Review Article | J Adv Med Biomed Res. 2022; 30(139): 86-100
Journal of Advances in Medical and Biomedical Research | ISSN:2676-6264
A Review of Bisphenol A Effects on White Adipose Tissue and Its Correlation
with Various Cancers
Amir Karbalaee Hasani
, Zivar Nejad Ebrahimi
Zahra Rasooli
, Neda Mahami
, Mohammad Alizadeh
,
, Mina Hemmati
Dept. of Biochemistry, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
Article Info
ABSTRACT
10.30699/jambs.30.139.86
Received: 2020/11/07;
Accepted: 2021/03/15;
Published Online: 31 Jan 2022;
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article online
Bisphenol A, as a primary substance used for making many plastic devices enters
the body through various routes such as skin penetration, oral ingestion, and
inhalation and is among the chemicals leading to the disruption of the endocrine
system. It exerts its destructive effects on the various tissues through estrogen,
androgen, thyroid, pregnane X, and aryl hydrocarbon receptors. This review study
was conducted to evaluate the pharmacological effects of bisphenol and its signaling
pathways especially in the adipose tissue. Studies have shown that the disruption in
the level of adipocytokines can contribute to the formation and progression of the
chronic diseases such as cancers. Decreased level of adiponectin (as an adipokine
secreted from white adipose tissue) and increased levels of IL-6, TNF-α, and leptin
are among the disruptions caused by bisphenol which can develop different types
of cancers. Accordingly, it seems that the use of bisphenol and contact with it should
be reconsidered with regard to its destructive effects on the endocrine system.
Keywords: Bisphenol A, Adipocytokines, Adipose tissue, Cancer
Corresponding Information:
Mina Hemmati,
Dept.of Biochemistry,School of Medicine, Zanjan University of Medical Sciences, Zanjan,Iran
E-Mail: : mina1hemmati@yahoo.com,
mhemmati@zums.ac.ir
Copyright © 2021, This is an original open-access article distributed under the terms of the Creative Commons Attribution-noncommercial 4.0 International License which permits
copy and redistribution of the material just in noncommercial usages with proper citation.
Introduction
Many synthetic chemicals are marketed aimed at
improving the living standards without considering the
negative consequences on human health (1). Bisphenol A
(BPA) (4, 4'_dihidroxy_2, 2 di phenyl propane), as a
synthesized chemical (material) is formed by the reaction
of two phenol groups with an acetone molecule (2, 3).
BPA is an estrogen monomer with a molecular weight of
228.29 g / mol and is known by the chemical formula of
C15H16O2. BPA is a white crystalline substance with a
mild phenolic odor and a melting temperature of 153-159
˚C (4, 5) which is used as a primary substance for the
production of the polycarbonate plastics, epoxy resins,
and polyester. Polycarbonates are used in making water
bottles, baby food bottles, toys, heat plates, home
appliances, sanitary ware, and medical equipment (5).
BPA is also utilized in the production of various plastics,
such as polyvinyl chloride, which is used in the
manufacturing of medical pipes, water pipes, and as a
lining in the dentistry (5). Exposure to BPA is mainly
through the hydrolysis of plastic containers containing the
polycarbonate and epoxy resins. BPA monomers obtained
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from BPA-produced polymers can be combined with the
foods and water; and the consumption of these
contaminated foods is the first source of human exposure
to BPA (6). Absorption of BPA by the human has been
estimated by 10 µg / kg / day (7). During 1995 - 2014,
BPA production in the United States and Europe has
increased by 37 and 84%, respectively, and this process is
expected to increasingly continue (8). Given the human
contact with BPA and its harmful effects on the human
health, the Environmental Protection Agency (EPA) has
introduced BPA as a destructive chemical against the
humans' endocrine system (9).
1.Pharmacokinetic of the BPA
In the United States, BPA has been observed in the
urine samples of more than 92% of the people at 6 years
of age and older (10, 11). The US EPA has stated the
reference dose of 50 µg /kg day for BPA. Meanwhile, the
European Food Safety Authority (EFSA) has reduced the
safe exposure rate to BPA from 50 to 4 µg /kg day (11).
Following ingestion, about 90% of BPA passes through
Journal of Advances in Medical and Biomedical Research
Amir Karbalaee Hasani et al. 87
the liver and its primary metabolism occurs in the intestine
and liver (12,13). Glucuronidated and sulfonated BPAs
are among the major secondary metabolites of BPA which
are excreted through the urine (Figure 1). BPA mostly acts
in the humans' body through binding to the steroid
hormone receptors, such as estrogen and androgen
receptors to alter the gene expression. The distribution of
these receptors varies in different tissues. Therefore, the
binding of BPA to these receptors creates a variety of
responses on the cell surface. BPA can bind to these
receptors both freely and in the conjugated form in the
bloodstream and then, exert its physiological functions
(13,14).
Figure 1. Chemical structure of BPA and its primary human metabolites, BPA-glucuronide. In humans, elimination of BPA is
via urine in the form of BPA or BPA conjugates, mostly BPA-glucuronide. The conjugation is done by UDP-glucuronyl
transferase (UGT) and sulfotransferase (SULT). Figure was prepared using templates on the servier medical art website (http://
smart.servier.comimage-set-download/).
2. BPA as an Endocrine Disrupting Compound
Endocrine Disrupting Compounds (EDCs) are the
compounds altering the function of the hemostatic and
hormonal systems. EDCs interfere with the function of the
nuclear receptors, estrogenic non-nuclear receptors, nonestrogenic receptors, and neurotransmitter receptors, such
as serotonin, dopamine, and norepinephrine receptors,
and also the orphan receptors including aryl hydrocarbon
receptor as well as the pathways involved in the steroid
synthesis or metabolism and other mechanisms converging with the endocrine and reproductive systems (15).
2.1. Estrogen Receptors
BPA can exert its physiological effects through various
physiological receptors including the Estrogen Receptors
alpha (ER ), Estrogen Receptors beta (ERβ), EstrogenRelated Receptors gamma (ERR γ), and Peroxisome
Proliferator-Activated Receptor gamma (PPAR γ) (16).
Compared to 17β-estradiol (E2), BPA tendency for
Volume 30, March & April 2022
binding to ERβ is higher than ER (17). BPA acts as an
ER agonist and creates the same change as E2, while
preventing the formation of the correct conformation of
the ligand-binding domain in ERβ and acting as an ERβ
antagonist (18, 19). Given the effect of E2 on induction of
the cellular proliferation, the effect of BPA has also been
investigated in this field. In fact, the balance between
signaling of ER and ERβ and the level of these receptors
causes the balance between the cell death and proliferation
regulated by E2 (20). BPA acts as a proliferative agent by
mimicking the E2 function in the presence of ER. While
in the presence of ERβ, BPA acts as an antagonist of the
E2-ERβ complex indicating that BPA leads to the
increase in the cell growth through ER and on the other
hand, it reduces the cell death through the antagonistic
activity during binding to ERβ (Figure 2). These two
functions of BPA in the presence of ERβ and ER can
create changes in the cells resulting in the development of
cancer (21).
Journal of Advances in Medical and Biomedical Research
88 Bisphenol A and risk of various cancers
Figure 2. Interaction of BPA with ER /ER resulting in the development of various cancers. In the presence of
ER /ER
BPA binds to these receptors and induces cell proliferation.
2.2. Androgen Receptor (AR)
BPA acts as an androgen receptor antagonist. Evidence
indicates that the antagonistic activity of BPA on the
androgen receptor prevents the transmission of the
receptor dimer to the nucleus and reduces the expression
of the synaptic proteins [Synapsin1 and Postsynaptic
Density Protein 95 (PSD95)] in the hippocampus of the
male rats resulting in a defect in the spatial memory (22).
There is insufficient information on the effect of BPA on
the AR transcription activity, and there is not sufficient
knowledge about the ability of these compounds to
interfere with the androgen-dependent extra-nuclear
signals (23). Androgen signaling appears to be less
influenced by the intervention of BPA, but BPA can
intervene in the treatment of the patients with advanced
prostate cancer through mutated ARs (24).
2.3. Thyroid Receptors
BPA has a low affinity for binding to the thyroid
receptors (TR) and reduces the self-induction effect of the
TR through antagonistic activity and at the same time
increases the serum thyroxine (22). BPA inhibits the
stimulated transcription activity by Triiodothyronine (T3)
through antagonistic activity. Through a Nuclear receptor
Co repressor (NCoR), BPA could reduce the expression
of the TR gene (5). According to the literature, BPA can
influence the expression of the genes involved in the brain
development by interfering with the thyroid hormone
receptor (25). These effects are mediated by the receptors
located in the nucleus, where they act as transcription
suppressors in connection with DNA through Silencing
Mediator of Retinoic acid and Thyroid hormone receptor
(SMRT) and NCoR. The extra-nuclear activity of the TR
depends on integrin αvβ3, which is responsible for
phosphorylation and activation of the nuclear TR through
activating the Mitogen-Activated Protein Kinase (MAPK) / cellular Sarcoma (c-Src) pathway (26). BPA directly
interferes with the β3 / integrin / c-Src / MAPK / TR-β1
pathway at low concentrations, which could affect TR
signaling.
2.4. Pregnane X Receptor
Human Steroid and Xenobiotic Receptor / rodent
Pregnane X Receptor (SXR / PXR) and Constitutive
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Androstane Receptor (CAR) are the two important
regulators for metabolism of the xenobiotic and steroid
hormones (19). These receptors in the liver and intestine
mediate the induction of the cytochrome enzymes p450
and transporters such as P-glycoprotein in response to
xenobiotic ligands and steroid hormones. SXR / PXR are
unusual nuclear receptors, which have extensive ligand
specificity and are activated by a lot of EDCs such as
BPA. Activation of the SXR / PXR and CAR, and
consequently an increase in the expression of their target
genes by various components causes an increase in the
levels of EDCs and at the same time changes the rate of
access to estrogens and androgens (27). In fact, BPA acts
as a strong agonist for hPXR. Combination of the effect
of BPA and other EDCs results in the synergistic effects
on the hPXR function (28).
2.5. Aryl Hydrocarbon Receptor
Aryl hydrocarbon receptor binds to several chemicals
and indirectly influences the metabolism of xenobiotics as
well as the synthesis and metabolism of steroids. Aryl
hydrocarbon receptors are the transcription factors
mediating the effects of various chemicals most
importantly, Tetrachlorodibenzodioxin. After binding the
ligand to the AHR in the cytoplasmic segment, it enters
the nucleus by the corresponding transmitter (ARNT)
which binds to the responsive elements in DNA and leads
to the transcription of the genes involved in the xenobiotic
metabolism including CYPs. The AHR repressor must be
bound to ARNT to disable this process or the messaging
path. BPA disrupts the AHR expression and its activity in
the embryo via AHR upstream transcriptional regulation
(29). BPA results in the changes in the primary
adipogenesis along with hypertrophic modification of the
adipocytes andoverexpression of the lipogenic genes such
as PPAR γ, Sterol Receptor Element-Binding Protein 1C
(SREBP-1C), Lipoprotein Lipase (LPL), and Fatty Acid
Synthetase (FAS) (30). BPA is able to increase the
expression of the PPAR γ -related-mRNA in the 3T3-L1
pri- adipocytes (31). The cAMP Response ElementBinding protein (CREB) also plays an important role in
the differentiation of the adipocytes, and the effects of
BPA on the differentiation of the adipocytes are likely to
occur through the rapid activation of CREB. Exposure to
low BPA concentrations for a long time influences the
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Amir Karbalaee Hasani et al. 89
adipogenic differentiation program by increasing the periadipocyte growth and altering the genes regulating the
adipogenesis (25). ERRγ is present in the adipose tissue.
Evidence indicates that ERRγ with its two isoforms
(ERRα / β) plays an important role in controlling the
energy homeostasis and biogenesis and the natural
function of the mitochondria. Studies have shown that
BPA exerts its effects on the body weight regulation
through ERRγ (30). BPA binds strongly to the human
ERR, and it also binds to ERRγ at low concentrations
while maintaining the ERR γ activity in the presence of 4hydroxydebrisoquine (4-OHD). The effects of BPA at
low concentrations on the energy homeostasis are likely
mediated by these nuclear receptors (19). BPA acts in the
body mainly through the estrogen receptor. This receptor
is expressed in various tissues of the body. BPA can cause
the disruptions in the tissues of these estrogen receptors
by binding to these receptors (32).
3. Expression of the ERs in the Adipose Tissue
Hormones are the main regulators of the adipose tissue
function and play an important role in the evolution and
development of the adipocytes. A wide range of growth
hormones and factors, such as thyroid hormone, glucocorticoids, catecholamines, insulin, glucagon, and insulinlike growth factors modify the activity and development
of the adipose tissue. Estrogens, especially E2 play an
important regulatory role in the metabolism and distribution of the adipose tissue (33). The sex steroids contribute to the function of the white adipose tissue through
controlling the lipolysis, lipogenesis, adipocyte differentiation, insulin sensitivity, and production and secretion
of the adipokines (34). In adults, increased estrogen
plasma concentration is associated with the decreased
food intake and body weight, and estrogen deficiency is
accompanied by the initiation of the menopause in
overweight women (35). Studies on the humans and
laboratory animals have suggested that estrogen is the
most important regulator of the white adipose tissue in
women (36). Estrogens exert their effects on the adipose
tissue through the steroid receptors (37). ER was
reported as the first receptor for estrogen in 1973. The
second steroid receptor, ERβ was identified in 1996.
Studies on the laboratory animals such as adult rats have
shown that the endogenous E2 is the most abundant and
predominant estrogen, and exerts its inhibitory effect on
the number of adipocytes and lipogenic cells through the
ER receptor (35). Both ER /β receptors are expressed
at the mRNA and protein levels in the human adipose
tissue with ER predominance. There is no regional or
gender difference in the adipose tissue for ER expression, while ERβ expression is higher in women than men
(38). Different roles have been attributed to ER and ERβ
regarding exerting the estrogen effects on the adipose
tissue. Obesity has been shown to increase in therats
without ER , while normal adipose tissue mass was
observed in the rats without ERβ (39). In the studies on
the 3T3-L1 cell line, ER receptors have also been
observed in the membrane and cell nucleus (40).
Estrogens can influence the adipose tissue activity in
several ways:
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1. A genomic response characterized by the changes in
the gene transcription that occurs from several hours to
several days.
2. Non-genomic signal events that occur from several
seconds to several minutes after cell stimulation (21).
With regard to the presence of the ERs in the adipose
tissue and their activities in the adipose tissue, BPA can
cause the disruptions in the adipose tissue by the ERs.
These disruptions include the changes in the normal
secretions of adipocytokines from this tissue (41).
4. Disruption in the Secretions of the Adipose Tissue
Leading to the Development of Cancer
The adipose tissue is a dynamic tissue involved in
regulation of the glucose and lipid metabolism, energy
homeostasis, and inflammation. In addition, the adipose
tissue is an active and complex endocrine organ playing a
role in the metabolism of sex steroids and the synthesis
and secretion of the active adipokines (42). In addition to
storing fat, the white adipose tissue is an active endocrine
gland that secretes more than 50 cytokines and other
molecules generally called adipocytokines including
adiponectin (APN), leptin, Tumor Necrosis Factor α
(TNFα), and Interleukin 6 (IL-6) (43, 44). There is a
special relationship between the adipose tissue and
different types of cancer including colorectal cancer,
kidney cancer, postmenopausal breast cancer, esophageal
cancer, etc. (45). The balance between the number of
adipocytes and cancer cells is created by cytokines
including IL-6, TNFα, and adipokines, such as APN and
other proteins produced from the adipose tissue to control
invasion and proliferation of the cancer cells (46). Recent
studies have confirmed the effects of the adipocytokines
in cancer (47). According to the recent studies, BPA can
cause changes in the secretions of the adipose tissue
through different cellular pathways (1). The following
investigates the effects of BPA on adipocytokines and the
role of these changes in cancer in detail.
5. The Effects of BPA on Cytokine Secretion
Numerous reports have shown that BPA influences the
levels of important hormones associated with metabolism,
such as APN and leptin which are among adipocytokines
(48). EDCs can disrupt the signaling by the regulatory
hormones including APN and leptin (32). Regarding the
presence of BPA around the world as well as the constant
exposure of humans to the it, inhibition of APN secretion,
and increased levels of the IL-6, TNFα, and leptin at
nanomolar concentrations may be the important factors in
the endocrine disruption and homeostasis of metabolism
(18).
5.1. The Effects of BPA on the APN Secretion from
the Adipose Tissue
APN is the most abundant adipocytokine secreted by
the adipocyte cells of the adipose tissue. APN, as an
adipokine is responsible for energy storage in the form of
TG, and has anti-apoptotic and anti-inflammatory
activities (49). Clinical studies have shown that the APN
level plays an important role in the protection against the
Journal of Advances in Medical and Biomedical Research
90 Bisphenol A and risk of various cancers
carcinogenic factors. Some cancer cells influence the
APN receptors and their downstream signaling pathways
to prevent the apoptosis (50). APN can prevent the
development of the cancers such as breast cancer, lung
cancer, thyroid cancer, and colorectal cancer by regulating
the signaling pathways, apoptosis, and the cell cycle (51).
Atrial Natriuretic Peptide (ANP) is a mediator between
the AMP-activated Protein Kinase (AMPK), Janus
Kinase (JAK) / Signal Transducer and Activator of
Transcription 3 (STAT3), and MAPK signaling pathways
(51, 52). ANP causes the activation of apoptosis and
inhibition of the cell proliferation through the AMPK
signaling pathways (52). Studies conducted on humans
and animals have shown that estrogen reduces APN
secretion. Results of a study on the rats without the
aromatase enzyme showed that the APN levels were
reduced by E2 consumption (53). EDCs act directly on
the steroid hormone receptors or indirectly through nonsteroidal receptors. Like E2, BPA activates the ERɑdependent signaling pathway leading to the MAPK /
Extracellular-Regulated Kinase (ERK), and Protein
Kinase B (AKT) phosphorylation (54). Low BPA
concentrations inhibit the APN secretion in the human
adipose cells in -vitro. It has been observed that BPA
accumulates in the adipose tissue. In addition, the ERRβ
receptor, as a nuclear receptor has a high tendency for
binding to BPA (55).
BPA regulates the expression and phosphorylation of
AKT acting on the downstream of the Phosphoinositide
3-Kinase (PI3K), and the PI3K signaling pathway is
accompanied by the production and secretion of APN.
The PI3K-AKT pathway is activated when the insulin
hormone binds to its receptor at the cell level that plays a
key role in regulating the gene expression and APN
secretion. In fact, BPA inhibits the expression and
phosphorylation of AKT, and APN levels have been
reported to be significantly lower in the cell cultures
treated with BPA. BPA does not act through the nuclear
ER pathway in the 3T3-L1 cells, but it also binds to the
estrogen-related receptor in the human (56). In fact, PI3K,
MAPK, and ER have been reported as the main
components of the signal transmitter for E2 or as foreign
estrogens in the regulation of the genes in the 3T3-L1 cell
line (40). Both BPA and E2 inhibit the APN secretion, but
they do not act through a single mechanism (32). APN
synthesis is stimulated by PPAR , insulin, and Insulinlike Growth Factor-1 (IGF-1) agonists. Increased expression of APN by PPAR is highly regarded, because
being an antagonist for PPAR is among the mechanisms
through which BPA can suppress the APN secretion.The
APN secretion is controlled at three levels: biosynthesis,
assembly, and release (57).The APN synthesis is
stimulated by PPAR , insulin, and IGF-1 agonists and is
inhibited by TNF- and catecholamines (18). Increase in
the APN expression is important because the mechanism
by which BPA can suppress the APN secretion is
performed by the PPAR antagonist. In fact, conjugated
compounds with BPA are potential antagonists for
PPAR activities in the adipocytes (58). In addition, BPA
can inhibit the Protein Disulfide Isomerase (PDI) enzyme
Volume 30, March & April 2022
playing an important role in the formation of the disulfide
bonds in APN, which is considered as a mechanism
involved in the reduction of APN by BPA (59).
5.1.1. Decreased Level of APN and Its Association
with Various Cancers
Endometrial Cancer (EC)
There is an inverse relationship between the serum level
of APN and the risk of endometrial cancer (60). APN
reduces the viability of the EC cells and decreases their
number through inhibiting the proliferation and inducing
the apoptosis (50). Previous studies have shown an
inverse relationship between the serum APN level and the
risk of EC in the women under 65 years of age (51, 61,
62).
Hepatic Cancer (HC)
The risk of liver cancer is directly associated with the
serum level of APN (50, 63). APN responds to liver
cancer by preventing the cell proliferation and pro –
apoptotic factors. The expression of Cyclin D1 and
Proliferating Cell Nuclear Antigen (PCNA) decreases and
instead, the expression of Caspase -3 increases in the liver
cancer cells. APN influences the hepatocellular cancer
cells through AMPK, c-Jun N-terminal Kinase (JNK),
and mammalian Target of Rapamycin (mTOR). APN
causes the JNK phosphorylation in the HepG2 and Huh7
cells and increases the AMPK activity through
phosphorylation (63).
Prostate Cancer (PC)
Prostate cancer is one of the most common cancers in
men metastasizing to other organs. Clipping the androgen
pathway is among the therapeutic methods for treatment
of PC; however, this therapeutic method does not respond
in some cases. APN level is lower than the normal in the
patients with PC and is inversely related to the disease
progression (50, 61, 63-65). The mRNA expression of
AdipoR1 / R2 receptors is also reduced in the PC cells.
Serum APN level and profile amount of its receptors can
predict the risk of PC (51, 52, 65). APN influences the
pathogenesis of PC through the JNK and STAT3
pathways. ANP causes the activation of the JNK, AMPK,
and PI3 kinase / AKT pathways in the PC cells. The
AMPK pathway inhibits the growth and proliferation of
the PC cells through 5-aminoimidazole -4-carboxamid
ribose (AICAR) (51, 63, 66).
Gastric Cancer (GC)
Low serum level of APN is directly associated with an
increased risk of gastric cancer. Increased expression of
the AdipoR1 receptor suppresses the growth of the GC
cells (50, 51). Serum level of APN is lower than the
normal range in the patients with esophageal cancer.
Esophageal cancer is among the malignant cancers
metastasizing to the gastrointestinal tract and in most
cases, the patients die within 5 years (50, 67). According
to literature, low serum level of APN also increase the risk
of pancreatic cancer (50).
Colorectal Cancer (CRC)
Journal of Advances in Medical and Biomedical Research
Amir Karbalaee Hasani et al. 91
Numerous studies have proved an inverse relationship
between the serum level of APN and the risk of colorectal
cancer (45, 46, 50, 63, 66, 68, 69). CRC is among the
most common cancers associated with obesity. Previous
studies have shown that low serum level of APN is
strongly associated with an increased risk of CRC (70).
AdipoR1 / R2 are expressed in the CRC cells and also
involve the lymph nodes. In the low stages of the disease,
the rate of AdipoR1 expression is associated with the
tumor size (46, 63, 64). High serum level of APN reduces
the risk of CRC by 60% (50, 71). Inhibition of the CyclinDependent Kinase (CDK) inhibitors, P21 / P27 through
AdipoR1 / R2 increases the cell cycle suppression.
Therefore, APN can control the proliferation of the cancer
cells by activating several tumor suppressor genes (68).
Thyroid Cancer (TC)
Thyroid cancer is the second most common cancer in
young women. APN receptors are expressed both in the
healthy thyroid and TC cells (46). Plasma APN level is
lower in patients with TC than the healthy individuals
(60).
as down-regulators (including the cytokine signaling
inhibitors) like JAK2-STAT3, MAPK, and PI3K / AKT
(80). Studies have shown that the leptin levels in the
bloodstream are higher in women than men. An increase
in the mRNA of Ob (human Obesity) gene in the presence
of E2 reflects the direct effect of estrogen on the
transcription of Ob gene. Evidence indicates that there are
several responsive elements to the Specificity Protein
1(SP1) in Ob gene promoter in humans. Thus, ER-SP1
relationship repre-sents the transcription by estrogen and
without the need for direct binding of ER to the DNA. In
-vitro studies have shown that the treatment of adipocyte
cells of the rats with estrogen increases the leptin secretion
(81). Specific activities of leptin in target tissues are
conducted by its interaction with specific receptors,
leading to the secondary activation of the JAK / STAT,
MAPK / ERK, and PI3K / AKT pathways (82).
Leptin, as a 16 -kDa peptide hormone contains 167
amino acids. The three-dimensional structure of leptin
consists of a motif containing four alpha helixes, which is
very similar to the structure of the (IL-6) family (73) .In
terms of the structure, leptin is a typical neuropeptide with
anorexic function. It is one of the important molecules
involved in the development of obesity, which is also
called the "satiety hormone" because it plays a key role in
absorbing the nutrients and controlling the energy
consumption. It is derived from the Greek word "leptos",
which means the slender and thin (74). Vokberg et al.,
showed that the exposure to BPA leads to weight gain and
accumulation of the adipose tissue mass, it also creates
some changes in the leptin level (75). Increased serum
level of leptin is associated with several cancers including
CRC, PC, and Breast Cancer (BC) (76, 77). Leptin
increases the proliferation, migration, and invasion of the
cancer cells (69, 78) and is able to induce the vascularization, increase the level of the Vascular Endothelial
Growth Factor (VEGF), and suppress the secretion of the
anti-inflammatory cytokines (79). Binding the leptin to its
receptor activates several signaling pathways in the form
of a cascade. So that, first, tyrosine kinase is activated, and
influences the cytokine receptor and binds it to the
transcription activators of STAT. STAT migrates toward
the nucleus and induces the expression of the genes, such
Previous studies have shown that BPA and leptin can
initiate similar intracellular messaging pathways that
induce cell proliferation. It has also been shown that BPA
increases the leptin receptor expression and, like leptin,
induces proliferation by activating the STAT3, ERK1 / 2,
and AKT messaging pathways. Similar to one of the
xenoestrogens, BPA increases the expression of the leptin
receptor gene in the ovarian cancer cells and activates the
intracellular signaling pathways (83, 84). There is normal
overexpression in the amount of leptin and its receptor in
the advanced stages of the BC (83). Leptin can bind to all
its four receptor forms (ob-Rd, ob-Rc, ob-Ra, ob-Rf) and
activate the JAK pathways, and phosphorylate the Insulin
Receptor Substrates (IRS), and initiate the AKT / PI3K
phosphorylation. Increased expression of the leptin
receptor in the cancer cells is associated with the decreased survival (69). Leptin inactivates various signaling
pathways including the AKT / PI3K, JAK / STAT, and
MAPK / ERK pathways (76, 83-85).The AKT / PI3K
pathway plays an important role in regulating the cell
growth and preventing the cell proliferation through
apoptosis (76). Estrogen is among the compounds that can
influence this pathway, which prevents the apoptosis by
activating the PI3K / AKT and MEK / ERK pathways, as
a common pathway between leptin and estrogen (78).
Leptin increases the D1 and c-Myc Cyclin expression, and
also increases the rate of cell cycle progression by
reducing G1. Cyclin D1 is overexpressed in the BC cells.
Cyclin D1 plays an essential and important role in
regulating and advancing the cell cycle from stage G1 to
S (78). Leptin reduces apoptosis through upregulation of
the growth stimulants such as the Cyclin D1 (to intensify
the cell proliferation) and downregulation of the tumor
suppressors such as P53 and P21 (78). Leptin produced
by the adipose tissue adjacent to the tumor causes a local
increase in the leptin level and stimulates the tumor
growth. In other words, the secretions of the adipose tissue
around the tumor into the intercellular space play an
important role in the local growth of the tumor (69). The
effects of BPA on adipokine secretion and related
signaling pathways are summarized in Figure 3.
Volume 30, March & April 2022
Journal of Advances in Medical and Biomedical Research
Renal Cell Cancer (RCC)
Low serum level of APN not only increases the risk of
kidney cancer but also causes metastasis. The expression
of AdipoR1 / R2 receptors is lower in the kidney tissues
than the other tissues resulting in a decrease in the protective potential of APN in kidneys (50, 60, 64, 70, 72).
5.2. The Effects of BPA on the Leptin Secretion from
the Adipose Tissue
92 Bisphenol A and risk of various cancers
Figure 3. Schematic representation of estrogenic activity of BPA in adipocytes through genomic and non-genomic pathways, as
described in the text. BPA mediates transactivation of OB gene. BPA also inhibits APN expression through inhibition of expression
and phosphorylation of AKT. Figure was prepared using templates on the servier medical art website (http://
smart.servier.comimage-set-download/).
5.2.1. Increased Level of Leptin and Its Association
with Various Cancers
Colorectal Cancer (CRC)
Leptin is usually released within the cycle of 2 - 3 hours
after a meal, and serum leptin is directly related to the fat
reserves; that is, it increases under the obesity conditions
and decreases following the weight loss. It has been
observed that if the number and size of the fat cells
increase, the LEP gene is activated with the synthesis of
leptin, which is then secreted into the bloodstream. CRC
occurs more in the obese people than the healthy people.
Numerous reports have shown that leptin plays an
important role in the progression and pathogenesis of
CRC. Leptin receptor expression has been observed in the
cytoplasm and the cell membrane of many tumor cells
including the CRC cells. Thus, it can be said that, the
leptin receptors are expressed in 77-95.5% of CRC cases
(84). Evidence indicates that obesity has a negative effect
on the cancer treatment and leads to the development of
drug- resistance, especially through leptin and its receptor.
Leptin adipokine, has been suggested to strengthen the
tumor and therapeutic resistance in many cancers.
Cytokine leptin increases the pre-inflammatory and
immune secretion of the cancer cells (86). Leptin also
Volume 30, March & April 2022
forms a tumor microenvironment to strengthen the
angiogenesis and metastasis. In addition, leptin is
associated with the expansion of the cancerous stem cells
population, and the expression of the leptin receptor is
essential for maintaining the properties of its cancerous
stem cells so that, leptin production increases the soluble
Intercellular Adhesion Molecule-1 (sICAM-1) in the
cancerous cells. ICAM-1 expression has not been
observed in the lung and breast cancerous cells, and this
effect is regulated by the leptin receptor (ObR). In
addition, leptin prescription causes an increase in the expression of ERK, JAK1 / 2 STAT3, and Focal Adhesion
Kinase (FAK) genes and also leads to the incidence of
ICAM-1 expression (86). Numerous studies have
confirmed that the Leptin Receptor (LEPR) signaling can
cause the adhesions, angiogenesis, migration, and survival
of the cancerous cells. A significant increase in the LEPR
expression in patients with metastatic forms of CRC
indicates that the LEPR activity is a valuable diagnostic
indicator of the metastatic potential of CRC (74).
Breast Cancer (BC)
Leptin is the most important mediator of obesity and
breast cancer, leading to tumorigenesis, development,
growth, and metastasis. Molecular mechanisms assoc-
Journal of Advances in Medical and Biomedical Research
Amir Karbalaee Hasani et al. 93
iated with obesity and BC are complex mechanisms, but
four mechanisms can explain this relationship including
the expression of the leptin receptor, chronic inflamemation of the adipose tissue, sex hormone replacement
(IGF-I), and insulin signaling. Leptin increases the risk of
BC by cross-reacting with other signaling molecules
including ERα, growth and Notch factors, and inflamematory factors. Cross signaling between leptin and IGF-I
causes invasion of BC through the reaction of the
Epidermal Growth Factor Receptor (EGFR). Mutual
signaling between the leptin-Notch and interleukin-1
(NILCO) causes the development of the cancer. Leptin –
NILCO axis is a mediator of activation of the stem cells.
Signaling of the cancer stem cells strengthens the
expression of the leptin receptors by activating the STAT3
pathway and increases the expression of the stem cells'
markers such as the octamer-binding transcription factor
4 (OCT4) and (sex determining region Y)-box 2 (SOX2)
(87).
prone to the migration, and exogenous leptin also
increases the ability of the glioma cells to migrate. In
addition, it has been reported that leptin plays a role in the
activity of the cancerous fibroblasts and the expression of
the matrix metalloproteinases greatly influencing the
metastatic behavior of the cancerous cells. In addition,
there is also evidence showing that leptin increases the
transmission of the epithelial cells through various
signaling mechanisms leading to the tumor invasion and
metastasis (86).
5.3. The Effects of BPA on the IL-6 Secretion from
the Adipose Tissue
Leptin may influence the migration of the thyroid cells.
Also, adipokines, such as APN, leptin, and hepatocyte
growth factors are able to regulate the proliferation and
invasion of the cancerous cells and may play a role in the
development of TC. Leptin serum level increases in the
patients with Papillary Thyroid Cancer (PTC). Decreased
APN level known as the angiogenesis inhibitor is
accompanied by the progression of TC under obesity conditions, and changes in the thyroid function and potential
mediators, such as cytokines, insulin, leptin, and APNs
may be related to an inflammatory condition (79).
Numerous clinical studies have shown that the lymphatic
invasion is more frequently observed in the cancers with
high leptin expression in different types of tumor. Growing evidence shows that leptin increases the invasion and
proliferation in the breast, ovary, lung, bile, and pancreatic
cancers and other cancers. Previous studies have
demonstrated that leptin is expressed in the cell categories
IL-6, as a 184-aa cytokine with a molecular weight of
about 25 KDa and pleiotropic function has both antiinflammatory and pre-inflammatory properties in the
immune and non-immune cells (88, 89). IL-6 is
synthesized in the immune cells and the peri-adipocytes
and adipocytes. IL-6 production is mediated through
stimulation by insulin through the cyclic Guanosine
Monophosphate (cGMP) / Protein Kinase G (PKG) /
CREB pathway, also requiring MAPK (86). Evidence
indicates that nanomolar concentrations of BPA may
induce a similar response of inflammation in the human
adipose tissue. Exposure to BPA causes the secretion of
the inflammatory factor of IL6. The activation of normal
inflammatory pathways is another finding associated with
the disruptions caused by BPA. In fact, the JNK, JAK /
STAT, and (nuclear factor kappa light chain enhancer of
activated B cells) NF-KB pathways have been shown to
be activated in the adipose tissue treated with BPA (86).
It is assumed that BPA can stimulate the Toll-Like
Receptors (TLRs) and leads to the proper regulation of
pre-inflammatory factors
such as IL-6 through
downstream signaling of JNK and NF-KB (86).BPA may
activate the intracellular signaling pathways through TLR
and ER ,or GPRC30, leading to the upregulation of IL6,
which in turn can stimulate and activate the common
inflammatory pathways such as JNK and JAK / STAT
pathways (86).After binding of IL-6 to its receptor (IL6R), it is bound to another receptor called glycoprotein
130 (gp130) and then, signaling is started (86. Dimer form
of gp130 activates the tyrosine kinase of JAK1leading to
the activation of the other signaling pathways including
the STAT1, PI3K, MAPK, and STAT3 pathways (8890). STAT3 acts as an oncogen and is the linker between
inflammation and cancer. Activation of SATA3 by IL-6
increases the expression of Cyclins B1, D2, D1 ,and CMyc and inhibits the expression of the CDKs, as a result
of which the cell enters the cell cycle. It also increases the
expression of a number of survival proteins including the
(B-cell lymphoma 2) Bcl-2, (myeloid leukemia cell
differentiation protein) Mcl-1, Survivin, and (B-cell
lymphoma-extra-large) Bcl-xl. Increased expression of
these proteins and continuation of the STAT3 activity lead
to the drug resistance in cancer patients. STAT3 activity
induces the expression of the Hypoxia-Inducible Factor α
(HIFα) dependent on the VEGF downstream protein of
this pathway (88, 91). Activating the JAK-STAT3
signaling pathway leads to an increase in the expression
of the matrix metalloproteinase (MMP7, MMP2, and
Volume 30, March & April 2022
Journal of Advances in Medical and Biomedical Research
Ovarian Cancer
Leptin and its receptor are overexpressed in the
epithelial ovarian cancer, which is significantly associated
with the progress-free survival. Increased expression of
the leptin receptor gene and protein in the ovarian cancer
cells occurs at nanomolar concentrations. Previous studies
have shown that leptin and BPA inhibit the expression of
the Caspase -3 gene in the OVCAR-3, as the ovarian
carcinoma cell line. However, there is no information on
the interaction between BPA and leptin in inhibiting the
apoptosis in cancer. Activation of the JAK / STAT,
MAPK / ERK1 / 2 ,and PI3K / Akt signaling pathways
has been investigated previously, and it has been hypothesized that two distinct combinations of leptin and BPA
(obesity-related) may regulate the apoptosis through
activation of the intracellular targets in the OvCAR-3 ,as
the ovarian cancer cells. It has been shown that BPA and
leptin interact to inhibit the gene and protein Caspase -3
through different intracellular signaling pathways so that
leptin works through STAT-3, while BPA works through
ERK1 / 2 (83).
Thyroid Cancer (TC)
94 Bisphenol A and risk of various cancers
MMP9). MMP9 plays an important role in the destruction
of the extracellular matrix and causes invasion of the
tumor cells (91). Cancer is also an inflammatory disease,
and the expression of the cytokines plays a major role in
the incidence of cancer (88, 92). Increased expression of
IL-6 is associated with the cancers such as colon, lung,
prostate, liver, etc (88).
Twenty percent of the cancers are caused by the chronic
inflammation. IL-6, as one of the pro- tumorigenic
cytokines controls and regulates the proliferation of the
cancer cells by regulating the signaling pathways of
growth factors including EGF and HGF family members
(91). TNFα increases the IL-6 expression during the
inflammatory response (88). Increased expression of IL-6
in several organs such as the brain, lungs, the liver, and
the bone marrow causes absorption and metastasis of the
circulating tumor cells in these organs. Activation of NFκB in the Kupffer cells stimulates the production of IL6causing the metastasis of the lung cancerous cells to the
liver (91).
5.3.1. Increased Level of IL-6 and Its Association
with Various Cancers
Colorectal Cancer (CRC)
CRC is accompanied by an increase in the IL-6
secretion, which also increases with the progression of the
cancer, but it is not considered as a prognostic factor of
the cancer. IL-6 increases the proliferation and growth of
the CRC cells. Proliferation and survival of the cancer
cells induced by IL-6 depend on the STAT3 activity in
anthrocytes (91, 93). In this type of cancer, IL-6 stimulates the proliferation of the epithelial cells through NFκB and STAT3 cascading pathways (88).
Gastric Cancer (GC)
STAT3 activity is associated with the reduced survival
(viability) in the patients with gastric cancer. Studies have
shown that the IL-6 activity and function are associated
with the enhanced initiating factors of GC. IL-6 is the
ligand -binding receptor of gp130 and strongly and
effectively upregulates gp130 in the gastric tumors (91).
Liver Cancer
HCC, as a common liver cancer is often caused by the
inflammation due to the chronic infection with the
hepatitis C and B viruses. IL-6 is strongly associated with
HCC, and the higher the serum level of IL-6, the larger the
size of the tumor. IL-6R and gp130 are highly expressed
in the hepatocytes (91).
Pancreatic Cancer
Increased STAT3 activity has been proven in patients
with pancreatic cancer. Serum level of IL-6 is higher in
patients with pancreatic cancer than the normal
individuals. STAT3-activated MMP7 is required for tumor progression but is dependent on other STAT3 targets
for tumor initiation (91).
Prostate Cancer
Volume 30, March & April 2022
IL-6 and its receptor are highly expressed in PC.
STAT3 activity is inversely related to the progression and
metastasis of PC (91).
Kidney and Bladder Cancers
IL-6 level is related to the tumor size, stage, and tumor
progression, and it is also a factor in metastasis of the
kidney and bladder tumors (91). The autocrine effect of
IL-6 in kidney cancer is associated with P53 (94).
5.4. The Effects of BPA on the TNF-α Secretion
from the Adipose Tissue
TNFα is a potent cytokine with an essential role in the
intrinsic immunity and also a transmembrane protein with
26KDa molecular weight that is expressed in a wide range
of cells, in addition to the macrophages including the
adipose tissue as well as the breast, colon, and pancreatic
cancer cells. TNFα has two types of receptors (92, 95-97):
1) R1 (also called as P55)
2) R2 (also called as P75)
R1 is expressed in all cells, and R2 is selectively
expressed in the endothelial and immune system cells.
TNFα has the same tendency for binding to both
receptors. TNFα is essential for the proliferation and proper functioning of the T cells, B cells, macrophages, and
dendritic cells (92, 95, 96).
Studies on the effect of BPA on the TNFα secretion
from the adipose tissue have proven that BPA increases
the expression and secretion of TNFα from the adipose
tissue cells through binding to the classic ERs present on
the surface of the adipose tissue (30, 98). Lack of TNFα
regulation is associated with the extensive changes, such
as the development of cancer. TNFα is associated with all
stages of cancer, such as tumorigenesis, cellular changes,
survival, proliferation, invasion, angiogenesis, and
metastasis (95). Most chronic inflammatory diseases
increase the risk of cancer, and it has also been proven that
most cancers develop in the chronic inflammatory sites.
TNFα is not usually detectable in the plasma of healthy
individuals, for example, in patients with PC, TNFα and
IL-6 levels are associated with the cancer progression
(96). Tumor cells that have high growth and proliferation
and migrate rapidly induce the TNFα expression, and this
cytokine increases the expression of the Vascular Cell
Adhesion Molecule-1(VCAM1). As a result, communication and interaction is established between the tumor
and endothelial cells resulting in the colonization in the
tissues and tumor metastasis to other tissues (99, 100).
TNFα induces the expression of the MMPs and dipeptidyl
peptidases and causes the growth, migration, and invasion
of ERs in the MCF7 and MDA-MB231 cell lines (101).
MMPs are the enzymes that regulate the extracellular
matrix and play a role in the angiogenesis, growth, proliferation, and metastasis of various tumors including the
BC cells. Epithelial-mesenchymal transmission is among
the other roles of TNFα in the progression of cancer.
During this process, epithelial cells lose their phenotypic
properties and increase the mesenchymal properties such
as loss of the E -cadherin (epithelial marker), induction of
Journal of Advances in Medical and Biomedical Research
Amir Karbalaee Hasani et al. 95
vimentin, loss of the cellular adhesion, disruption of the
cell adhesion, resistance to apoptosis, and increased
mobility and invasion (101).
5.4.1. Increased Level of TNF-α and its Association
with Various Cancers
Conflict of Interest
The authors confirm that there are no conflicts of
interest.
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BPA is a synthetic chemical that is increasingly
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How to Cite This Article:
Karbalaee Hasani A, Nejad Ebrahimi Z, Mahami N, Alizadeh M, Rasooli Z, Hemmati M. A Review of Bisphenol
A Effects on White Adipose Tissue and Its Correlation with Various Cancers. J Adv Med Biomed Res. 2022; 30
(139): 86-100.
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