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Bisphenol A and human chronic diseases:

Current evidences, possible mechanisms, and
future perspectives

Article in Environment international March 2014

DOI: 10.1016/j.envint.2013.12.007

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 Environment International 64 (2014) 8390

Contents lists available at ScienceDirect

Environment International
j o u r n a l h o m e p a g e : w w w.e l s e v i e r . c o m / l o c a t e / e n v i n
t

Review

Bisphenol A and human chronic diseases: Current evidences,

possible mechanisms, and future perspectives
Raja Rezg a,b,
, Saloua El-Fazaa a, Najoua Gharbi a, Bessem Mornagui a,c
a
University of Tunis El Manar, Faculty of Sciences of Tunis, Laboratory of Physiology of the Aggressions, Tunisia
b
University of Monastir, High Institute of Biotechnology of Monastir, Department of Biology, Tunisia
c
University of Gabes, Faculty of Sciences of Gabes, Department of Life Sciences, Tunisia

a r t i c l e i n f o a b s t r a c t
Article history: Bisphenol-A (BPA) is one of the highest volume chemicals produced worldwide, with over 6 billion pounds
Received 29 August 2013
pro- duced and over 100 t released into the atmosphere each year. Recent extensive literature has raised
Accepted 5 December 2013
concerns about its possible implication in the etiology of some human chronic diseases such as diabetes,
Available online 29 December
2013 obesity, reproduc- tive disorders, cardiovascular diseases, birth defects, chronic respiratory and kidney
diseases and breast cancer. In this review, we present the highlighted evidences on the relationship between
Keywords: BPA exposure and human chronic diseases and we discuss its eventual mechanisms of action, especially
Bisphenol A genetic, epigenetic and endocrine disrup- tion mechanisms with the possible involvement of oxidative stress,
Chronic human diseases mitochondrial dysfunction and cell signaling.
Etiology 2013 Elsevier Ltd. All rights reserved.
Mechanisms

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
1.1. Source of exposure in different life stages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
2. Evidences for the relation between exposure to bisphenol A and chronic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
diseases
2.1. Diabetes and obesity induction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
2.2. Cardiovascular disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
2.3. Chronic kidney disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
2.4. Birth defects and developmental disorders . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
2.5. Reproductive disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
2.6. Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
2.7. Chronic respiratory disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
3. Mechanisms linking bisphenol A exposure to chronic diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
. 3.1. Genetic damages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
3.2. Epigenetic effects of BPA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
3.3. Endocrine disruption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
3.4. Oxidative stress and mitochondrial dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
3.5. Cell signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
4. Conclusion and perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
Conict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88

Abbreviations: AR, androgen receptor; BPA, bisphenol A; CpG, cytosine-guanine dinucleotide; DNMT, DNA methyltransferases; ER, estrogen receptor; ERK, extracellular signal-
regulated kinase; ERR-, estrogen-related receptor gamma; GPR 30, G protein-coupled receptor 30; GR, glucocorticoid receptor; IVF, In vitro fertilization; JNK, c-Jun N-terminal
kinase; LOAEL, lowest observed adverse effect level; NF-b, nuclear factor-kappa B; POP, persistent organic pollutant; TDI, tolerable daily intake; THR, thyroid hormone receptor.
Corresponding author at: Laboratory of Physiology of the Aggressions, Department of Biology, Faculty of Sciences of Tunis, University of Tunis El Manar, Campus Universitaire
2092 El
Manar, Tunisia. Tel.: + 216 22238489; fax: + 216 71871666.
E-mail address: raja.rezg@laposte.net (R. Rezg).

0160-4120/$ see front matter 2013 Elsevier Ltd. All rights

reserved. http://dx.doi.org/10.1016/j.envint.2013.12.007
 R. Rezg
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1. Introduction 2. Evidences for the relation between exposure to bisphenol A
and chronic diseases
Bisphenol-A (BPA) is one of the highest volume chemicals pro-
duced worldwide. Current estimation indicates that over 6 billion Chronic diseases are characterized generally by their slow
pounds were produced annually (Van d enberg et al., 2 0 09 ) in progres- sion and long term duration, which are considered as the
the manufacturing of polymers (such as polycarbonate, epoxy leading
resins, polysulfone, or polyacrylate), polyvinyl chloride plastics and
ame retar- dant tetrabromobisphenol-A (Geens et al., 2012a).
Polycarbonate is used in materials of foodstuffs (such as baby bottles,
reusable plastic bottles, plates, goblets, cups, microwave ovenware,
and storage containers) and the epoxy resins are used for internal
coating of food and beverage cans (Geens et al., 2011). Currently,
the applications of polycarbonate and epoxy resins were extended
into other uses of life such as sunglasses, thermal papers, building
materials, CD-ROM, medical devices, and dental materials (Geens et
al., 2012a). Thus, over 100 t of BPA are released into the atmosphere
every year of production (Vandenberg et al., 2009).

