Environmental Toxicology and Pharmacology 77 (2020) 103373

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Environmental Toxicology and Pharmacology

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Review or Mini-review

Bisphenol A-induced metabolic disorders: From exposure to mechanism of T

action
Muhammad Sajid Hamid Akasha,*, Shakila Sabira, Kanwal Rehmanb,*
a
Department of Pharmaceutical Chemistry, Government College University Faisalabad, Pakistan
b
Department of Pharmacy, University Agriculture, Faisalabad, Pakistan

A R T I C LE I N FO A B S T R A C T

Keywords: Bisphenol A (BPA) is considered as ubiquitous xenooestrogen and an endocrine disrupting chemical which has
Endocrine disrupting chemicals deleterious effects on endocrine functions. Human populations are continuously exposed to BPA as it is abundant
Metabolic programming in daily life. It has been found to be associated with wide range of metabolic disorders notably type 2 diabetes
Epigenetic modifications mellitus (DM). Numerous epidemiological studies have been conducted to find its role in development of DM.
Experimental studies have found that BPA exposure is associated with pathogenesis of DM and also considered as
a risk factor for gestational diabetes. Being a lipophilic compound, BPA is preferably accumulated in adipose
tissues where it alters the production of adipokines that play important roles in insulin resistance. BPA induces
apoptosis by caspase activation after mitochondrial damage and it impairs insulin signaling pathways by altering
associated ion channel activity especially potassium channels. Perinatal exposure of BPA makes offspring more
susceptible to develop DM in early years. Epigenetic modifications are the key mechanisms for BPA-induced
metabolic re-programming, where BPA alters the expression of DNA methyltransferases involved in methylation
of various genes. In this way, DNA methyltransferase controls the expression of numerous genes including genes
important for insulin secretion and signaling. Furthermore, BPA induces histone modifications and alters miRNA
expression. In this article, we have briefly described the sources of BPA exposure to human being and sum-
marized the evidence from epidemiological studies linking DM with BPA exposure. Additionally, we have also
highlighted the potential molecular pathways for BPA-induced DM.

1. Introduction contaminants which are known as endocrine disrupting chemicals

Type 2 diabetes mellitus (T2DM) has been considered as a complex
metabolic disorder characterized by impaired metabolism of carbohy-
drates, lipids and proteins (Akash et al., 2013; Rehman and Akash,
2017). Hyperglycemia and dyslipidemia are collectively involved to
provoke the multifactorial transcriptional, metabolic and enzymatic
pathways that once initiated, induce the generation of oxidative stress
and inflammatory responses (Akash et al., 2013; Donath and Shoelson,
2011; Prasad et al., 2009; Rehman and Akash, 2017; Rehman et al.,
2017). Chronic exposure of inflammatory response along with oxidative
stress may lead to the development of several causative factors that are
responsible for paghogenesis of T2DM. Among the causative factors, the
most important and crucial factors are insulin resistance in peripheral
tissues, impaired insulin secretion β-cells of pancreatic islets, abnormal
hepatic glucose production and decreased glucose uptake (Akash et al.,
2018; Donath and Shoelson, 2011; Rehman et al., 2017).
Along with the genetic background, a number of environmental
(EDCs) play a crucial role in pathogenesis of T2DM (Zheng et al., 2018).
EDCs are defined as a chemical or mixture of chemicals that have the
potential to disrupt endocrine functions (Zoeller et al., 2012). They are
comprised of heterogeneous range of compounds that are extensively
used in daily consumed products, such as personal care products, food
packaging, pesticides, building materials, and many others. Exposure to
EDCs occurs through different routes such as oral, dermal or inhalation
(Gore et al., 2015). It is well established EDCs may interrupt hormone
related signaling pathways by binding hormone receptors and mod-
ifyiing either the production, metabolism or transport of hormones
(Casals-Casas and Desvergne, 2011; Gore et al., 2015). It has been re-
vealed that EDCs are responsible for interrupting the key metabolic
processes that may lead to disruption of energy and/or glucose home-
ostasis and impaired carbohydrate, protein, and lipid metabolism
(Alonso-Magdalena et al., 2011; Heindel et al., 2017; Nadal et al.,
2017).
Bisphenol A (BPA) is one of the most familiar examples of EDCs. It

⁎
Corresponding authors.
E-mail addresses: sajidakash@gcuf.edu.pk (M.S.H. Akash), kanwal.akash@uaf.edu.pk (K. Rehman).

