barker DJ, Eriksson JG, Forsen T, Osmond C. Fetal origins of adult
disease: strength of effects and biological basis. Int J Epidemiol 2002;
31:1235–9.
12. Kaufman D, Banerji MA, Shorman I, et al. Early-life stress and the
development of obesity and insulin resistance in juvenile bonnet
macaques. Diabetes 2007;56:1382–6.
13. Levin ED. Fetal nicotinic overload, blunted sympathetic responsivity,
and obesity. Birth Defects Res A Clin Mol Teratol 2005;73:481–4.
14. Gluckman PD, Hanson MA, Pinal C. The developmental origins of
adult disease. Matern Child Nutr 2005;1:130–41.
15. Gilbert SF. Mechanisms for the environmental regulation of gene ex-
pression: ecological aspects of animal development. J Biosci 2005;30:
65–74.
16. Herbst AL, Ulfelder H, Poskanzer DC. Adenocarcinoma of the vagina:
association of maternal stilbestrol therapy with tumor appearance in
young women. N Engl J Med 1971;284:878–9.
17. Herbst AL, Bern HA. Developmental effects of diethylstilbestrol
(DES) in pregnancy. New York, NY: Thieme-Stratton Inc, 1981.
18. Giusti RM, Iwamoto K, Hatch EE. Diethylstilbestrol revisited: a review
of the long-term health effects. Ann Intern Med 1995;122:778–88.
19. Hatch EE, Palmer JR, Titus-Ernstoff L, et al. Cancer risk in women
exposed to diethylstilbestrol in utero. JAMA 1998;280:630–4.
20. Blatt J, Van Le L, Weiner T, Sailer S. Ovarian carcinoma in an ado-
lescent with transgenerational exposure to diethylstilbestrol. J Pediatr
Hematol Oncol 2003;25:635–6.
21. Taylor HS, Vanden Heuvel GB, Igarashi P. A conserved Hox axis in the
mouse and human female reproductive system: late establishment and
persistent adult expression of the Hoxa cluster genes. Biol Reprod
1997;57:1338–45.
22. Miller C, Degenhardt K, Sassoon DA. Fetal exposure to DES results in
de-regulation of Wnt7a during uterine morphogenesis. Nat Genet 1998;
20:228–30.
23. Li S, Hansman R, Newbold R, Davis B, McLachlan JA, Barrett JC.
Neonatal diethylstilbestrol exposure induces persistent elevation of
c-fos expression and hypomethylation in its exon-4 in mouse uterus.
Mol Carcinog 2003;38:78–84.
24. Tang WY, Newbold R, Mardilovich K, et al. Persistent hypo-
methylation in the promoter of nucleosomal binding protein 1 (Nsbp1)
correlates with overexpression of Nsbp1 in mouse uteri neonatally
exposed to diethylstilbestrol or genistein. Endocrinology 2008;149:
5922–31.
25. Caballero B. The global epidemic of obesity: an overview. Epidemiol
Rev 2007;29:1–5.
26. Cunningham E. Where can I find obesity statistics? J Am Diet Assoc
2010;110:656.
27. Flegal KM, Carroll MD, Ogden CL, Curtin LR. Prevalence and trends
in obesity among US adults, 1999-2008. JAMA 2010;303:235–41.
28. Baillie-Hamilton PF. Chemical toxins: a hypothesis to explain the
global obesity epidemic. J Altern Complement Med 2002;8:185–92.
29. Heindel JJ. Endocrine disruptors and the obesity epidemic. Toxicol Sci
2003;76:247–9.
30. Heindel JJ, Levin E. Developmental origins and environmental influ-
ences—introduction. NIEHS symposium. Birth Defects Res A Clin
Mol Teratol 2005;73:469.
31. Newbold RR, Padilla-Banks E, Jefferson WN. Environmental estro-
gens and obesity. Mol Cell Endocrinol 2009;304:84–9.
32. Newbold RR, Padilla-Banks E, Jefferson WN, Heindel JJ. Effects of
endocrine disruptors on obesity. Int J Androl 2008;31:201–8.
33. Grun F, Watanabe H, Zamanian Z, et al. Endocrine-disrupting orga-
notin compounds are potent inducers of adipogenesis in vertebrates.
Mol Endocrinol 2006;20:2141–55.
34. vom Saal FS, Akingbemi BT, Belcher SM, et al. Chapel Hill bisphenol
A expert panel consensus statement: integration of mechanisms, effects
in animals and potential to impact human health at current levels of
exposure. Reprod Toxicol 2007;24:131–8.
35. Howdeshell KL, Hotchkiss AK, Thayer KA, Vandenbergh JG, vom
Saal FS. Exposure to bisphenol A advances puberty. Nature 1999;401:
763–4.
36. Ashby J, Tinwell H, Haseman J. Lack of effects for low dose levels of
bisphenol A and diethylstilbestrol on the prostate gland of CF1 mice
exposed in utero. Regul Toxicol Pharmacol 1999;30:156–66.
37. Takai Y, Tsutsumi O, Ikezuki Y, et al. Preimplantation exposure to
bisphenol A advances postnatal development. Reprod Toxicol 2001;15:
71–4.
38. Honma S, Suzuki A, Buchanan DL, Katsu Y, Watanabe H, Iguchi T.
Low dose effect of in utero exposure to bisphenol A and di-
ethylstilbestrol on female mouse reproduction. Reprod Toxicol 2002;
16:117–22.
39. Nikaido Y, Danbara N, Tsujita-Kyutoku M, Yuri T, Uehara N, Tsubura
A. Effects of prepubertal exposure to xenoestrogen on development of
estrogen target organs in female CD-1 mice. In Vivo 2005;19:487–94.
40. Nikaido Y, Yoshizawa K, Danbara N, et al. Effects of maternal xen-
oestrogen exposure on development of the reproductive tract and
mammary gland in female CD-1 mouse offspring. Reprod Toxicol
2004;18:803–11.
41. Rubin BS, Murray MK, Damassa DA, King JC, Soto AM. Perinatal
exposure to low doses of bisphenol A affects body weight, patterns of
estrous cyclicity, and plasma LH levels. Environ Health Perspect 2001;
109:675–80.
42. vom Saal FS, Myers JP. Bisphenol A and risk of metabolic disorders.
JAMA 2008;300:1353–5.
43. Somm E, Schwitzgebel VM, Toulotte A, et al. Perinatal exposure to
bisphenol a alters early adipogenesis in the rat. Environ Health Per-
spect 2009;117:1549–55.
44. Ryan KK, Haller AM, Sorrell JE, Woods SC, Jandacek RJ, Seeley RJ.
Perinatal exposure to bisphenol-a and the development of metabolic
syndrome in CD-1 mice. Endocrinology 2010;151:2603–12.
45. Sakurai K, Kawazuma M, Adachi T, et al. Bisphenol A affects glucose
transport in mouse 3T3-F442A adipocytes. Br J Pharmacol 2004;141:
209–14.
46. Masuno H, Kidani T, Sekiya K, et al. Bisphenol A in combination with
insulin can accelerate the conversion of 3T3-L1 fibroblasts to adipo-
cytes. J Lipid Res 2002;43:676–84.
47. Masuno H, Iwanami J, Kidani T, Sakayama K, Honda K. Bisphenol
a accelerates terminal differentiation of 3T3-L1 cells into adipocytes
through the phosphatidylinositol 3-kinase pathway. Toxicol Sci 2005;
84:319–27.
48. Alonso-Magdalena P, Laribi O, Ropero AB, et al. Low doses of bi-
sphenol A and diethylstilbestrol impair Ca2+ signals in pancreatic
alpha-cells through a nonclassical membrane estrogen receptor
within intact islets of Langerhans. Environ Health Perspect 2005;
113:969–77.
49. Alonso-Magdalena P, Morimoto S, Ripoll C, Fuentes E, Nadal A. The
estrogenic effect of bisphenol A disrupts pancreatic beta-cell function
in vivo and induces insulin resistance. Environ Health Perspect 2006;
114:106–12.
50. Ben-Jonathan N, Hugo ER, Brandebourg TD. Effects of bisphenol A
on adipokine release from human adipose tissue: Implications for the
metabolic syndrome. Mol Cell Endocrinol 2009;304:49–54.
51. Hugo ER, Brandebourg TD, Woo JG, Loftus J, Alexander JW,
Ben-Jonathan N. Bisphenol A at environmentally relevant doses in-
hibits adiponectin release from human adipose tissue explants and
adipocytes. Environ Health Perspect 2008;116:1642–7.
52. Ropero AB, Alonso-Magdalena P, Garcia-Garcia E, Ripoll C, Fuentes
E, Nadal A. Bisphenol-A disruption of the endocrine pancreas and
blood glucose homeostasis. Int J Androl 2008;31:194–200.
53. Takeuchi T, Tsutsumi O, Ikezuki Y, Takai Y, Taketani Y. Positive re-
lationship between androgen and the endocrine disruptor, bisphenol A,
in normal women and women with ovarian dysfunction. Endocr J 2004;
51:165–9.
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