1.1. Source of exposure in different life

stages

Aquatic environment, air and soil can be a source of human BPA

ex- posure, but food is believed to be the major source of exposure
(Kang
et al., 2006). Indeed, under various conditions, BPA can leach out of
con- tainers and pass to the food or beverage which is then a
source for human exposure. Co op er et a l. ( 2 011 ) have
detected 0.234 ng/ml
( 1 nM) of BPA after 5 days of water incubation at polycarbonate
plas-
tic water bottles at room temperature and this amount can increase
when hot water was used. The authors concluded that detectable
con- centrations of BPA leach from everyday plastic containers and
that heating can increase this leaching (Cooper et al., 2011). In the
same con- text, food cans often contain BPA during the sterilization
process at high temperature or when heated for use. This raises
questions about using plastic products for holding solutions or for
heating food. Indeed, BPA was detected in canned food products from
Canadian markets within diverse concentration which differed
considerably among food types. To name but few, canned tuna
products had the highest BPA concentra- tions (137534 ng/g) (Ca o
et al., 2010).
In addition to consumption of contaminated drinks and foodstuffs,
dermal exposure was suggested through paper contact especially
ther- mal printed paper which are typically used in point of sale
receipts (fast food restaurants, retailers, grocery stores, gas stations,
and post ofces) (Bi ed er m a nn et al ., 2 010). BPA was detected
in thermal paper with detectable concentration recorded in many
developed countries (Belgium, Denmark, Sweden, Switzerland and
US). This let us suggest dermal route as an important additional
exposure source for the general population, which warrants further
inclusion in the overall risk assess- ment of BPA (Geens et al.,
2012b). Also, gestational and lactational ex- posures are proved in
human (Braun et al., 2009, 2011; Fenichel et al.,
20 12) and in rodent model at and below the published LOAEL
dose
(0.05 mg/kg BW/day) (Table
1).
However, it has been suggested that daily intake of BPA for
humans (infants, children and adults) may be considerably less than
the tolerable daily intake (TDI) of 0.05 mg/kg BW/day in the USA and
the temporary TDI of 10 g/kg BW/day in the European Union
because the divergence between country migration levels of BPA in
foods. The daily human in- take of BPA must be less than 1 g/kg
BW/day (Kang et al., 2006). In- deed, several in vivo studies have
reported signicant effects in animals with doses below the
published LOAEL of 0.05 mg/kg BW/day (Table 2) which was
established based on toxicological studies conduct- ed in the 1980s in
which the lowest dose tested was 1000-fold higher than this
predicted safe (Welshons et al., 2006).
 R. Rezg
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et /al.Environment
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8 of mortality in the new world, representing
cause over 60% of all
90 90
deaths. According to the WHO report, 36 million people died from
chronic dis- ease in 2008 with approximately 29% under 60 years old
(http://www. who.int/topics/chronic_diseases/en/). Positive
correlations between BPA levels and some human diseases have
been reported in epidemio- logical studies which reveal a pressing
need for further studies in devel- oped and developing countries in
order to more conrm this link (Table 3).
2.1. Diabetes and obesity
induction
347 million people worldwide are considered to be diabetic and
based on WHO belief, diabetes deaths are expected to double
between
2005 and 2030 (http://www.who.int/diabetes/en/index.html)
making diabetes disease one of the most important public health
challenges to all nations. At the same time as genetic link, a number of
lifestyle behav- iors and inevitable xenobiotics exposure have also
been suggested as contributing factors in the development of this
disease (Alonso- Magdalena et al., 2010). Indeed, recent
experimental studies have sug- gested that BPA affects glucose
metabolism through diverse mecha- nisms including insulin
resistance, pancreatic beta-cell dysfunction, adipogenesis,
inammation and oxidative stress which presumed a plausible
connections between BPA and diabetes (Alonso-Magdalena
et al., 2006, 2010, 2011). It has been reported that higher BPA
exposure, reected in higher urinary concentrations of BPA recorded
in the gener- al adult population of the United States (1455 adults
aged 18 through
74 years), may be associated with diabetes (Lang et al., 2008). More
re- cently Shankar and Teppala (2011) and Silver et al. (2011) found
the same conclusion in a representative sample of U.S. adult cohort
(2003 to 2008 National Health and Nutritional Examination
Survey), (Shankar and Teppala, 2011; Silver et al., 2011). A positive
association between urinary BPA levels and prediabetes in 3516
subjects free of di- abetes risk factors (body mass index, alcohol
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intake, blood pressure and serum cholesterol) has been reported. In8
subgroup analysis, this associ- ation was stronger among women and
obese subjects (Sabanayagam
et al., 2013). Thus, it has been suggested that exposure to BPA can
be a promoter for other risk factors of diabetes like obesity by
distressing neural circuits that regulate feeding behavior or altering
differentiation of adipocytes. Indeed, a positive association between
urinary BPA and obesity in general adult population of the United
States (Carwile and
Michels, 2011) as well as in children and adolescents has been
reported
(Brent, 2013).
2.2. Cardiovascular disease
Studies investigating the relation between cardiovascular diseases
and human BPA exposure are few, but an important predictive risk of
coronary artery disease in apparently healthy men and women
exposed to BPA has been reported. Indeed, urinary BPA
concentrations were higher in those with severe coronary artery
stenoses compared to those with no vessel disease (Melzer et al.,
2012a,b). Also, Lang et al.
(2008) have reported that BPA may be associated with avoidable
mor- bidity in the adult population. Indeed, urinary BPA
concentrations were associated with medical disorders and
laboratory abnormalities reecting cardiovascular diagnoses in age
and sex (Lang et al., 2008). More studies are needed to estimate
true doseresponse relationships and mechanisms of action.
2.3. Chronic kidney disease
In recent study, it has been reported that BPA concentrations is
high- ly and inversely correlated with renal function compared to
healthy controls (range 9.1 4.512.0 6.0 ng/mL vs. 0.2 0.1
ng/mL; P b 0.001). The authors suggested that due to high protein
binding,
the removal of BPA by hemodialysis is limited (Krieter et al., 2013). In
addition, dialyzers are considered as one additional source of BPA.
Table 1
Source of contamination with BPA and exposure pathways in different life stages.

Source of contamination Exposure pathway Age class/life stages Estimated daily intake Reference of epidemiological studies

Via father or mother exposed to BPA Fecondation and embryo transfer Embryos Bloom et al. (2011); Fujimoto et al. (2011)
Via mother exposed to BPA Placental and lactational routes Embryos and infant Braun et al. (2009, 2011); Fenichel et al. (2012)
Total food Alimentation Children 17002700 ng/day Wilson et al. (2007)
Contaminated air Inhalation Children 7.814 ng/day Wilson et al. (2007)
Dental surgery Children (N 6y) 215 ng/day von Goetz et al. (2010)
Total food Alimentation Adults 156010,453 ng/day von Goetz et al. (2010)
Dust Inhalation Adults 8.44109 ng/day Loganathan and Kannan (2011)
Thermal paper Dermal route General population 17.4541 ng/day Liao and Kannan (2011a)
Thermal paper Dermal route Occupational exposed 130340,590 ng/day Liao and Kannan (2011a)
Paper other than thermal paper Dermal route General population 0.1 ng/day Liao and Kannan (2011b)

2.4. Birth defects and developmental disorders
Welshons et al. (2006) have classied the birth defects or
congenital and developmental disorders induced by BPA among its
Large effects from small exposures (Welshons et al., 2006).
Indeed, birth defect causes physical or mental disabilities. It is
induced via structural or func- tional abnormalities existing at birth
or before birth and diverse types have been recognized as the
principal cause of death for infants during the rst year of life. There is
evidence that fetus is rapidly exposed, when the mother is fed BPA,
with very limited capacity to metabolize this ubiquitous compound
and other related molecules leading to serious complications (B ra u
n et a l. , 200 9, 20 11; F e ni c h el et al ., 2 012). It has been
reported that in-utero BPA exposure may affect male genital de-
velopment in a total of 153 boys, among them 56 with parental
occupa- tional exposure during pregnancy and 97 without (Miao et
al., 2011). Also, prenatal BPA exposure is correlated with adverse
birth outcomes including lower birth weight, smaller size for
gestational age and adipokine expression especially in male infants
in a birth cohort study (Chou et al., 2011).
2.5. Reproductive disorders
It seems that exposure to BPA might affect human reproductive
health by complicated mechanisms. Indeed, recent epidemiological
data showed that BPA exposure is associated with higher risk of male
sexual dysfunction in BPA-exposed workers reected by signicantly
increased risk of reduced sexual desire, erectile difculty, ejaculation
difculty and reduced satisfaction with sex life (Li et al., 2010a,b).
Re- cently, it has been reported that BPA exposure is signicantly
associated with decreased semen quality (Li et al., 2011),
androstenedione levels, free testosterone levels, free androgen
index, and increased sex hormone-binding globulin levels (Zh ou et
al., 20 13) as well as Jasarevic et al. who reported that exposure to
BPA at low doses can affect sexual
behaviors, even with no changes in sexual phenotypes or hormones
(Jasarevic et al., 2011). In women undergoing IVF, increased BPA
levels are correlated with a decrease in peak estradiol levels and
decreased oo- cyte retrieval numbers (Mok-Lin et al., 2010). Animal
studies showed that PBA can alter female as well as male
reproductive endpoints in BPA exposure via disruption of sexually
dimorphic pathways (Rubi n
et al ., 2 006), estrous cycles, number of oocytes, receptor
expression and cell proliferation in multiple compartments of the
uterus, testis weight at puberty and in adulthood, prostate size etc.
(Ric hte r et al .,
2 007; Vandenberg et al.,
2009).
2.6. Cancer
Few epidemiological studies have linked BPA to different types of
cancer, except breast cancer. Indeed some associations between BPA
levels and risks of breast cancer, such as age at rst birth and null
parity, in cohort of Korean women (N = 167) have been reported (Ya
ng et al .,
20 09a) and according to the Institute of Medicine (IOM), BPA is
consid- ered as a potential risk factor to breast cancer (Smith-
Bindman, 2012). Also, in vitro reports showed that low BPA doses can
accelerate mam- mary tumorigenesis and metastasis in MMTV-
erbB2 mice (Je nk in s
et al., 2011) and can induce a prole of tumor aggressiveness in
high- risk cells from breast cancer patients (Dairkee et al., 2008).
Hiroi et al.
(2004) have suggested the presence of associations between BPA
expo- sure and complex endometrial hyperplasia and endometrial
cancer (Hiroi et al., 2004).
2.7. Chronic respiratory
disease

Asthma is considered as the most common disorder among

chronic respiratory dysfunctions affecting both children and adults.
The preva- lence of asthma in children has risen in the last few
decades, currently

Table 2
In vivo studies of signicant effects at and below the published LOAEL of 0.05 mg/kg BW/day.

Species Dose Observed effect Ref.

Nonhuman primate 50 g/kg/day BPA exposure alters endometrial progesterone receptor expression Aldad et al. (2011)
Rat 40 g/kg/day Perinatal BPA exposure alters behavior Adriani et al. (2003)
2.4 g/kg/day Posnatal exposure alters testicular steroidogenesis Akingbemi et al. (2004)
50 g/kg and 50 mg/kg Neonatal exposure alters reproductive development and ovarian morphology Adewale et al. (2009)
50 g/kg/day Prenatal exposure offspring to metabolic syndrome Wei et al. (2011)
25 and 250 g/kg/day Prenatal exposure alters hypothalamic-pituitary-gonadal axis Ramos et al. (2003)
0.2, 2.0 and 20 g/kg/day BPA exposure induces reactive oxygen species generation Bindhumol et al. (2003)
Mice 5, 25 and 100 g/kg/day BPA exposure alters male and female fertility Al-Hiyasat et al. (2002, 2004)
20 g/kg BPA exposure alters female estrogen production Arase et al. (2011)
10 g/kg BPA exposure disrupts the pancreatic - cell function Alonso-Magdalena et al. (2006)
30 g/kg/day Prenatal exposure modulates regulates immune responses Yoshino et al. (2004)
20 g/kg Prenatal and lactational exposure alters behavior Nakamura et al. (2012)
10 g/kg/day fetal life or in adulthood exposure alters maternal behavior Palanza et al. (2002)
Table 3
Epidemiological studies of the relationship between bisphenol A and human diseases.

Disease Observed effect Ref.

Diabetes type 2 BPA exposure affect glucose metabolism Shankar and Teppala (2011); Silver et al. (2011)
Obesity BPA can be a promoter for obesity by distressing neural circuits that Bhandari et al. (2013); Carwile and Michels (2011)
regulate feeding behavior or altering differentiation of adipocytes
Cardiovascular disease Laboratory abnormalities reecting cardiovascular diagnoses in age Lang et al. (2008)
and sex and risk of severe coronary artery stenoses
Reproductive disorders Risk of male sexual dysfunction Galloway et al. (2010)
Risk of female sexual dysfunction Takeuchi et al. (2004)
Risk of delivering prematurely and recurrent miscarriage Cantonwine et al. (2010); Sugiura-Ogasawara et al. (2005)
Chronic kidney disease BPA exposure may affect renal function in addition to the Krieter et al. (2013)
consideration of dialyzers as one additional source of BPA
Birth defects and development disorders Male BPA exposure affect embryo quality during in vitro fertilization Bloom et al. (2011)
(IVF) Fujimoto et al. (2011)
Female BPA exposure may interfere with oocyte quality during IVF Miao et al. (2011)
Utero BPA exposure may affect male genital development Chou et al. (2011)
Prenatal BPA exposure is correlated with adverse birth outcomes
Respiratory diseases Risk of Asthma in children Spanier et al. (2012)
Behavior and executive disorders Impact of early-life bisphenol A exposure affect childhood behavior Braun et al. (2009)
and executive function in children Braun et al. (2011); Miodovnik et al. (2011)
Cancer Risk of endometrial hyperplasia and endometrial cancer Hiroi et al. (2004)
Risk of breast cancer Yang et al. (2009a)
Autoimmune diseases BPA may negatively affect human immune function Clayton et al. (2011)

affecting 1 in 10 children (Bloom et al., 2010). Recently, it has been In general, epigenetic mechanisms are frequently involved to
re- ported an association between postnatal urinary BPA switch on or off the genes that produce permanent changes associated
concentrations and asthma in children in a prospective birth cohort with the
study (n = 568) (Donohue et al., 2013). As well, BPA increased odds
of wheeze in early life, and the effect diminished over time from birth
to 3 years of age in the rst report focused to the prenatal association
of prenatal BPA expo- sure and wheeze in humans (Sp an ier et al. ,
2012). It has been demon- strated that BPA at low levels can cross
the human placenta in an ex vivo model (Balakrishnan et al., 2010).

3. Mechanisms linking bisphenol A exposure to chronic

diseases

3.1. Genetic damages

Genetic damages are considered as an important mechanism for

chronic diseases especially within the context of carcinogenesis and
ter- atogenesis. These are caused by direct interaction with genetic
material resulting in:
- Chromosomal aberrations: including aneuploidy (loss or gain of
whole chromosome), clastogenicity, and chromosomal segments
or rearrangements and/or
- DNA damage: including DNA strand breaks, DNA adducts or
sched- uled DNA synthesis and gene's mutation.
In vitro studies have shown that BPA can induce DNA adduct,
aneu- ploidy (George et al., 2008; J ohnson and Parry, 2008) and
mutagenicity (Takahashi et al., 2001), which can contribute to
infertility, miscarriages, and birth defects in humans. In reference to
the genotoxicity of BPA to the male reproductive system, DNA
adducts were shown to form in prostate cell lines that were
treated with either high-dose BPA for
24 h or low-dose BPA for 2 months (De Flora et al., 2011). Also,
several in vivo studies have demonstrated the formation of DNA
adducts and proteome alterations in the mammary tissue of mice
exposed to BPA through drinking water (Izzotti et al., 2009, 2010).
BPA was reported to induce micronuclei and modify the functioning
of the microtubule organising centers (MTOCs) of the mitotic spindles
of cultured mamma- lian cells in a dose-dependent manner and to
disrupt meiotic double- strand break repair (DSBR) progression
(Allard and Colaiacovo, 2010).

3.2. Epigenetic effects of

BPA
differentiation of diverse cell types and currently, are gaining new
per- spectives in human diseases such as cancer, diabetes type 2 (Liu
et al.,
2008), aging (Gr a vi n a a nd Vi j g, 201 0) chronic kidney
disease (Dwivedi et al., 2011), and atherosclerosis (Lund and Zaina,
2011). Re- cent investigations have examined the relationships
between exposure to environmental chemical xenobiotics and
epigenetic effect induction and have reported that several toxicants
have a potential role in modi- fying epigenetic marks (Liu et al.,
2008). Supporting this idea, exposure to bisphenol A has been
observed to alter developmental pathways and cell processes, at least
in part, through epigenetic mechanisms (Singh
an d Li , 201 2). Generally, an epigenetic effect is dened as
heritable changes in gene expression or cellular phenotype without
any alter- ations in the DNA sequence, and its mechanisms include
DNA methyla- tion, histone modications and expression of
non-coding RNAs (including microRNAs) (Singh and Li, 2012). So,
the neonatal exposure to BPA was shown to induce
hypermethylation of estrogen receptor promoter regions in rat
testis, indicating methylation mediated epige- netic changes as one
of the possible mechanisms of BPA induced ad- verse effects on
spermatogenesis and fertility (Doshi et al., 2011). Also, a signicant
decrease in CpG (cytosineguanine dinucleotide) methyla- tion
upstream of the Agouti gene in viable yellow mice has been report-
ed. Whereas this hypomethylating effect of BPA was prevented by
maternal dietary supplementation with a methyl donor like folic acid
or the phytoestrogen genistein (D ol in oy et al ., 2 007). The
authors have concluded that early developmental exposure to BPA
can change offspring phenotype via epigenome alteration. Exposure
of human pri- mary breast epithelial cells to low-dose BPA was
reported to increase DNA methylation at CpG islands of lysosomal-
associated membrane protein 3 (LAMP3) gene and repress the
expression of LAMP3 gene in- dicating that BPA may increase breast
cancer risk later in life (Weng et al., 2010). On the other hand, it has
been demonstrated that BPA al- ters the gene expression of
epigenetic regulatory factors such as DNA methyltransferases
(DNMTs) and methyl-CpG binding protein 2 (MECP2) in a dose-
dependent mechanism in developing hypothalamic cells exposed to
BPA (0.02200 M BPA). The authors have concluded that BPA
disrupts the stability and the exibility of epigenetic gene reg-
ulation, which could disturb later the normal development of
hypotha- lamic functions (Warita et al., 2013). Also, as an epigenetic
mechanism linking endocrine disruptors to breast, it was established
that BPA in- creases the expression of the histone methyltransferase
Enhancer of Zeste Homolog 2 (EZH2) level in human breast cancer
MCF7 cells and mammary glands of six-week-old mice exposed to
BPA in utero (Do h er ty et al . , 201 0). In addition, BPA exposure
has been shown to
Fig. 1. Cellular and molecular mechanisms of action of BPA in human chronic disease induction. AR: androgen receptor, ER: estrogen receptor, ERK: extracellular signal-regulated
kinase, ERR-: estrogen-related receptor gamma, GPR 30: G protein-coupled receptor 30, GR: glucocorticoid receptor, JNK: c-Jun N-terminal kinase, NF-b: nuclear factor-kappa B
THR: thyroid hormone receptor. -Bisphenol A has a potential role in the etiology of some human chronic diseases. It can act via molecular mechanisms including genetic alterations
(DNA adduct, an- euploidy, mutagenicity), epigenetic alterations (DNA methylation, histone modications, microRNA expression) and endocrine disruption via binding to
membrane estrogen receptors (GPR 30) classical hormone nuclear receptors (AR, ER, GR) and cytosolic hormone receptors (THR, ERR-). Also oxidative stress, mitochondrial
dysfunction and cell signaling disruption
can be included.

alter microRNA expression, in the fetal ewe ovary (Nagel and transcription of target genes by inhibiting ERbeta degradation and
Bromel d, ubiquitination (Mas uyam a an d
2013) and in human placental cell lines (miR-146a) (Avissar-Whiting H ira mats u,
et al., 2010) suggesting a potential impact in reproductive system 2004).
and developmental pathways. Nevertheless, presenting epigenetic
modi- cations as a mechanism by which bisphenol A develops these
chronic diseases needs more investigations and depend on the future
studies.

3.3. Endocrine
disruption

Endocrine disruption refers to a mechanism of toxicity that can

be implicated at different physiological levels via -alteration
(up/down) in the secretion of hormones and/or -interference with
hormonereceptor interaction and/or -modifying the metabolism of
circulating hormones; resulting in a wide variety of adverse health
effects including birth de- fects, reproductive, developmental,
metabolic, immune, and neurobe- havioral disorders as well as
hormone dependent cancers. BPA is considered as a xenoestrogen
but not estrogen mimics (Gould et al.,
1998; Van denb erg et al., 200 9) via its ability: 1/ to bind classical
nuclear receptors estrogen (ER) (Vandenberg et al., 2009), 2/to
bind classical and non-classical membrane estrogen receptors (Alon
so- Mag dale na
et al. , 200 5) as well as the G-protein-coupled receptor 30
(GPR30) (Th omas and Dong, 2006), and 3/ to act through non-
genomic pathways (Ro pe ro et al ., 200 6). These effects can lead
to diverse changes in estrogen-target organs including the brain,
ovary, mammary gland, and uterus, among others which presented
as the endpoints affected in perinatally BPA-exposed females (Van
de nbe rg et al ., 200 9). Also, BPA may affect the ERbeta-mediated
 In addition, BPA can act by interfering with thyroid hormone
path- ways, glucocorticoid receptor, estrogen related receptor
gamma, andro- gen receptor (Rubin, 2011; Vandenberg et al.,
2009) and dopaminergic system (affecting expression, release and
turnover) leading to behavior disorders (Jo nes and M iller, 20 08).
3.4. Oxidative stress and mitochondrial
dysfunction
Increased Reactive Oxygen Species (ROS) production and/or de-
creased capacity of antioxidant defense can disrupt oxidative balance
leading to modication of all components of the cell, including lipids,
proteins, carbohydrates and nucleic acids in mitochondria and to
activate/inactivate signaling pathways by oxidative modication of
redox-active factors. Oxidative stress has been implicated in aging
and many pathological disorders, such as ischemic diseases,
neurodegenera- tive diseases, diabetes, and cancer, although the
underlying mechanisms are not always completely understood (Lenaz,
2012). On the other hand, growing evidence suggests that BPA-
induced damage is associated with oxidative stress (Anjum et al.,
2011; Tiwari et al., 2012). Indeed, it has been revealed that
bisphenol A can disturb oxidative homeostasis through direct or
indirect pathways, including mitochondrial function (Ooe et a l.,
2005), modulation of antioxidant enzymes and increase thio-
barbituric acid-reactive substances in the brain, kidney and testis of
mice exposed throughout embryonic/fetal route (Kabuto et al.,
2004). However, co-administration of vitamin C can reverse the
effects of bisphenol A-induced oxidative stress in rat liver (Bin dh
umo l et al .,
200 3) and brain tissue (Ay do ga n et al ., 20 08). In
epidemiological study, it has been reported that BPA exposure
apparently promotes oxidative stress and inammation in women
(Yang et al., 2009b). In- deed, urinary BPA concentrations were
positively associated with
malondialdehyde (MDA), 8-hydroxydeoxyguanosine (8-OHdG), and
C- reactive protein (CRP). Recently, it has been reported that
oxidative stress induced by BPA can accelerate toxic aggregation of Conict of interest
human islet amyloid polypeptide (hIAPP), (a hormone synthesized
and secreted by the pancreatic -cells) leading to -cell death, The authors have no conicts of interest to declare.
which is regarded as one of the causative factors of type 2 diabetes
(Gong et al., 2013).
On the other hand, it has been reported that exposure to BPA
impairs mitochondrial function in the liver within doses below the
NOAEL (Moon et al., 2012) leading to hepatic toxicity and also, in rat
insulinoma (INS-1) cells, evidenced by depletion of ATP, release of
cytochrome c, loss of mitochondrial mass and membrane potential,
and alterations in expression of genes involved in mitochondrial
function and metabolism leading to pancreatic dysfunction (Lin et
al., 2013).

3.5. Cell
signaling

It has been reported that BPA can affect cell-signaling

mechanisms by increasing intracellular calcium and phosphorylation
of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal
kinase (JNK), and nuclear translocation of nuclear factor (NF)-b
(Lee et al., 2008). The authors concluded that calcium, ROS, ERK,
and JNK are involved in BPA-induced apoptotic cell death in HT-22
cells and in contrast, an NF-B cascade was activated for survival
signaling after BPA (Lee et al.,
2008). Also, BPA can activate several kinases at very low
concentrations in rat pituitary cell lines and mixtures of
xenoestrogen pollutants can have dramatic disrupting effects on
hormonal mechanisms of cell regu- lation and their downstream
functional responses, altering cellular re- sponses to physiologic
estrogens (Vi n a s a nd Wat s on , 201 3; Vi n a s
et al.,
2012).

4. Conclusion and
perspectives

We do not regard our ndings as denitive evidence but the data

collected from epidemiological studies are sufciently robust to raise
concerns about the potentially deleterious impact of BPA on human
de- velopment and chronic human disease induction as the most
important global health problems (Fig. 1).
The differences between studies (from in vivo to in vitro studies,
from rodent to human, from an exposure route to another, from an
ex- perimental dose to another, from mixture compounds exposure
to sin- gle compound exposure and from country to another
especially considering the occupational conscience) are in favor to
difference in the results and consequently to alternative hypothesis
and mechanisms. Clearly additional fundamental non-human
primates and clinical re- search are required to understand more the
mechanisms of BPA action that looks too complicated. Indeed,
despite that mouse and rat have been shown to be excellent models
to understand human chronic dis- eases mechanisms, a variety of
differences among species have been re- ported. Also, as a preventive
and precautionary principle, urgent further investigations are
required, particularly to developing fetuses and young children as
they may be the most susceptible to adverse effects of this
ubiquitous compound in developed as well as in developing
countries which need more attention even through public
sensitization programs. On the other hand, in reality we are exposed
to a mixture of pollutant, so the possibility of additive and synergistic
effects of BPA with other prevalent compounds should not be
overlooked. Also, actual tolerable daily intake must be revised
because several in vivo studies have reported signicant effects in
animals with doses below the pub- lished LOAEL of 0.05 mg/kg
BW/day.
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