https://doi.org/10.1016/j.etap.2020.103373
Received 16 December 2019; Received in revised form 10 March 2020; Accepted 12 March 2020
1382-6689/ © 2020 Elsevier B.V. All rights reserved.
M.S.H. Akash, et al.
was first synthesized by Dianin in 1891 but as early as the 1930s, it was
reported that BPA has oestrogenic properties (Dodds and Lawson,
1936). It is primarily a monomer that is utilized as a basic component
for manufacturing of polycarbonate and plastics. It is found in coating
materials of cans and jar caps that are used for food preservation
(Oldring et al., 2014), as well as in dental materials. BPA-based coatings
are used to avoid the direct contact of metal with food and for thermal
stability as well as to enhance the mechanical strength of jars for food
packing (Cao et al., 2010). This coating is usually comprised of epoxy
resins. Nearly, 9% of total BPA produced is annually utilized for the
manufacturing of can lining material (Ashcroft and Rorsman, 2013).
BPA is commonly used as a color developer in manufacturing of thermal
printing paper that is widely used for payment and cash registers.
BPA has received special attention from researchers as a ubiquitous
chemical since it was first introduced in plastic manufacturing in-
dustries in 1950. Currently, it is among the most abundantly produced
chemicals with over 6 billion pounds produced every year (Lee et al.,
2018). As human populations worldwide are routinely exposed to BPA,
it can be detected in most individuals (Calafat et al., 2004; Vandenberg
et al., 2007). Keeping in view the regulatory issues, in the 1980s, the
United States Environmental Protection Agency (EPA) set the lowest
adverse effect level of BPA at 50 mg/kg/day for human populations
(EPA, 2010).
Alternatively, the European Food Safety Authority (EFSA) declared
no adverse effect level of 5 mg BPA/kg/day for for rats. EFSA has re-
cently established the tolerable daily intake (TDI) (estimated amount of
BPA in drinking water or food that may be ingested daily over a lifetime
without considerable health risk) for BPA i.e 50 μg/kg/day (WHO,
2009). The TDI and reference dose are greater than the 95th percentile
of BPA intake level (1.5 μg/kg/day) for the adults estimated by World
Health Organization (WHO). This estimated safe dose is on the basis of
published data of BPA exposure estimation in various countries and
information available about BPA level in foods (Shelnutt et al., 2013;
Tudurí et al., 2018).
According to European Union Commission, the migration of BPA
into food from varnishes or coatings applied to containers should not
exceed 0.05 mg of BPA per kg of food (mg/kg). Migration of BPA has
been prohibited from varnishes or coatings applied to containers in-
tended to use for infants and children (EU, 2018). BPA-induced ecolo-
gical risks has been investigated by the European Union (2008), Canada
(2008), and Japan (2007). The Japanese authories stated that “the
current exposure levels of BPA will not pose unacceptable risks to the
local populations of aquatic life, particularly fish.” The European Union
view was that “although the predicted exposure concentrations were
significantly below its hazard values, there was a need for further in-
formation and/or testing on other organisms as freshwater snails”.
Canada’s position was that “BPA concentrations in water have potential
to cause adverse effects on populations of pelagic organisms in Canada
and BPA concentrations in biota have the potential to cause adverse
effects in populations of wildlife in Canada, but that there is a low risk
of direct adverse effects to sediment organisms and to avian wildlife
species in Canada” (EPA, 2010).
In view of these positions, the purpose of the present review is to
summarize the potential sources of BPA exposure and its hazardous
effects on health. Moreover, we have also focused on potential mole-
cular pathways for BPA-induced metabolic disorders.
2. Sources of BPA exposure
As described previously, there are multiple routes for human BPA
exposure and many significant sources of the chemical. These include
thermal paper (54.000–79.0 ng/cm2), dust (0.8–10 μg/g), meat
(17–602 ng/g) and meat products. Fish (5–109 ng/g), fruits and vege-
tables (9–76 ng/g), beverages (1–18 ng/g), dairy products (21–43 ng/
g), dental material (0.013–30 mg), infant formula (0.1–13 ng/g) and
plastic (0.2–26 ppb) have also been identified as important contributors
2
Environmental Toxicology and Pharmacology 77 (2020) 103373
to daily intake of BPA in human beings (Geens et al., 2012b; Valentino
et al., 2016). Besides these dietary sources, BPA may also be found in
various fresh foods, such as meat, eggs, and milk (Van Landuyt et al.,
2011). Additionally, BPA has also been detected in food products that
are packed in cardboard boxes. Foodstuff canning processes such as
sterilization are the major sourse of the leaching of BPA into food
content from the can walls (Cooper et al., 2011). Heating temperature is
more important, compared with heating duration, in terms of its impact
on BPA migration from the can lining to the food. There is a maximum
leakage of BPA when products are heated for 90 min at 121 °C (Kang
and Kondo, 2003). The process of sterilization causes the leakage of
80–100% of unconjugated BPA and it may also depend upon the con-
ditions as well as food contents nature (Goodson et al., 2004). The
lower the pH and the greater the fat content, the more BPA migration
will occur (Munguia-Lopez et al., 2002). Contamination may also
happen due to the migration of BPA to the food from polycarbonate
plastic container (reusable containers, drink dispensers and water/baby
bottles) in which food is stored or heated by microwaves (Viñas et al.,
2010).
In thermal papers, BPA is present in free and unbound forms that
can be easily released (Geens et al., 2012c). Therefore, handling of
thermal paper is a major source of human BPA exposure, when eating
food with hands that are contaminated with thermal paper contact. For
instance, cashiers routinely handle thermal receipts, have higher urine
BPA level in comparison with general population (Braun et al., 2010).
Thermal paper receipt is the second common source of BPA exposure
after the dietary intake (EFSA Panel on Food Contact Materials and
Aids, 2015).
BPA may also be found in dust coming from the laminate flooring,
paints, electronic equipment, and adhesives comprising of epoxy resins
(Hanaoka et al., 2002). BPA was present in 95 % of 56 different samples
of dust with concentration ranges from 0.8−10 mg/g of dust sample
(Geens et al., 2009). Comparatively higher BPA levels were detected in
dust samples obtained from laboratories and offices, which is com-
mensurate with their reliance on many electronic devices and furniture.
Exposure among infants and children is linked with the oral or in-
halation routes (Calafat et al., 2007). Dust contributes only about 5% of
total BPA exposure (Geens et al., 2012c). BPA exposure through in-
halation route is < 0.4 ng/kg/day in adults and 5.3 ng/kg/day in in-
fants (Loganathan and Kannan, 2011).
Dental materials may comprise of BPA-containing monomers,
mostly in the form of BPA-glycidyl methacrylate. BPA is frequently
leached out from dental sealants, fillings and tooth crowns (Drozdz
et al., 2011). The maximum BPA concentration was found in patient’s
saliva immediately after dental filling insertion,whilst the levels de-
clined soon afterward. However, leaching of BPA is known to occur
from artificial dental material (Fleisch et al., 2010). After the re-
construction of a tooth crown, almost 13−30 mg/day BPA was released
(Van Landuyt et al., 2011). These studies suggest that dental treatment
may contribute significantly to BPA exposure. Therefore, patients with
multiple dental fillings are at higher risk of BPA exposure (Geens et al.,
2012a). Lower BPA concentration (0.3 to 0.35 mg) may be leaked from
number of medical devices, which are comprised of polysulfone or
polycarbonate plasticizers, for example, contact lenses, probes, in-
travenous cannulas, inhalers, catheters, hemodialysis apparatus or
neonatal incubators (Calafat et al., 2008; Geens et al., 2012c; Haishima
et al., 2001).
Another important source of chronic BPA exposure are toys and
other products that are used by young children and infants such as
dummies (pacifiers) and teething aids that are usually held in the
mouth for many hours on daily basis. It has been reported that saliva
BPA level was detected from 0.14 to 2.1 mg/l after exposure to rattles
and from 0.11 to 14 mg/l saliva for dummies (pacifiers), after 24 h
contact with these products (Konieczna et al., 2015). After 1 min ex-
posure to teethers and dummies (pacifiers), BPA saliva level was
5.9 mg/l and 0.3 mg/l respectively (Viñas et al., 2010).
M.S.H. Akash, et al.
3. BPA exposure and metabolic programming
