1.

Abbreviations
BPA- Bisphenol A

DIT- Diiodotyrosine

EDC- Endocrine disrupting chemical

LBD- Ligand binding domain

MIT- Monoiodotyrosine

NCoA- Nuclear receptor Co-activator

NCoR- Nuclear receptor Co-repressor

NIS- Sodium iodide symporter

RXR- Retinoid X-receptor

SMRT- Silencing Mediator of Retinoic acid and Thyroid hormone receptor

T3- Triiodothyronine

T4- Thyroxine

TBG- Thyroid binding globulin

TBL1- Transducer β like protein 1

TDC- Thyroid disrupting chemicals

TG- Thyroglobulin

TH- Thyroid hormone

TPO- Thyroid peroxidase

TR- Thyroid receptors

TRE- Thyroid hormone response elements

TSH- Thyroid-stimulating hormone

TTR- Transthyretin

Bisphenol A; A Potrntial Threat As Thyroid Disruptor |

 2. Abstract
Since 1950s BisphenolA (BPA) has been used vigorously to harden polycarbonate plastics
and make epoxy resin. It is used extensively throughout the world and is present in a diverse
range of manufactured articles including dental resins, polycarbonate plastics, baby bottles,
medical devices and the inner coating of food cans. However, BPA is now recognized as an
‘Endocrine Disrupting Chemical’ (EDC) with multiple adverse effects on animals and humans.
An endocrine disruptoris an exogenous substance or mixture that alters function(s) of the
endocrine system and consequently causes adverse health effects in an intact organism, or its
progeny, or (sub)populations. Thyroid disruptors (TDs) or thyroid disrupting chemicals (TDCs)
are a sub-family of endocrine disruptors which interfere with thyroid function by affecting the
hypothalamo-pituitary-thyroid axis or directly via thyroid hormone receptors (TR). The thyroid
gland has a complex physiology while its secretions affect overall metabolism of the body. The
EDCs can affect the thyroid gland in multiple ways. In brief, the basic areas of interference with
thyroid metabolism include: (1) inhibition of iodide uptake at the cellular membrane of the
thyrocyte via blockage of the NIS transporter; (2) synthesis inhibition via thyroperoxidase; (3)
binding of transport protein TTR in the bloodstream; (4) altered hepatic phase 2 catabolism by
glucuronosyltransferase and sulfotransferase metabolism of T3 and T4; (5) alteration of
deiodinase-regulated T4 metabolism; and (6) alterations of transport across cellular membranes
and alteration of cellular receptors (TSH receptor). BPA may disrupt thyroid receptor (TR)
transcription simply by (1) binding to TR and directly inhibiting the action of endogenous TH.
Transcription may be inhibited by the recruitment of nuclear co-repressors. (2) BPA may bind to
TR and lower transcription of target TH-response genes by inhibiting co-activator binding. (3)
Alternatively, BPA may bind to TR and directly activate TH-response genes via the recruitment
of nuclear co-activators. Further studies, such as animal experiments and epidemiological
investigations will allow proper evaluation of the effects of BPA on the human endocrine
system. Presently, the molecular mechanism of thyroid disruption induced by BPA is discussed
in the dissertation.

Key Words:-
Bisphenol A, Endocrine Disruptors, Thyroid Disruption, Thyroid Disrupting
Chemicals, Thyroid Hormone, Thyroid Receptors, Nuclear Co repressors.

Bisphenol A; A Potrntial Threat As Thyroid Disruptor |

 3. Introduction

Bisphenol A (BPA) is an industrial chemical used primarily to make polycarbonate plastic

and epoxy resins – both of which are used in countless applications that make our lives easier
each and every day. It is an indispensable ingredient of all plastic goods as it makes plastics clear
and tough. Since 1950s BPA has been used vigorously to harden polycarbonate plastics and
make epoxy resin which is used in the lining of beverage and food containers. In 1930s a British
biochemist Edward Charles Dodds found BPA to have an estrogenic effect, though relatively far
less than natural estradiol (Dodds and Lawson, 1936).However it was never been used as a drug
but within subsequent years BPA was found to put adverse impacts on laboratory animals even
in very low dose. Use of BPA has been banned in some countries whereas in other countries like
ours, research and debates are ongoing as to whether to ban it or not! Nevertheless, over the past
few years, the growing scientific literature correlating environmental BPA exposure to adverse
effects in humans, along with laboratory studies in many species including primates, provides
increasing support that environmental BPA exposure can be harmful to humans (Rochester,
2013).

Bisphenol A (BPA) is used extensively in the world and is present in a diverse range of
manufactured articles including dental resins, polycarbonate plastics, baby bottles, medical
devices and the inner coating of food cans. It is a high volume chemical, with global production
at 3.6 × 109 kg per year. BPA was identified as a high priority for assessment of human health
risk because it was considered to present greatest potential for human exposure. Most studies on
the health effects of BPA have focused on endocrine disruption leading to reproductive toxicity,
but it displays additional side effects, including liver damage, disrupted pancreatic β-cell
function and thyroid hormone disruption (Le Corre et al., 2015).

Bisphenol A; A Potrntial Threat As Thyroid Disruptor |

 BPA is now recognised as an ‘Endocrine Disrupting Chemical’ (EDC) with multiple
adverse effects on animals and humans. The present study is aimed to highlight the mechanism
of BPA induced thyroid disruption.

4. Endocrine Disrupting Chemicals (EDCs)

In 1962, Rachel Carson published ‘Silent Spring’, an account of the severe reproductive
toxicity of pesticides in avian species (Carson, 1962). This launched investigations into the role
of chemicals as potential environmental toxins. Over the past decade, the list of chemicals with
endocrine disrupting activity has dramatically increased. An endocrine-disrupting compound was
defined by the U.S. Environmental Protection Agency (EPA) as “an exogenous agent that
interferes with synthesis, secretion, transport, metabolism, binding action, or elimination of
natural blood-borne hormones that are present in the body and are responsible for homeostasis,
reproduction, and developmental process” (Kavlock et al., 1996). Few years later, the
International Programme on Chemical Safety (IPCS), a joint programme of WHO, UNEP and
the International Labour Organization held at Geneva, Switzerland, developed a report in 2002
entitled Global Assessment of the State‐of‐the‐Science of Endocrine Disruptors (IPCS, 2002).
According to IPCS, 2002, “An endocrine disruptor is an exogenous substance or mixture that
alters function(s) of the endocrine system and consequently causes adverse health effects in an
intact organism, or its progeny, or (sub)populations.” In addition, “A potential endocrine
disruptor is an exogenous substance or mixture that possesses properties that might be expected
to lead to endocrine disruption in an intact organism, or its progeny, or (sub)populations”
(IPCS, 2002).

To put it simply, endocrine disrupting chemicals (EDCs) are synthetic chemicals that were
originally designed for a specific action such as a pesticide, plasticizer, or solvent, but now have
been found to have side-effects that when absorbed into the body causes them to either mimic or
block hormones and disrupt the body’s normal functions. This disruption can occur by altering
normal hormone levels, inhibiting or stimulating the production and metabolism of hormones or

Bisphenol A; A Potrntial Threat As Thyroid Disruptor |

changing the way hormones travel through the body, thus affecting the functions that these
hormones control.

In 2009, The Endocrine Society published a Scientific Statement regarding the probable
role of environmental EDCs in human pathology. In it, recommendations were made “to
increase understanding the effects of EDCs, including enhancing increased basic and clinical
research, invoking the precautionary principle, and advocating involvement of individual and
scientific society stakeholders in communicating and implementing changes in public policy and
awareness” (Diamanti-Kandarakis et al., 2009). This was soon followed by a document on the
state-of-the-science of EDCs in 2012 by the United Nations Environment Programme (UNEP)
and the World Health Organization (WHO) in collaboration with international experts to address
the growing concerns in this particular subject (UNEP/WHO, 2012).

5. Occurrence and Physiological Effects of EDCs

The EDCs are widespread in modern times. Thousands of chemicals, some banned and
some still in use, have been classified as EDCs. They are mainly found in several products
including plastic bottles, metal food cans, detergents, flame retardants, packaged foods, toys,
cosmetics, pesticides etc. that have widespread daily usage in industries, agriculture as well as at
home. These mainly comprise of a diverse group of compounds like organochlorine pesticides,
alkylphenols, polychlorinated biphenyls, polybrominateddiphenyl ethers, dioxins, phthalates and
bisphenol A mainly used in PVC plastics. As the plasticizers are not chemically bound to PVC,
they can leach, migrate or evaporate into indoor air, foodstuff and other materials. Natural
chemicals found in human and animal food (e.g., phytoestrogens, including genistein and
coumestrol) can also act as endocrine disruptors. These substances are widely consumed and are
components of infant formula products (Kuiper et al., 1998).

Humans are exposed through ingestion, inhalation and dermal contact. The agricultural and
urban run-off, sewage and industrial effluents contaminate the aquatic systems, thus posing
increased risk of exposure of aquatic organisms to the EDCs as well. Several reports have
suggested impairment of reproductive and developmental processes due to thyroid dysfunction,
5

Bisphenol A; A Potrntial Threat As Thyroid Disruptor |

increased embryo mortalities and deformities, loss of sexual characteristics, neuroendocrine
system anomalies, and varied physiological dysfunction in fish due to estrogenic and other
effects of EDCs. Industrialized areas are typically characterized by contamination from a wide
range of industrial chemicals that may leach into soil and groundwater. These complex mixtures
enter the food chain and accumulate in animals higher up the food chain such as humans.
Exposure occurs through drinking contaminated water, breathing contaminated air, ingesting
food, or contacting contaminated soil. People who work with pesticides, fungicides, and
industrial chemicals are at particularly high risk for exposure and thus for developing a
reproductive or endocrine abnormality (Diamanti-Kandarakiset al., 2009).

It is plausible that all endocrine systems are to some degree affected by environmental
chemical exposures. Since EDCs activate the same receptors and signaling pathways as
hormones and act at low concentrations, they are subject to the same biological regulatory
systems as hormones; and since hormones control all aspects of physiology across the lifespan,
the same can be expected from chemicals with endocrine disrupting activity (Schug et al., 2011).
The most important aspects of endocrine disruption are related to xenoestrogens, xenoandrogens,
anti-estrogens, anti-androgens, disruption of thyroid function, and disruption of corticoid
function, and other metabolic effects (Coster and Larebeke, 2012).

6. Thyroid Disruptors

Thyroid disruptors (TDs) or thyroid disrupting chemicals (TDCs) are a sub-family of

endocrine disruptors which interfere with thyroid function by affecting the hypothalamo-
pituitary-thyroid axis or directly via thyroid hormone receptors. The alteration in hormonal
milieu may cause developmental defects, tumors, hypo or hyper-functions of thyroid hormones
(Murthy and Murthy, 2012).

Thyroid disruptors are widely prevalent in the ecosystem as pollutants or products of day
to day use. Besides BPA, the primary environmental chemicals identified as thyroid disruptors
are PCBs, perchlorate, tetrachlorodibenzo-p-dioxin (TCDD) and polychlorinated dibenzofuran

Bisphenol A; A Potrntial Threat As Thyroid Disruptor |

(PCDF) (both commonly referred to as dioxins), pentachlorophenol (measured in mammals as
the source chemical hexachlorobenzene, a common pesticide that breaks down into
pentachlorophenol), triclosan, polybrominateddiphenyl ethers (PBDEs) and
tetrabrominateddiphenyl ethers commonly known as flame retardants, and naturally-occurring
chemicals such as soy isoflavones and thiocyanate in cruciferous vegetables, and phthalatesused
as plastic emollients in feeding tubes and plastic containers (Patrick, 2009).

In order to study thyroid disruption, it is very important to understand the complex

physiology of the thyroid gland.

7. Biosynthesis of thyroid hormones-

Thyroid gland is a bilobed organ placed in the neck region on the upper end of trachea.
Each lobe is composed of a large number of closed follicles (100-300 micrometers in diameter)
filled with a secretary substance called colloid and lined with cuboidal epithelial cells that secrete
into the interior of the follicles. The major constituent of colloid is the large glycoprotein
thyroglobulin, which contains the thyroid hormones within its molecule. Once the secretion has
entered the follicles, it must be absorbed back through the follicular epithelium into the blood
before it can function in the body. The thyroid gland has a blood flow about five times the
weight of the gland each minute, which is a blood supply as great as that of any other area of the
body, with the possible exception of the adrenal cortex. Thus thyroid gland is one of the most
important glands, any exogenous contamination can very easily and quickly perfuse into the
gland.
Firstly the iodide ions are oxidized in form of iodine, which is then capable of combining
directly with the amino acid tyrosine. This oxidation of iodine is promoted by the enzyme
peroxidase and its accompanying hydrogen peroxide. The next step is binding of iodine with the
thyroglobulin molecule called organification of the thyroglobulin catalyzed by iodinase enzyme
in the thyroid cells. This takes place as soon as the thyroglobulin molecule is released from the
Golgi apparatus or as it is secreted through the apical cell membrane into the follicle. