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Annales dEndocrinologie 74 (2013) 211220

Review

Bisphenol A: An endocrine and metabolic disruptor

Bisphnol A : un perturbateur endocrinien et mtabolique
Patrick Fenichel , Nicolas Chevalier , Francoise Brucker-Davis
Inserm U1065/C3M, service dendocrinologie, diabtologie et reproduction, hpital de lArchet 2, CHU de NICE, 151,
route Saint-Antoine-de-Ginestire, 06202 Nice cedex 3, France

Abstract
Bisphenol A (BPA), initially designed, like diethylstilbestrol, as a synthetic estrogen, has been rapidly and widely used for its cross-linking
properties in the manufacture of polycarbonate plastics and epoxy resins. Because of incomplete polymerization and degradation of the polymers
by exposure to higher than usual temperatures, BPA leaches out from food and beverage containers, as well as from dental sealants. In humans,
free active unconjugated BPA is metabolized by rapid glucurono- or sulfo-conjugation and eliminated via renal clearance. However, exposure to
environmental nanomolar concentrations of BPA is ubiquitous and continuous via different routes: oral, air, skin. In rodents, fetal and perinatal
exposure to such environmentally relevant doses of BPA has been shown to affect the brain, liver, gut, adipose tissue, endocrine pancreas, mammary
gland and reproductive tract and function. Similar concentrations are also able in vitro to impact human malignant breast, prostate, male germ
or adipocyte cell lines (with a promoting effect and by interfering with chemotherapy drugs), or to stimulate pancreatic ! cell insulin secretion.
High levels of BPA have recently been correlated with obesity, diabetes, cardiovascular diseases, polycystic ovarian disease or low sperm count.
However, before the real impact of BPA on human health can be clearly assessed, prospective longitudinal epidemiological studies are needed as
well as characterization of selective biomarkers to verify long-term exposure and selective imprinting.
2013 Published by Elsevier Masson SAS.
Rsum
Le bisphnol A (BPA) est une substance chimique trs ubiquitaire prsente dans la plupart des plastiques polycarbons et les rsines poxy, qui est
relargu sous leffet de la chaleur et considre comme prsentant un effet de perturbateur endocrinien estrogno-mimtique. Il est essentiellement
absorb dans lespce humaine par voie alimentaire et est retrouv sous forme libre active dans le sang et sous forme conjugue dans les urines
en vue de son limination, chez la majorit des individus. La mise en vidence de troubles du dveloppement, de la reproduction, du mtabolisme
chez les rongeurs exposs des taux quivalents, pendant des priodes critiques dexposition ftale et/ou prinatale, a conduit sinterroger
sur sa responsabilit dans les pathologies humaines correspondantes. Dautant quil est capable dinduire in vitro sur des cellules humaines, via
des rcepteurs membranaires des estrognes, la prolifration de cellules malignes mammaires ou testiculaires ou dadipocytes et de rguler la
scrtion insulinique par les lots !-pancratiques. Bien que des tudes pidmiologiques transversales, rtrospectives mettent en vidence une
corrlation entre obsit, insulinorsistance, diabte, hypofertilit et les taux de BPA, elles ne permettent pas elles seules dattester dune relation
causale et dvaluer exactement la part de ce potentiel facteur de risque. Seules des tudes prospectives longitudinales pourraient conforter cette
hypothse ainsi que la caractrisation de biomarqueurs permettant la fois dvaluer lexposition prolonge et continue de faibles doses de BPA
et en mme temps de mettre en vidence des modifications molculaires conduisant faire la part de lexposition chronique et de la susceptibilit
individuelle.
2013 Publi par Elsevier Masson SAS.

1. Introduction
The concept of endocrine disruptor was proposed 20 years
ago [1] when various observations of deleterious effects on

Corresponding author.
E-mail address: fenichel.p@chu-nice.fr (P. Fenichel).

0003-4266/$ see front matter 2013 Published by Elsevier Masson SAS.

http://dx.doi.org/10.1016/j.ando.2013.04.002

wildlife or humans were put together, in association with the

intensive use of pesticides in agriculture. It refers to natural or
synthetic chemical products, which are able to mimic and/or
interfere with hormone receptors generating as unexpected ligands deleterious effects on animal or human health [2]. Many of
these products, such as dichlorodiphenyltrichloroethane (DDT)
or other organochlorides, demonstrated estrogenic or antiandrogenic effects and could interact during development and/or

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reproduction [3]. These observations have been compared with

the human unwilling experiment of fetal exposure to diethylstilbestrol (DES) used in prevention of miscarriages from 1950
to 1975. An increased risk of different pathologies, including
genital malformations, infertility, or hormone dependent cancers, have been reported [4] for these exposed children, sometimes several decades later [5], underlining the critical window
of fetal period for exposure to environmental exposure disruptors
(EED). This concept is very similar to the one proposed by David
Barker, based on the fetal nutritional environment influencing
the developmental origin of chronic adult diseases [6].
However, an objective causative role for EED exposure in
human chronic disease remains very difficult to assess, except
for this unique experimental story of distilbene, because
of methodological limitations. These difficulties concern epidemiological designs as well as toxicological and mechanistic
aspects. These concerns represent a real challenge for the scientists and the physicians who have to assess the possible toxicity
or the harmlessness of a given molecule, and for the politicians
who will have to establish regulation for allowed thresholds or
decide the authorization for common use of a new molecule
(REACH program).
The case of bisphenol A represents a perfect example for
this emerging concept and should be of particular interest for
French endocrinologists and diabetologists, considering that its
links with this compound has been pointed out for reproduction,
diabetes, obesity and endocrine related cancers in the very recent
ANSES document (Agence nationale de scurit sanitaire de
lalimentation, de lenvironnement et du travail) published in
December 2011 by the French Ministry of Environment [7].
2. Historical record
BPA is a chemical product, first synthesized at the beginning of the 20th century from two phenol molecules (bisphenol)
linked by one acetone molecule (A) (Fig. 1). BPA was first
designed as a synthetic estrogen because of its action on rodents
uterus [8]. In fact, diethylstilbestrol, a structural analog, was
found to be much more potent. Later, BPA has been widely used
for its cross-linking properties in the manufacture of polycarbonate plastics and epoxy resins. Due to real advantages in terms
of heat resistance and elasticity, the use of BPA has progressively increased all over the world with an annual production,
higher than 10 millions of tons. It has become ubiquitous in a lot
of domestic products such as plastic bags, bottles, coated tins,
dental sealants, paintings, CD-Rom, etc. Because of incomplete
polymerization and degradation of the polymers by exposure to
higher than usual temperatures such as microwaves use with
plastic film or containers [9], BPA has been found to leach
out from food and beverage, as well as from dental sealants.
Exposure to environmental nanomolar concentrations of BPA is
ubiquitous and continuous, via different routes: oral absorption,
air, skin. In humans, free active unconjugated BPA is metabolized by rapid glucurono- or sulfono-conjugation and eliminated
via renal clearance. It is present in the urine of 90% of cases in
an American reference population (0.21.6 ng/mL) [10] and in
most bloods, maternal milk or amniotic fluid [11].

Its structural analogy with DES (Fig. 1), with its supposed
xenoestrogenic effect, as well as its increasing underspread
background exposure have led to numerous toxicological tests in
rodents. After fetal or perinatal exposure, these tests have shown,
at low, environmentally relevant concentrations, to affect the
brain, liver, gut, adipose tissue, endocrine pancreas, mammary
gland and reproductive tract and function. Similar concentrations are also able in vitro to impact human malignant breast,
prostate, male germ or adipocyte cell lines with a promoting
effect [12,13], or by interfering with chemotherapy drugs, or
to stimulate pancreatic ! cell insulin secretion. High levels of
free active BPA have recently been correlated with obesity, diabetes, cardiovascular diseases, polycystic ovarian disease or low
sperm count. All these experimental and epidemiological data
have led to increasing concerns about the real impact of chronic
BPA exposure on human health and what should be an objective and realistic regulatory policy concerning the determination
of maximum thresholds or even its prohibition, as was recently
decided [14] in France concerning baby bottles in 2011 leading
to complete prohibition after 2014.
3. Obesity and metabolic syndrome
A recent working document of ANSES proposed the recommendation of a total BPA prohibition because of indirect
evidence supporting its involvement in obesity, metabolic syndrome and diabetes [7]. In mice, fetal or perinatal exposure
to low, environmentally relevant doses of BPA induces in the
offspring an increase of adult weight, depending on sex, dose
and window of exposure [1519], associated to metabolic syndrome [20]. Similar effects have been described after neonatal
exposure to DES [21]. BPA stimulates in vitro differentiation of
murine fibroblasts into adipocytes and increases lipid storage in
a dose-dependent manner [2224]. Low doses of BPA inhibit
adiponectin secretion by human adipocytes cultures in vitro
and stimulate the secretion of interleulin 6 and TNF", two
inflammatory adipokines, suggesting its possible involvement
in obesity, metabolic syndrome and insulin resistance [2527].
It also results in deleterious effects observed both on the energetic inbalance and glucose homeostasis via its effects on liver,
adipose tissue and pancreatic islets [27]. In humans, although
rapidly metabolized in the liver into inactivated glucurono- or
sulfo-conjugates and theoretically immediately eliminated by
renal excretion, BPA was shown to accumulate into the adipose
tissue. This could explain its blood persistence during fasting
[28]. A recent French epidemiological study reported a nonmonotonous, inversed U shape dose-response relation between
maternal urinary BPA and newborn weight [29] quite concordant
with what was observed in rodents [15]. Several recent epidemiological studies in adults have tried to correlate urinary BPA
and obesity. First an American study concerning 2700 adults
reported a positive correlation with general obesity, central obesity, and insulin resistance [30]. A Chinese study involving 3400
middle age adults found quite similar results [31]. However,
both studies were retrospective, cross-sectional with a single
urinary sample, traducing only the recent exposure. Both wondered with honesty whether this correlation was causal or linked

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213

Fig. 1. Xenoestrogens: notice the bisphenol A structural analogy with various xenoestrogens like diethylstilbestrol, un estrogne de synthse, DDT, an organochloride
pesticide, PCB an industrial chemical and resveratrol, a phytoestrogen.

to an excessive intake of sweet beverages from canned tins well

appreciated by over-weight people. In women, blood BPA levels
have been correlated with PCO, an endocrine disease associated
with obesity, insulin resistance and hyperandrogenia [32,33].
Indeed, nowadays exposure to BPA has emerged as a possible
risk factor able to accelerate, the development of obesity and
metabolic syndrome [7,27].
4. Diabetes
Animal experimental models, cell cultures using murine or
human pancreatic ! cells and epidemiologiocal studies, suggest
also that exposure to BPA might participate to the increasing
incidence of type 2 diabetes. Adult male mice exposed to BPA
develop both hyperinsulinemia and mild insulin resistance [20].
This impairment occurs through a direct effect on pancreatic
cells, as described later, but also by impairment of insulin signal
transduction at the level of peripheral tissues (muscle, liver, adipose tissue). BPA induces an oxidative stress in rodent liver by
decreasing expression of anti-oxydative enzymes [34]. Sakurai et al. [35] have shown that in adipocytes, BPA increases,
basal and insulin-activated glucose transport, by stimulating
GLUT4 expression. At the level of pancreatic islets, BPA is
able to suppress in vitro, glucose-induced calcium oscillations,

which control glucagon secretion [36] in " cells. On ! cells,

very low doses of BPA (0.1 nM) increase glucose-induced calcium oscillations frequency leading to a higher insulin secretion
[37]. These rapid effects observed in vitro are confirmed on
entire murine pancreatic islets [37]. These effects mimic the
rapid effects induced by estrogens, which are mediated by
non-classical membrane estrogen receptors as described later
[20]. In vivo BPA is able as estrogens to decrease very rapidly
(30 minutes) glucose blood level by stimulating insulin secretion [20] and by stimulating AMP dependent transcription factor
CREB which regulates both insulin gene expression and ! cells
survival [38]. A longer exposure to BPA in rats, induces after 4
days, chronic hyperinsulinemia and insulin resistance [20]. Two
kinds of arguments allow a possible extrapolation to humans.
First, identical rapid effects of BPA have been reported on human
pancreatic ! cells [39]. Secondly, several epidemiological, retrospective cross-sectional studies found a correlation. All these
studies belong to the American study of the National Health
and Nutrition Examination Survey (NHANES). The first one
was performed during the period of 20032004 with adults
aged 18 to 74 years from the general. After normalization for
age, sex, ethnic background, education level, smoking, BMI,
waist circumference, and urinary creatinine level, it found a
positive correlation between urinary BPA and the presence of

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a self-reported diabetes [13]. The highest levels of BPA were

associated with the highest BMI values and one may wonder
one more time whether it represents the recent exposure to BPA
leached out from soda cans, which are more frequently used
by the obese people or if it could be a marker of exposure to
multiple EED including BPA [13]. Several similar studies performed from 2005 to 2008 found discordant results [40,41].
However, Shankar et al. [42], selecting from these different
studies of NHNAES the patients for whom biological results
were provided, could find after similar normalization, a positive
correlation with diabetes diagnosed either by fasting glycaemia
greater than 1.26 g/L; fasting or not fasting glycaemia greater
than 2.00 g/L or HBA1c greater than 6.5%. This possible risk
factor independent from classical risk factors of type 2 diabetes
has to be confirmed by prospective longitudinal studies.
5. Reproductive studies
5.1. Polycystic ovaries and BPA exposure
Polycystic ovaries (PCO) is considered to be the result of both
genetic and environmental factors. Neonatal exposure to BPA
in rats induces an adult syndrome very similar to human PCO
[43]. In vitro BPA stimulates testosterone secretion by ovarian
theca cells in rats [44]. In adult women with PCO, blood BPA
level is higher than in control women with normal ovulation and
without hyperandrogenia, independently of the presence or not
of obesity [33], and BPA correlates with androgens.
5.2. Cryptorchidism
Cryptorchidism or undescended testis (UDT) is the most frequent male congenital malformation and its incidence at birth
(>2%) may have increased over the last decades. UDT is a risk
factor for hypofertility and testicular cancer. It remains idiopathic in most cases but genetic and environmental factors have
been suggested [45,46]. We and others have found in mother
milk higher levels of some EED in UDT [46,47]. While cord
blood BPA was not found significantly increased in UDT [48]
(Fig. 2), we could identify in the whole population (UDT and
controls) a negative correlation between cord blood BPA and
insulin-like peptide 3 (iNSL3) a Leydigian hormone involved in
testicular descent, with INSL3 significantly lower in the UDT
group versus control [49].

Fig. 2. Human bisphenol A (BPA) cord blood levels. Free BPA cord blood levels
were compared in male born after 35 weeks of amenorrhea with or without
undescended testis (UDT).
From Fnichel et al. [48].

could find a correlation between urinary BPA, number, motility

and sperm vitality.
6. Hormone dependent cancer studies

5.3. Male hypofertility

6.1. Breast cancer
Estrogenic and anti-androgenic effects of BPA have been
demonstrated in vivo and in vitro in rodents [50]. For this reason,
testicular function has been particularly studied. In rodents, BPA
reduces Leydigian secretion of testosterone [51]. In Sertoli cells,
it induces an impairment of junctional proteins [52] and stimulates in vitro human seminoma cell proliferation [53,54]. In utero
exposure in rats, leads in adult male to impaired spermatogenesis [55]. Few human epidemiological studies have been able to
correlate urinary BPA and sperm quality. Recently, Ly et al. [56]

Breast cancer is the most frequent cancer in women with

one million of new cases every year all over the world including 40,000 in France corresponding to 32% of feminine cancers
[57]. It represents 2% of all causes of women deaths and the
first cause by cancer. Its incidence is still increasing (two-fold
increase within the last 20 years), 2 to 5% more every year
depending on the part of the world, with a great disparity between
on the one hand North America, Europe and Australia which are

P. Fenichel et al. / Annales dEndocrinologie 74 (2013) 211220

high-incidence areas, versus on the other hand, Asia or Africa

with a lower incidence [58]. These geographical differences suggest environmental factors supported by the data obtained from
migrant populations from Asia to America and the fact that less
than 10% of breast cancers are associated with germinal mutations [59,60]. For all these reasons, nutritional and/or toxicant
factors including EED with estrogenic effects have been suggested. Indeed, the carcinogenic effect of fetal programming
by exposure to low doses of some of them, including BPA, has
been clearly established in rodent models. Fetal exposure to BPA
induces in mice at the peripubertal period, an impaired development of the histological architecture of the mammary glands
with an enhanced sensitivity to estrogens, an increase in area and
number of terminal buds when normalized to the total canalar
structures, a decrease of apoptotic activity, an increase of the
number of epithelial cells expressing the progesterone receptor
and an increase of lateral canalar ramifications [61,62]. These
observed abnormalities suggest that development and morphogenesis have been disturbed during the fetal exposed period.
This was identified and confirmed during this period in fetal
mice [63]. Moreover, in Wister rats, prenatal exposure to BPA
was associated in adults with changes in epithelial and stromal
tissues, an increased ratio proliferation/apoptosis and a clear
decrease of the doses of carcinogens necessary to induce neoplastic lesions, doses which remain without any effect in control
animals non exposed in utero to BPA. All these elements support an increased susceptibility to develop a mammary cancer.
BPA is able to stimulate in vitro human breast cancer cell proliferation [64]. Strikingly, BPA is also able at very low doses
(nM) similar to the blood level found in the general population,
to induce in vitro a chemo-resistance on several human malignant breast cell lines whether these cells are ER" positive or
negative, while it increases expression of several anti-apoptotic
proteins [65]. Nevertheless, up to now, no epidemiological study
has been reported correlating chronic exposure to BPA with an
increased risk of breast cancer as it has been shown for some
EED [59], although one has to consider the methodological
difficulties associated to such a demonstration [66].
6.2. Prostate cancer
Prostate cancer is the most frequent cancer of the elderly man
more than 50 years and the second cause of male death by cancer. Its incidence is still increasing independently of age [67].
Despite a better screening and treatment, its mortality remains
high when the androgen dependent phase is over. Among the
risk factors, only nutritional (high fat diet) and genetic (familial and ethnic) have been well identified but here too the role
of EED has been suggested. The prostate gland is classically
androgen dependent, develops during puberty under androgen
control. Androgen dependence of prostate cancer allows antiandrogenic treatment. But additive hormonal control through
estrogens in normal and malignant prostate development is supported by many experimental data [68]. Aromatase and ER
(both ER" and ER!) are expressed in human prostate [68].
Maternal estrogens allow at the third trimester of pregnancy
the growth of the prostate gland in men. When exposed to DES

215

given during the pregnancy to their mothers the newborn presented prostate hyperplasia [69]. A recent study performed in the
French Antilles, have clearly illustrated the likely risk factor of
chronic exposure to chlordecone, an estrogenic organochloride
pesticide in the occurring of prostate cancer [70]. Chlordecone
or kepone has been widely used in the French Antilles during 1973 and 1993 in the culture of banana. Its degradation
is very slow and it will persist in groundwater during several
decades. In rodents, it acts as a carcinogen able to induce liver
cancer. In men this case/control study has been performed in
a limited geographical area with a controlled exposure, which
has allowed to support the relation between chlordecone exposure and prostate cancer risk independently of ethnical origin
or other statistical bias or confounders. The risk was positively
correlated to chlordecone blood levels and enhanced in men
greater than 60 years, with familial antecedent and/or in presence of a specific polymorphism for the chlordecone reductase
gene coding for an enzyme involved in hepatic detoxification
[70]. Moreover, tumoral aggressiveness was correlated with
chlordecone blood levels [70]. These epidemiological data are
supported by experimental ones. Fetal or perinatal BPA or DES
exposure in rodents, are associated in adults with prostate hyperplasia and pre-malignant lesions [68]. This perinatal exposure
to BPA or to estradiol increases the susceptibility to develop a
prostate cancer either spontaneously or after a second estrogenic
shot [71]. In order to explain the therapeutic escape to antiandrogens in prostate cancer becoming androgen independent,
several mechanisms have been proposed including the occurring of secondary mutation of the androgen receptor gene [72].
In some of these cases, it has been shown in vitro that cancer
cells became sensitive to BPA, activating proliferation through
this mutated receptor [73].
6.3. Testicular cancer
Testicular germ cell cancers (TGCC) represent only 2% of
all cancers but they are the most frequent cancer in young man
with an increasing incidence all over the world estimated as 2
to 3% every year [74]. This increase remains unexplained but
the possible role of in utero exposure to EEP interfering in the
malignant transformation of fetal stem germ cells, the gonocytes,
into TGCC [75], are supported by several epidemiological and
experimental data. In the USA, among the agriculture workers exposed to pesticides, an odd ratio of 6 has been found for
testicular cancer when compared to control [76,77] especially
for atrazine, an organochloride estrogenic pesticide which is still
widely used in the West of France. Hardell et al. [78] have studied
in Sweden the correlation between TGCC and the blood levels
of several EED in patients and their mothers. Strikingly, no correlation was observed with the patients levels but the mothers
levels when elevated were associated with an increasing risk
with an odd ratio of 4 for PCB (bisphenyls polychlors), HCB
(hexachlorobenzene), nonachlordane, all estrogenic EED, but
not with ppDDE a stable anti-androgenic derivative of DDT supporting the role of fetal exposure to xenoestrogens [78]. However
is TTGC really estrogen dependent as other classical estrogen dependent cancers? In fact we and others have shown that

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Fig. 3. Bisphenol A (BPA) regulates human seminoma cell proliferation. Very low doses of BPA (pM) stimulates human seminoma cell proliferation in vitro. Notice
that the dose/response curve is not monotonic but an inversed U shape, which can be explained by two different effects mediated by two different receptors. FIRST
BPA stimulates at low doses cell proliferation through a non-classical membrane estrogen receptor, GPR30 for whom it presents a very high affinity; secondly BPA
triggers a suppressive effect through ER! at high doses because of a relative low affinity.
From Bouskine et al. [53].

seminoma, the most frequent testicular germ cell cancer,

expresses both aromatase and ER! but not ER" [79]. At the
opposite of prostate or breast cancer, it is not possible to induce
experimentally a TGCC in rodents by fetal exposure to BPA or
other estrogenic EED and seminoma rodent models do not exist
at all. For this reason we have used a human seminoma cell line to
demonstrate that estrogens and xenoestrogens were able to stimulate cell proliferation in vitro [79,80]. Estradiol 17!, the natural
estrogen induced a suppressive effect on seminoma cell proliferation through the classical estrogen receptor ER! [79]. Estradiol
when coupled to bovine serum albumin which cannot cross the
cell membrane, stimulate at the opposite of the free molecule,
cell proliferation through a non-classical G protein coupled
estrogen receptor (GPR30/GPER) [54,80]. Human seminoma
are therefore estrogen dependent and xenoestrogens may act
through two different receptors depending to their respective
affinity for them. We have screened several EED such as atrazine,
DES and BPA and observed different effects depending on the
resultant of the two receptors. Concerning BPA (Fig. 3), we were
able to demonstrate that very low doses of BPA (pM) under the
levels found in male cord blood [48] stimulate seminoma cell
proliferation through GPR30, a membrane associated estrogen
receptor, different from classical ERs [48]. The dose-response
curve was not monotonic but showed a inversed U shape (Fig. 3),
which could be explained by the resultant of the double opposite effect on ER! and GPR30 [53,81]. At low doses (nM or
pM), BPA acted only through GPR30 by a promotive effect.
At higher doses (mM), BPA acted also through ER!, which
counteracted the promotive GPR30 mediated effect [79]. Low
doses of BPA (nM) are similar to the one able in rodents when
exposed in utero, to induce mammary or prostatic malignant
lesions in adult [82,83] as described before. We have recently
shown that seminoma over express GPR30 [81] likely through a
specific polymorphism abnormally present in men with TGCC
conferring likely a genetic susceptibility to such cancers.
7. Exposure to BPA and thyroid function
BPA may interfere with thyroid hormone action [84]. A
recent human epidemiological study reported an inverse relation

between BPA concentration in maternal urine and maternal

serum total T4, during pregnancy [85]. The association was
stronger when maternal urinary BPA and serum total T4 were
measure closer together, suggesting a transient effect of BPA,
and when measured in the third trimester of pregnancy [85].
They also reported an inverse correlation between maternal BPA
and neonatal TSH but only in male, which could be explained
by a sexual differentiation of UDP-glucuronosyl transferase
expression as shown in rat [86]. A negative correlation between
cord blood fT4 and maternal milk PCB118, PCB180 and DDE
has also been reported [87].
8. Metabolism, storage, waste, dosage
Free BPA, the active form, is theoretically in humans rapidly
glucurono or sulfo conjugated by the liver and evacuated
by the kidney as demonstrated by the pharmacokinetic study
after absorption of an unique oral dose [88]. This kinetics is
different from rodents and this difference has been used to contest any chronic potential deleterious effect [89,90]. However,
lots of studies have nevertheless identified relatively high levels of free BPA in cord blood, amniotic fluid, plasma or urine
of adults from general populations [11]. Its blood persistence
during fasting [28] suggests that BPA is stored in adipose tissue and unless a relative lipophility [28]. Moreover daily oral
absorption contributes to maintain constant high blood levels.
Moreover sulfatases and/or glucuronidases are present in several adults organs and highly expressed in the placenta which
could explain that relative high free BPA levels are present in
the blood flow, which is the only form able to induce deleterious effects as EED. The fetus and the newborn seem to be
particularly exposed [91,92] in part due to hepatic immaturity of
detoxification enzymes. Chromatography and mass spectrometry represent the reference in term of free or conjugated BPA
in blood or urine. Moreover a RIA (roter interaction analysis) has been proposed and validated by H. Dchaud at Lyon
[48,93]. It allowed us to confirm the presence of free BPA in cord
blood and pregnant women between 1 and 10 ng/mL [48]. However, one must be very careful to avoid plastic contamination
from transport, storage and manipulation of the samples at the

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217

Table 1
Interactions bisphenol A (BPA)/hormone receptors.
Receptor

Location

Effect

References

ERK
ERK
ERK
GPR3Q
ERRK
AR
PPARK
TR

Nuclear
Membrane
Nuclear
Membrane
Nuclear
Nuclear
Nuclear
Nuclear

Agonist
Agonist
Agonist
Agonist
Agonist
Antagonist
Antagonist
Antagonist

[14,63,90,94]
[14,39]
[14,39,90]
[36,37,52,53,63,77]
[9294]
[95]
[96]
[81,97]

laboratory and the simple perfusion of the patient before

increases the BPA concentrations due to release from the tubulures and perfusion bottles.
8.1. BPA, an endocrine disruptor: which receptors?
One important question concerning the endocrine disruption
mediated by BPA is whether it acts really as a weak estrogen
since its affinity for the classical nuclear ER" is 10,000 times
weaker as for estradiol 17 ! and 1000 weaker than affinity for
ER! [94]. For this reason BPA at the nanomol concentration
found in humans should not been considered as an estrogenomimetic at all [95]. Different explanations have been proposed
for this apparent paradoxal criteria, especially the involvement
of non-classical membrane estrogen receptors. One of this receptor G protein coupled, GPR30 have been identified. This GPCR
is present in breast cancer cells, ! Langerhans islets, adipocytes
with a very high affinity for BPA and mediates activation of
signaling pathways classically involved in the control of cell
proliferation, apoptosis and survey. In our laboratory, we have
shown its promoter role on human seminoma cells [53,54].
Another receptor, ERR# (estrogen-related receptor-gamma), a
nuclear receptor, has also a good affinity for BPA [96]. It is
present on adipocytes [97]. GPR30 and ERR# are both expressed
by ER" and ER! negative breast cancer cells which respond to
estrogens and BPA [98]. An anti-androgen effect has also been
identified at the AR level for BPA [99]. It can also interact with
PPAR# as an antagonist [100] able to inhibit adipocyte proliferation and also as an antagonist for thyroid hormone receptors
TR (Table 1) [101].
8.2. Molecular mechanisms programming in utero the
developmental origin of adult diseases induced by EED
Fetal or perinatal developmental origin of adult diseases has
been nicely analyzed for bisphenol A concerning mammary carcinogenesis consecutive to very low doses administrated during
this critical period in rats and mice which have later developed
pre or malignant lesions. Bromer et al. in 2009 have characterized the imprinted molecular mechanisms, which have led after
in utero exposure to DES, to uterus cancer in mice. They identified one gene HOXA10 coding for a transcription factor involved
in uterus growth and which promoter region was hypomethylated through BPA exposure [102]. This epigenetic modification
is traduced into adult overexpression of HOXA10, influencing

Fig. 4. Fetal exposure to environmental exposure disruptors (EED), epigenetical modifications and hormone dependent cancers. Hormonal disruptions during
development such as for example exposure to EED are able to induce epigenetical modifications, which will later at adult participate to the malignant
cell transformation when associated to de novo mutations or new epigenetical
alterations.
From Chiam et al. [109].

carcinogenesis. Other DES induced epigenetic changes have

been reported for the oncogene c-fos which showed a similar
gene hypomethylation leading to its overexpression in adult
uterus stimulating cell proliferation [103]. Similar modifications concerning HOXA10 gene have been reported with BPA
[104] and methoxychlore an estrogenic organochloride pesticide
[105]. DNA methylation is an epigenetic hallmark involved in
the initiation and/or promoting phase of carcinogenesis [106].
Ho and Prins [71,83] have studied the epigenetic changes
induced in prostate rat by BPA or estrogens fetal or perinatal
exposure. Out of 50 gene sequence changes they identified a gene
coding for a particularly interesting enzyme phosphodiesterase
4D4, which degrades cAMP. Hypomethylation of this gene is
correlated with the overexpression of the protein. Hypomethylation could be identify before adult age before any histological
modification and could therefore serve as an early biomarker
[83]. Hypomethylation of this, gene is also present in human
prostate cancer. These modifications observed after EED exposure are likely induced through the action of DNA methyltransferases (DNMT), enzymes which control DNA methylation on
the CpG islets [102]. There are some data suggesting that these
enzymes are regulated by classical estrogen receptors [103]
and/or other nuclear or not nuclear receptors [37,107,108]. Fig. 4
summarizes the proposed mechanism through which EED will
imprint epigenetic changes after fetal in utero exposure which

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P. Fenichel et al. / Annales dEndocrinologie 74 (2013) 211220

will contribute with others deleterious factors to malignant transformation by enhancing chromosomal instability [109].
9. Conclusion
In conclusion there are solid arguments to support a deleterious role for bisphenol A after chronic exposure but its real
participation in human health remain to be demonstrated. BPA
is ubiquitously present in the current environment. Low doses
of BPA environmentally relevant might interfere in the development of chronic metabolic diseases, reproductive pathologies,
hormone dependent cancers (prostate, breast, testes). However,
prospective longitudinal studies are needed to confirm such a
responsibility. It is also necessary to identify biomarkers of duration and intensity of exposure and to recognize early induced
molecular imprintings (gene methylation, histone modifications,
microRNAs). ANSES works has led first to the prohibition of
baby bottles in 2011 in France and for 2014 to the complete
prohibition of BPA use.
Disclosure of interest
The authors declare that they have no conflicts of interest
concerning this article.
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