Barker and his colleagues were the first to propose that nutrition
provided to children in early-life may be associated with hypertension,
coronary heart disease, and DM (Barker, 1996, 1995; Hales and Barker,
1992). These observations became the foundation of foetal origins of
adult disease hypothesis; it stated that events happening during early
developmental stages may enhance the risk for particular diseases in
adult life (Gluckman and Hanson, 2004). It is well documented that
exposure of particular hazardous environmental agents during devel-
opmental stages may make a person more prone to develop non-com-
municable diseases such as DM (Heindel and Vandenberg, 2015). The
molecular mechanism behind this hypothesis is still controversial.
However, studies have proposed a number of mechanisms working
during this sensitivity window such as alteration in various gene ex-
pression, hormone regulation, cell metabolism, or cellular plasticity,
etc. These molecular changes have the potential to permanently alter
the physiological and metabolic set points for homeostasis and cause
the programming of an individual to develop metabolic diseases on-
ward (Heindel et al., 2017). Epigenetic modifications have been sug-
gested as key mechanisms behind the altered programming made
during early developmental stage (Alavian‐Ghavanini and Rüegg,
2018). Besides early developmental exposure, it is also well docu-
mented that meternal dietry intakes and placental transfer during the
prenatal life may have great influence on postnatal health (Barker,
1998; Kim, 2009) which may also include meternal exposure to toxins
like BPA. Epidemiological and experimental studies conducted on ani-
mals and humans have suggested that birth weight may act as a risk
factor for developmental of DM in later life (Gilbert and Epel, 2009).
There are various animal studies showing a negative impact of BPA in
metabolic developmental programming. Numerous animal studies have
been conducted where pregnant females were exposed to BPA and al-
tered glucose homeostasis was observed in offspring during postnatal
life (Table 1).
Epigenetics refers to heritable modifications that do not involve an
altered DNA sequence. Rather, epigenetic modifications such as DNA
methylation, histone modification and expression of non-coding RNA,
alter DNA accessibility and chromatin structure, thereby regulating the
patterns of gene expression (Handy et al., 2011; Loscalzo and Handy,
2014). It has been revealed that human insulin-like growth factor 2
(Igf2) and insulin genes are found in same genomic region and strong
association has been found between DM and insulin/Igf2 locus. Over-
expression of Igf2 induces β-cell damage and makes them more sus-
ceptible to immune attack (Casellas et al., 2015). BPA exposure, during
early developmental stages, induces DNA hyper-methylation with
subsequent over-expression of Igf2 which impairs β-cell function in the
rodent offspring (Mao et al., 2017). Recently, a study has been con-
ducted in order to evaluate the impact of BPA in both F1 and F2 gen-
erations. This study showed that perinatal BPA exposure may induce
Igf2 methylation in F2 male but this alteration was not observed in F2
female foetus. Furthermore, this study showed that BPA exposure
during pregnancy may induce Igf2 over-expression in a pregnant female
which resulted in glucose intolerance and GDM (Susiarjo et al., 2015).
Pancreatic and duodenal homeobox-1(Pdx1) gene encoded tran-
scription factor plays a crucial role in transcription regulation. It con-
tributes considerably in production of different types of pancreatic cells,
β-cell development, and adult β-cell physiology. Altered Pdx1 expres-
sion is connected with hyperglycaemia and suppressed β-cell pro-
liferation (Spaeth et al., 2017). Chang et al. has observed in their study
that maternal exposure of BPA during gestational period reduces Pdx1
expression in offspring. Histones H3 and H4 deacetylation, demethy-
lation of histone 3 lysine 4 (H3K4) and methylation of histone 3 lysine 9
(H3K9) were found at the promoter of Pdx1. All these modifications
induced Pdx1 downregulation (Chang et al., 2016). miR-338 acts as
epigenetic regulatory machinery for Pdx1 gene. Acute BPA treatment
downregulated miR-338 by activating G-protein-coupled oestrogen
3
Environmental Toxicology and Pharmacology 77 (2020) 103373
receptor 1 (Gpr30). On the other hand, Chronic BPA treatment upre-
gulated miR-338 by suppressing glucagon-like peptide 1 receptor
(Glp1r). BPA alters Gpr30/Glp1r activation to control miR-338 expres-
sion which in turn controls Pdx1-dependent insulin secretion (Wei
et al., 2017). Glucokinase, encoded by Gck, is an important enzyme to
maintain glucose homeostasis. It is involved in the production of gly-
cogen (Chakera et al., 2018). Hypermethylation of Gck is involved in
epigenetic pathogenesis of DM (Tang et al., 2014).
Hepatic hypomethylation and upregulation of DNA methyl-
transferase 3B have been observed in male progeny of BPA-treated
rodents. Furthermore, studies have shown that BPA exposure may in-
duce hypermethylation of Gck promoter in the male progeny of rats.
Altered hepatic DNA methylation and Gck downregulation followed by
BPA exposure resulted in insulin resistance along with with decreased
hepatic glycogen level in the offspring of BPA exposed rats. These
findings suggest that oral intake of BPA by female rats during their
gestational and lactation time period may enhance the risk of DM in
their next generation (Ma et al., 2013). In the same study, second
generation progeny of BPA exposed rats developed glucose intolerance
owing to insulin resistance in addition to decreased hepatic Gck level.
Moreover, the altered methylation Gck gene has been noticed in the
liver of F2 generation. Therefore, it is suggested that dysregulation of
glucose homeostasis due to BPA treatment may be transmitted in sub-
sequent generations (Li et al., 2014). Obesity is considered as a major
etiological factor for DM. A number of investigations have been made to
evaluate the obesogenic effect induced by various EDCs like BPA ex-
posure via oral or parenteral route. BPA has an hyperlipidemic effect
through epigenetic modifications as underlying mechanisms (Bhandari
et al., 2013; de Sousa et al., 2018; Liu et al., 2017).
BPA may alter human lipid profiles and promote obesity, resulting
in insulin resistance and/or DM (Alonso-Magdalena et al., 2016). It has
been revealed that BPA exposure (0.5 μg of BPA/kg/day) in male mice
from its birth to 10 months, exhibited significant accumulation of tri-
glycerides and cholesterol in liver. Moreover, liver cells exposed with
BPA exhibited increased expression level of lipid biosynthesis genes via
increased expression levels of Srebf1 and Srebf2. BPA exposed liver cells
showed decreased the DNA methylation level of Srebf1 and Srebf2 genes
(Ke et al., 2016). This alteration in hepatic genes leads to the increased
lipid synthesis and accumulation in liver that may be due to the epi-
genetic reprogramming of hepatic genes, involving DNA methylation
pattern alteration, that influences lipid metabolism (Ke et al., 2016).
During a study in which mice were treated with BPA for 3 months,
considerable reduction in hepatic miR-192 was recorded. Additionally,
srebf1 gene overexpression was also observed in the hepatocytes. The
authors suggested that miR-192 might be an epigenetic modulator of
srebf1 and thus lipid synthesis. BPA treatment might impair the normal
functioning of miR-192 resulting in the srebf1 gene upregulation (Lin
et al., 2017). Indeed, when rats were treated with BPA, their male
offspring showed comperatively higher hepatic lipid accumulation in
comparison to female offspring, thus they were more susceptible to
develop fatty liver disease. It was observed that carnitine palmitoyl-
transferase 1A (Cpt1a) expression, encodes a important enzyme for fatty
acid metabolism, was considerably reduced in male offspring, particu-
larly in the group fed with high-fat diet. In addition to hypermethyla-
tion of Cpt1a gene, decreased level of histone 3 lysine 4 dimethylation
(H3Me2K4) was the key epigenetic dysregulation detected following
perinatal BPA exposure. Furthermore, Kmt2c expression, a key histone
methyltransferase enzyme that induces gene expression was con-
siderably decreased. On the basis of these outcomes, it was concluded
that the chief epigenetic regulatory pathway of Cpt1a gene in BPA ex-
posed rodents could be K4 dimethylation of H3 (Strakovsky et al.,
2015) (Fig. 3). Recently, it has also been found that epigenetic mod-
ifications of few lipogenic genes followed by BPA treatment during
developmental phases were evaluated. Female offspring of BPA treated
mice exhibited hypomethylation of Fasn, Nrf2, and SREBP-1C genes
with subsequent gene upregulation (Shimpi et al., 2017).
 M.S.H. Akash, et al.

Table 1
Impact of BPA exposure on metabolic programming.
Animal model Dose/ route Duration Follow up Observations Ref

Pregnant Sheep 0.05, 0.5, 5 mg/kg/d GD30-GD90 21 months after delivery BPA disrupted the insulin sensitivity mediators. BPA elevated oxidative stress level in (Puttabyatappa et al., 2019)
S.c. injection metabolic tissues, dyslipidemia and lipotoxicity in liver and muscles.
NMRI male mice 100 μg/kg/d 4 weeks 13-13.5 weeks of age Elevated fasting blood glucose level, lowered level of insulin and adiponectin and HOMA-β (Veissi et al., 2018)
S.c. injection
Pregnant sheep 0.5 mg/kg/d GD30-GD90 21 months aftr delivery BPA upregulated genes associated with adipogenesis in visceral adipose tissues. (Dou et al., 2019)
S.c. injection
Pregnant OF-1 mice 10 μg/kg/d GD9-GD16 4 months after delivery Body weight gain in offspring, enhanced insulin secretion due to reduced insulin sensitivity, (Alonso-Magdalena et al.,
S.c. injection increased triglycerides, glycerol and leptin levels. Impaired glucose tolerance. 2010b)
Pregnant CD-1 mice 5 μg/kg/d GD9-GD18 18-19 weeks old (offspring) Increase in body weight and liver weight, abdominal adipocyte mass, number and volume, (Angle et al., 2013a)
Oral and in serum leptin and insulin.
Pregnant C57BL/6 10 μg/kg/d and 10 mg/kg/ From 2 weeks prior to 16-21 weeks old (male F1 Dose and sex specific effects, impaired insulin secretion, reduced β cell mass, increased β (Bansal et al., 2017)
d mating until weaning and F2 offspring) cell death, levels of pro-inflammatory cytokines and altered islet DNA methylation.
Oral

4
Pregnant NOD mice 0.1, 1, 10 mg/L GD0-PND21 7-28 weeks old female Increased α and β cells and tissue resident macrophage apoptosis, augmented number of (Bodin et al., 2013)
Drinking water offspring regulatory T cells and active caspase-3 positive cells in pancreatic islets. Increased severity
of insulitis and incidence of DM.
Pregnant OF-1 mice 10 μg/kg/d GD9-GD16 17 & 28 week Increased fasting blood glucose, insulin secretion and NEFA levels. In liver, increased (García-Arevalo et al., 2014)
S.c. inject mRNA expression of PPARγ and increased triglyceride content.
Pregnant OF-1 mice 10 or 100 μg/kg/d GD9-GD16 PND 0, 21, 30 and 120 Increased β cell mass and hyperinsulimenia during early PND but decreased in late PND. (García-Arévalo et al., 2016)
S.c. inject
Pregnant C3H/HeN 50 μg/kg/d Orally/0.1 % GD15-PND21 From weaning to PND170 Impaired glucose tolerance, decreased insulin sensitivity. (Malaisé et al., 2017)
mice ethanol in corn oil
CD1 male mice 5, 50, 500 or 5,000 μg/kg/ 28 days 10 weeks old Increased plasma insulin levels, hepatic mRNA and protein related to lipid biosynthesis and (Marmugi et al., 2012b)
d lipid content.
Diet
C57BL6 male mice 50 μg/kg/d 12 weeks 18 weeks old Glucose intolerance and decreased Akt phosphorylation in skeletal muscle. (Moon et al., 2015)
Drinking water
C57BL6 male mice 50 μg/kg/d 2 weeks 6 and 6.5 months old Diminished glucokinase activity after acute exposure. (Perreault et al., 2013)
Drinking water

PND; Post-natal days.

Environmental Toxicology and Pharmacology 77 (2020) 103373
 M.S.H. Akash, et al.

Table 2
Clinical studies reported the association of BPA and DM.
Country Year Study design Population, Sample Technique BPA level Results Ref
Case/ control (Mean)

Saudi Arabia 2018 Case control 54/47 Urine HPLC 3.9* Urinary BPA is associated with increased risk for DM. (Li et al., 2018)
Missouri 2018 Cross over 8 Serum LC-MS 7.3 ng/ml Environmental Protection Agency–estimated “safe” daily dose alters the insulin/C-peptide in (Stahlhut et al., 2018)
response to glucose.
Turkey 2018 Case control 50/50 Urine HPLC 24.13 ng/ml No significant association between urinary BPA levels and T1DM in children aged between 5–18 (İnce et al., 2018)
years.
Denmark 2018 Cross sectional 107 Urine LC–MS 2.55 ng/ml A study on healthy normal-weight children suggests an inverse association between BPA and (Carlsson et al., 2018)
insulin resistance.
China 2018 Nested case 232/232 Serum ELISA 1.3 ng/ml BPA is not associated with a 5-year DM incidence. (Shu et al., 2018)
control
China 2018 Case control 251/251 Urine HPLC 0.503* μg/g Several urinary bisphenols were positively associated with DM. (Duan et al., 2018)
creatinine
Thai 2017 Cross sectional 240 Serum Competitive ELISA 1.1 ng/ml There is an association between BPA exposure and impaired glucose tolerance, but not DM. (Chailurkit et al., 2017)
United states 2008 Cross sectional 1455 Urine HPLC-MS 4.6 ng/ml Higher BPA level was positively associated with DM. (Lang et al., 2008)

5
Canada 2016 Cross sectional 4320 Urine GC-MS 1.21 μg/l* Urinary BPA was positively associated with adverse glucose homeostasis in men. (Tai and Chen, 2016)
Lebanon 2017 Cross sectional 501 Urine HPLC-MS 3.67 μg/l Urinary BPA is linked with metabolic syndrome, obesity and diabetes. (Mouneimne et al., 2017)
United states 2015 Cross sectional 382 Urine GC-MS-MS 3800 ng/l Urinary monochlorinated BPA derivative was significantly associated with DM, whereas the (Zhou et al., 2015)
parent compound (total BPA) was not.
China 2015 Cross sectional 3423 Urine HPLC-MS 0.95 ng/ml No association found between BPA and DM. (Ning et al., 2011)
Thai 2014 Cross sectional 2581 Serum ELISA 0.34 ng/ml* Serum BPA level was not associated with impaired fasting glucose, but positively associated with (Aekplakorn et al., 2015)
DM.
Iran 2014 Case control 239 Urine GC-MS 2.9 μg/l Urinary Bisphenol A levels are found to be associated with DM independent of traditional DM risk (Ahmadkhaniha et al.,
factors. 2014)
United States 2014 Case control 971/970 Urine LC-MS 4.4 μg/l BPA exposures may be associated with the risk of DM among middle-aged, but not older women. (Sun et al., 2014)
Korea 2013 Cross sectional 1210 Urine GC-MS 2.2 ng/ml* High body BPA burden may not be associated with an increased prevalence of DM. (Kim and Park, 2013)
United States 2013 Cross sectional 3516 Urine GC-MS 2.075 ng/ml Higher urinary BPA levels are found to be associated with prediabetes independent of traditional (Sabanayagam et al., 2013)
diabetes risk factors. association was stronger among women and obese subjects.
India 2017 Case control 30/30 Urine ELISA 1225.01 No co-relation was found. (Kumar et al., 2018)
pg/mg creatinine
United States 2011 Cross sectional 4792 Urine GC-MS 3.93 ng/ml Urinary BPA is associated with DM independent of traditional risk factors. (Shankar and Teppala,
2011)

* Geometrical mean.
Environmental Toxicology and Pharmacology 77 (2020) 103373
M.S.H. Akash, et al. Environmental Toxicology and Pharmacology 77 (2020) 103373

4. BPA exposure and DM: evidences from clinical studies

(Chiu et al., 2017)

(Robledo et al.,
(Bellavia et al.,

(Shapiro et al.,
Numerous clinical studies conducted around the globe have found
(Wang et al., that there is a strong association between BPA exposure and DM in-
2017b) dependent of traditional risk factors (Table 2). (Aekplakorn et al., 2015;

2018)

2015)

2013)
Ref

Chailurkit et al., 2017; Duan et al., 2018). However, few clinical based
studies fail to show correlations between BPA and metabolic disorders
BPA exposure during the second trimester may have adverse effect on blood

Moderately high BPA concentrations were associated with increased glucose

Higher maternal exposure to BPA may be associated with decreased risk of

(Ning et al., 2011; Shu et al., 2018). Data from US National Health and
Nutrition Examination Survey (NHANES) revealed that BPA was de-
tectable in almost 90 % of U.S. population aged ≥6 years old, with
concentration ranging from 0.4−149 μg/L. Adolescents and children
have greater urinary BPA concentration than adults. Important socio-
economic and ethnic differences has also been observed. It has been
noted that there is an inverse correlation between income and urinary
BPA excretion. BPA has also been found in foetal cord blood and breast
milk (Mirmira and Evans-Molina, 2014). Recently, a meta-analysis was
conducted on sixteen clinical based studies by Hwang and his collea-
levels among overweight/obese women

gues. They have concluded that BPA exposure to human showed posi-
glucose levels but not in 1st trimester

tive associations with onset of DM (OR 1.28, 95 % CI 1.14, 1.44)

(Hwang et al., 2018).
GDM and lower birth weight.

Lang et al. investigated the association between DM and urinary

BPA level by examining cross-sectional NHANES data from 2003 to
No association found

No association found

2004. They observed that higher BPA levels were positively associated
with self reported diagnosis of either DM or borderline diabetes (Lang
et al., 2008). Afterward, Melzer et al. analyzed NHANES data from
2003 to 2004 and 2005 to 2006 and observed a considerable associa-
Results

tion between DM and urinary BPA level in pooled data. However, the
association was not significant after analysis by using fully adjusted
models. The diagnosis of DM in clinical based study was self-reported in
1.23 & 1.01 μg/L* for 1st and
1.39 & 1.27 μg/L for 1 and

which DM and borderline DM were taken as a single outcome (Melzer

st

et al., 2010). Shankar and Teppala examined samples from NHANES

participants (adults) between 2003–2008. This study was superior to its
peers as the authors did a reliable assessment of DM cases, which were
2nd trimester

2nd trimester

diagnosed on the basis of standards provided by American Diabetes

1.32 μg/L*
BPA level

0.9 μg/L*

0.8 μg/L*

Association i.e. fasting serum glucose and HbA1c levels. The results of
(Mean)

this study also showed a positive correlation between urinary BPA level
and diagnosis of DM (Teppala et al., 2012). Moreover, Silver and col-
leagues also noted the similar findings. They also investigated pooled
HPLC-MS/MS
Technique

HPLC–MS

NHANES data from 2003 to 2004, 2005 to 2006, 2007 to 2008. In this
HPLC-MS

GC–MS

clinical based research, DM was diagnosed on the basis of HbA1c ≥ 6.5

HPLC

% or through the intake of medications for DM. Notably, when data of

three different time periods was separately analyzed, it was found that
Sample

Urine

Urine

Urine

Urine

Urine

the association was more pronounced during 2003–2004, where con-

centration of urinary BPA was highest as compared to that of other two
time periods (Silver et al., 2011). The same researchers conducted an-
Mean Maternal

other pooled analysis of cross-sectional NHANES data (2003–2008) and

cross examined the correlations between BPA level and metabolic
syndrome. Similary, they obtained a positive association between me-
Clinical studies reported the relationship of BPA and GDM.

≥25
age

tabolic syndrome and higher urinary level of BPA independent of other

31

35

32

32

confounders i.e age, race and diet. In this study, the diagnosis was made
1st and 2nd trimester

on the basis of revised Adult Treatment Panel III guidelines included:

Gestational week

higher waist circumference, glucose intolerance, increased blood pres-

1st trimester

sure, increased triglycerides level, and decreased HDL level (Teppala

24 to 28

et al., 2012). In contrast to the above, LaKind et al. conducted another

38.7

26.6

analysis on all NHANES data obtained during 2003–2010 and observed

no association between cross sectional urinary levels of BPA and DM
Population

diagnosis. DM was diagnosed on the bsis of either doctor diagnosed DM,

fasting glucose level > 126 mg/dl and two hours blood glucose
1274
620

245

350

level > 200 mg/dl after an oral glucose tolerance test (LaKind et al.,
94

* Geometrical mean.

2012). Carwile and Michels investigated cross sectional pooled data

2017

2017

2018

2015

2013
Year

from adult participants in 2003–04 and 2005–06 NHANES cohorts.

Results provided the evidence that participants falling in upper quar-
United states

United states
United state

tiles were more likely to be obese and presented with abdominal obesity
Country

Canada

(Carwile and Michels, 2011). Similar results were obtained from ana-
Table 3

China

lysis of NHANES data from 2003 to 2008, which investigated associa-

tion between obesity (durig childhood and adolescence) and urinary

6
M.S.H. Akash, et al.
BPA levels. Children from lower quartiles of urinary BPA level showed
the lowest rates of obesity (Carwile and Michels, 2011). These results
were confirmed by another group, and later analysis of NHANES pooled
data from 2003 to 2010 ha s revealed that higher BPA levels was in-
dependently correlated with childhood obesity plus abdominal obesity
(Eng et al., 2013).
Studies have also reported an increased rate of GDM from the last
few years (Zhu and Zhang, 2016). Up-to some extent, exposure to en-
vironmental chemicals including BPA also contributes to this trend
(Table 3). A clinical study conducted in Mexico has revealed that higher
urinary BPA level in women may increase the frequency of premature
deliveries (Cantonwine et al., 2010). Miao et al. reported low birth
weight in new born of BPA-exposed mothers. Similar obervations were
also seen in infants of BPA-exposed fathers (Miao et al., 2011). It is
evident from the literature that there is an increased risk of altered
glucose metabolism due to BPA exposure in obese pregnant women
(Bellavia et al., 2018). Chiu et al. refined these findings, observing that
the BPA effect on glucose tolerance is trimester specific. They reported
that BPA is positively associated with blood glucose level in second
trimester, but they found no association in first and third trimester
(Chiu et al., 2017). Interestingly, contrast to these studies, Shapiro et al.
showed that there is no association between BPA exposure and glucose
tolerance disorders during pregnancy (Shapiro et al., 2015). Similarly,
Robledo et al. did not support the relationship of BPA and altered
glucose metabolism during pregnancy.
Sugiura et al. conducted a study in order to evaluate the risk factors
working behind miscarriages during 1st trimester of pregnancy. They
analyzed serum BPA level alongwith other biological parameters.
Furthermore, immunoassays for antinuclear antibodies were also per-
formed for each partner. The mean serum BPA concentration of female
with recurrent pregnancy loss was 2.59 ± 5.23 ng/ml. On the other
hand, the mean serum BPA concentration of women in normal control
group was 0.77 ± 0.38 ng/ml. The antinuclear antibodies-positive
women had considerably greater BPA concentration than the anti-
nuclear antibodies-negative women. The results of this clinical study
showed that high BPA exposure may be correlated with recurrent
pregnancy loss, especially in antinuclear antibody-positive women
(Sugiura-Ogasawara et al., 2005).
5. BPA and oestrogen receptors
The oestrogen receptors ERα and ERβ, play key roles in energy and
glucose homeostasis (Alonso-Magdalena et al., 2008). However ERα is
considered as the chief regulator. It has also been confirmed by Heine
et al. that the rodents show obesity and insulin resistance which were
ERα knockout. ERα has the ability to maintain physiological function of
glucose metabolism in several tissues like adipose tissue, brain, skeletal
muscles, pancreas and liver (Alonso-Magdalena et al., 2008; Barros
et al., 2006). It has been found that insulin release, synthesis and β-cell
maintenance and regulation is depended on ERα. BPA and 17-estradiol
(E2) activated ERα can enhance the production of insulin by non
classical pathway of oestrogen activation through ERK1/2 phosphor-
ylation. It is E2 concentration depended activation of ERα which has a
significant role in changes of endocrine pancreas to pregnancy. Yet,
ERα is upregulated by elevated concentrations of E2 or BPA, which
increases insulin production unnecessarily. Hence it may promote is-
sues related to T2DM, by negative effects on beta-cell health and insulin
resistance in liver and muscle (Nadal et al., 2009).
GLUT4 (glucose transporter-4) is believed to be important in insulin
signaling and is considered as key regulator in peripheral utilization of
glucose by muscles and adipocytes through insulin stimulation. Here
ERα promotes GLUT4 expression particularly in skeletal muscle cell
membrane which has been confirmed through analysis by Barros et al;
upregulation of GLUT4 occurred in ArKO mice, was unchanged in
ERβKO mice and greatly reduced in ERαKO mice (Barros et al., 2006).
ERα is the main influence over hepatic insulin sensitization. In fact, it
7
Environmental Toxicology and Pharmacology 77 (2020) 103373
was verified that ERα knockout mice show adaptation of glucose uti-
lization by skeletal muscle and extreme hepatic insulin resistance
(Bryzgalova et al., 2006). In addition, oestrogen can control the process
of adipose tissue metabolism and body fat distribution through ERα and
ERβ (Cooke et al., 2001). Oestrogen also regulates the distribution of
white adipose tissue (WAT) not only females but also males. It has also
been confirmed that ERα deficiency will lead to hypertrophy in WAT
and adipocyte hyperplasia along with insulin resistance and glucose
intolerance, but not in brown adipocyte tissue (BAT) (Cooke et al.,
2001). Human data has also underlined the importance of both re-
ceptors in fat metabolism and obesity. The relative amount of ERα/ERβ
is related to obesity, high serum level and synthesis of leptin in omental
adipose tissue of females (Cooke et al., 2001). ERα disturbance in
ventromedial nucleus of the hypothalamus can cause hyperphagia,
hyperglycaemia, weight gain, visceral adiposity, and imbalance of en-
ergy utilization in female mice (Musatov et al., 2007). Furthermore ERβ
has been found to produce an anorectic effect which is started from
central nervous system (CNS) (Liang et al., 2002). Also it has been
confirmed on mice treated with high fat diet that ERβ play main role in
adiposity regulation (Foryst-Ludwig et al., 2008).
Oestrogen-related receptors (ERRs) belong to a subfamily of orphan
nuclear receptors that are closely related to ER (ERα and ERβ). There
are further three types of these ERRs (ERRα, ERRβ, and ERRγ).
However, oestrogen does not show significant affinity to ERRs, but
these receptors possess significant homology with ERs, especially in the
ligand binding and DNA binding domains (Ascenzi et al., 2006). The
ERRs have constitutive transcriptional activity which is repressed by
certain chemicals (such as dexamethasone and 4-hydroxytamoxifen).
BPA shows strongly binding with ERR with a half maximal inhibitory
concentration (IC50) value of 13.1 nmol/L, which can preserve ERRγ
constitutive activity in the presence of 4-hydroxytamoxifen. It is evi-
dent from the studies that low-dose BPA effects may be mediated
through these nuclear receptors (Acconcia et al., 2015).
6. Mechanism of BPA-induced metabolic disorders
6.1. Effect of BPA on adipocytes
BPA is a lipophilic compound and is preferentially accumulated in
adipose tissues (Fernandez et al., 2007). It may promote the differ-
entiation of adipose stem/stromal cells. BPA may also alter the adipo-
genic genes expression including DLK, C/EBPα, IFG1, PPARγ, and LPL
(Ariemma et al., 2016; Ohlstein et al., 2014b). When animals were
treated with oestrogen receptor (ER) antagonist following administra-
tion of BPA, there was weakened BPA–induced adipogenic effect. These
observations showed that BPA produces the adipogenic effect through
an ER-dependent pathway (Ohlstein et al., 2014a). As BPA accumulates
in adipocytes, it may bring alterations in cell signaling pathways. BPA
has an effect on adipokines secretion. Adiponectin enhances the insulin
sensitivity via adiponectin receptor signaling pathway; abundantly
present in liver and skeletal muscles. Angle et al. observed that adi-
pocytes exposed to BPA reduces adiponectin secretion in human and
adult mice (Angle et al., 2013b). PPARγ is considered as a major factor
stimulating the adiponectin expression. It is evident from the literature
that BPA may reduce adiponectin production by antagonizing PPARγ
(Ben-Jonathan et al., 2009; Volberg et al., 2013). Reduced serum leptin
has been observed after BPA exposure (Angle et al., 2013b). Literature
has shown that BPA has the potential to activate Toll-like Receptors
(TLR) resulting in activation of JNK and NF-kB signaling pathways with
subsequent up-regulation of some pro-inflammatory cytokines such as
IL-6 and IFN-γ (11). During a cohort study, prenatal BPA exposure
stimulates TLR with subsequently enhanced secretion of TNF-α, IL-10
and IL-6 (Liao et al., 2016). A cross-sectional study, exclusively with
male adults, has revealed that blood BPA level is positively associated
with raised pro-inflammatory cytokines (TNF-α and IL-6) and they
contribute significantly towards insulin resistance development
M.S.H. Akash, et al.
Fig. 1. BPA promotes the adipogenesis and inflammation by activating ER and
TLR respectively. But BPA reduces the adiponectin level by antagonizing
PPARγ. All these pathological changes contribute to the development of insulin
resistance. Abbreviations| BPA: Bisphenol A, DM: Diabetes mellitus, ER:
Oestrogen receptor, PPARγ: Peroxisome proliferator-activated receptor-alpha,
TLR: Toll-like receptor.
(Savastano et al., 2015) (Fig. 1). Several genes, including PLIN2, Nie-
mann-Pick 2 (NPC2), ACACA, apolipoprotein A1-binding protein
(APOA1BP), FADS1 and PPAP2A were found to be upregulated through
microarray study with the application of BPA in TG and lipid metabo-
lism (Skogsberg et al., 2008). In addition, BPA also improves the pro-
cess of lipid metabolism and accumulation through amplification in
expression of LDLR as it’s been clear that Low-density lipoproteins
(LDL) are known to reduce intracellular lipolysis. It has also been
confirmed by DAVID analysis that upregulated genes in cholesterol and
sterol metabolic processes play a significant role in IPA. GDF15 and
MIR503HG genes show modulation in their expression by usage of BPA.
GDF15 being a part of TGFB family is associated with two important
process adipogenesis and obesity, that is identified and produced in
both human and 3T3L1 adipocytes (Ding et al., 2009). Atlas establishes
a link between BPA and DEX on GDF15 expression in vice versa order as
BPA show increment while DEX show decline (Lee et al., 2011). It is
evident that BPA application produce highest decline in MIR503HG
gene expression. In the differentiation of human preadipocytes
MIR503HG is the gene which comprises of microRNA miR-503 se-
quence and being able of down-regulation (Ortega et al., 2010). An-
other important gene which shows upregulation by BPA was SREBF
linked to adipogenesis and has characteristics of transcriptional acti-
vation in adipocyte differentiation, PPARG activation and lipid meta-
bolism (Kim et al., 1998). BPA-treated mice show SREBP1c and SREBP2
gene expression which is upregulated and modulation in hepatocytes
(Marmugi et al., 2012a). It has also been stated that SREBF1gene was
expressed in human preadipocytes which was induced through DEX. It
is SREBF1which is identified in fatty acid synthase (FAS), ACACA, LPL
and LDLR that has the ability to direct lot of protein sequence and their
expression. BPA-treated preadipocytes show SREBF1-cleavage acti-
vating protein (SCAP) capable of positive upstream regulation. BPA
produce an important mechanism of SCAP activation which can sti-
mulate PPARG, and/or SREBF1 in adipogenesis process (Boucher et al.,
2014).
6.2. BPA-induced mitochondrial damage
This can result in the dysfunctioning of β-cells of pancreatic islets
8
Environmental Toxicology and Pharmacology 77 (2020) 103373
(Lin et al., 2013a). Approximately 98 % of total ATP production in β-
cells is generated via mitochondrial oxidative mechanism (MacDonald
et al., 2005). A study conducted on rat offsprings that were perinatally
exposed to BPA at the dose of 50 mg/kg/day, showed structural defects
in mitochondria in β-cells resulting in altered glucose homeostasis (Wei
et al., 2011). Moreover, isolated rat islets were exposied to BPA, it
caused mitochondrial swelling and altered mitochondrial gene expres-
sion. In addition, there was decreased activity of the respiratory en-
zyme, COX IV, present in mitochondria as well as reduced ATP content
(Song et al., 2012). BPA eroded the structural integrity of mitochondria
and reduced mitochondrial mass of INS-1 cells. These structural ab-
normalities were accompanied by altered gene regulation that is pivotal
for proper functioning of mitochondria and energy metabolism (Lin
et al., 2013b; Shirani et al., 2019). For instance, Atp6 expression and
citrate synthase were considerably reduced in cells after the exposure of
BPA (0.020–2.0 mM), suggesting the decreased mitochondrial capacity
to produce ATP following BPA exposure at concentrations greater than
supraphysiological levels. α-ketoglutarate dehydrogenase or ox-
oglutarate dehydrate is an enzyme which plays a pivotal role in TCA
cycle. It is encoded by gene Ogdh. Similarly, mitochondrial uncoupling
protein-2 is a pprotein that is encoded by UCP2 gene. Lin et al. observed
that downregulation of mRNA expression of Ogdh and upregulation of
mRNA expression of UCP2 after BPA exposure (Lin et al., 2013b). Be-
sides the effect on INS-1 cells, BPA also has potential to induce the
apoptosis in other cell types including hepatocytes, germ cells and
bronchial epithelial cells (George and Rupasinghe, 2018; Kourouma
et al., 2015; Wang et al., 2010). BPA may trigger apoptosis in germ cells
via upregulating the mitochondrial apoptotic pathway (Wang et al.,
2010). Ogdh catalyzes the oxidative decarboxylation of α-ketoglutarate
to succinyl-CoA in mitochondria, while UCP2 regulates glucose-induced
insulin secretion from β-cells of pancreatic islets and mitochondrial
membrane potential (Bo et al., 2016; Song et al., 2012; Zhang et al.,
2001). Altered expression of these genes contributes to the BPA-induced
disrupted glucose-induced insulin secretion and ATP production. Tfam
encodes a mitochondrial transcription factor that provides a molecular
basis for the connection between environmental stimuli and mi-
tochondrial biogenesis. BPA treatment may also reduce the expression
of Tfam (Hock and Kralli, 2009). Mitochondrial dysfunction may po-
tentially affect the viability of the cells and induce the apoptosis. It is
well documented that BPA may induce apoptosis in a number of cells
and tissues via activation of apoptosis signaling pathways (Gong et al.,
2017; Kaur et al., 2018; Wang et al., 2017a). Lin et al. have observed
that BPA exposure may trigger apoptosis in INS-1 cells through acti-
vation of mitochondrial apoptotic pathways via involvement of cas-
pases and Bcl-2 family (Lin et al., 2013b). Bcl-2 family, including anti-
apoptotic and pro-apoptotic members, plays a pivotal role in the mi-
tochondrial apoptotic pathway (Edlich, 2018).
The pro-apoptotic protein Bax may enhance the mitochondrial
membrane permeability with subsequent release of apoptogenic factors
from the mitochondrial membrane which induces the cell death (Karch
et al., 2013). Unlike Bax, Bcl-2 has been reported as an anti-apoptotic
protein, which maintains the integrity of the outer membrane of mi-
tochondria (Gross, 2016). BPA has been found to be involved in Bax
expression upregulation and Bcl-2 expression downregulation resulting
in altered permeability of the mitochondrial membrane. Thus mi-
tochondrial cytochrome c is released from mitochondria, thus inducing
the caspase cascade activation in the cytosol (Hwang et al., 2013).
Various caspases have an essential role in transduction of such apop-
totic signals (Green and Llambi, 2015). Some of the caspases are con-
sidered as initiators(8, 9, and 10), whilst some act as effectors (3, 6, and
7). When INS-1 cells were exposed to BPA, these cells give response to
Apaf-1 (apoptotic protease activating factor-1) activation at dose-de-
pendent manner. Apaf-1 and cytochrome c are combined to make
apoptosome complex. The apoptosome initiates the activation of a
series of caspases that is responsible for the induction of cell death
(Lakhani et al., 2006). BPA may trigger the pro-caspase-9 activation, it
M.S.H. Akash, et al.
Fig. 2. BPA potentiates the pro-apoptotic protein (Bax) and suppresses the anti-
apoptotic protein (Bcl-2) followed by the activation of a series of caspases.
Activated caspases cause the induction of apoptosis in pancreatic β-cells.
9
Environmental Toxicology and Pharmacology 77 (2020) 103373
is evident from the considerable increase of cleaved caspase-9 (active)
(Barbonetti et al., 2016). Activated or cleaved caspase-9 is remained to
attach along with apoptosome, act like a holoenzyme, in order to sus-
tain the catalytic activity of this complex and further activates caspase-
3. Indeed, this caspase is among the most important effectors that
trigger apoptotic events (Estaquier et al., 2012) (Fig. 2). These findings
have shown that the mitochondrial apoptotic pathway may be involved
in BPA induced INS-1 cell death. The INS-1 cell line is considered very
important model for monitoring the insulin secretion and pancreatic β
cells function. Apoptosis of INS-1 cells reflected the impairment of
carbohydrate metabolism followed by the development of metabolic
disorders (Hectors et al., 2013).
6.3. BPA-induced altered ion channel activity in β-cells
At low concentration of glucose, KATP channels remain open in β-
cells of pancreatic islets. When glucose levels increase, ATP to ADP
ratio raises resulting in KATP channel closure. After that, there is a de-
polarization of membrane causing the opening of voltage-gated Ca2+
channels and an increase in the intracellular calcium level (Ashcroft
and Rorsman, 2013). Calcium triggers the insulin release from β cells
that counteract the raised serum glucose level. (Dyachok et al., 2008).
Thus KATP channel is considered as a key ion channel for insulin release
from pancreatic cells. There is a rapid closure of KATP channels in
pancreatic β cells by estradiol exposure. The maximum inhibition is
achieved within 3−7 min after estradiol exposure and the effect is re-
versible and returns to normal levels after 30 min (Nadal et al., 1998;
Soriano et al., 2009). Thus there is an enhanced insulin secretion.
During an ex vivo experiment, the enhanced insulinotropic effect was
produced by co-administration of estradiol and glucose and this glucose
provides additional stimulation for insulin secretion (Nadal et al.,
2011). BPA has the potential to induce insulinotropic effect by
Fig. 3. Epigenetic mechanisms for BPA-induced me-
tabolic disorders. BPA is associated with altered DNMT
expression. DNMT controls the regulation of certain
important genes (Gck, Igf2, Srebf2, Nrf2 and Fasn) by
altering methylation pattern having critical role in the
development of metabolic disorder. Abbreviations|
BPA: Bisphenol A, DNMT; DNA methyltransferase.
M.S.H. Akash, et al.
modulating KATP channel activity in rodents and human β cells and BPA
diminishes KATP channel activity at environmental exposure level
(Soriano et al., 2012, 2016). Experimental studies have shown that BPA
promotes glucose-induced calcium oscillations in β-cells just like es-
tradiol and nanomolar concentration of BPA is sufficient to trigger this
effect (Alonso-Magdalena et al., 2010a; Nadal et al., 2000). Although
the mechanism behind the BPA-induced insulinotropic effect is yet not
clear, it is most probable that it is through ER similar to estradiol. in vivo
experiments have shown that BPA rapidly reduces the hyperglycemia
by promoting the insulin secretion. Like estradiol, administration of
BPA (10 μg/kg) increases blood insulin level within 30 min. After four
day exposure of either estradiol or BPA, mice developed chronic hy-
perinsulinemia (Alonso-Magdalena et al., 2006). Similar to estradiol,
BPA induces the activation of a ubiquitous transcription factor known
as cAMP response element binding protein (CREB) rapidly, just five
minutes after the stimulation produced at low doses (Quesada et al.,
2002). This effect is of great interest as CREB activation is found to be
involved in insulin gene expression and β cell survival (Jhala et al.,
2003; Oetjen et al., 1994).
7. Conclusion
BPA has been found in urine and blood samples of the general po-
pulation which indicates that BPA exposure is a global issue that should
be urgently addressed. In addition to inducing endocrine disruption in
adults, BPA has a potential to accelerate the metabolic programming in
young children that is an actual matter of debate. BPA exposure may
even impair the neurological development of infants and children.
Owing to these neurological effects, FDA has recently introduced new
regulations for its control and mandated its complete removal from
commonly used baby products. Although there are various pathways
through which BPA alters energy metabolism, impairment of insulin
signaling pathways is the key factor for the disruption of carbohydrate
metabolism. BPA exposure and its potential consequences should be
taken more seriously and more regulatory action taken to control
human and environmental exposure to BPA. A focus on developing
safer alternatives to replace this commonly used chemical agent will
make significant progress in safeguarding future generations from the
numerous hazards and dangers posed by BPA and its fellow EDCs.
Declaration of Competing Interest
Nothing to declare.
Acknowledgement
This work has been financially supported by the research grant
(5661/Punjab/NRPU/R&D/HEC/2016) received from Higher
Education Commission (HEC) of Pakistan.
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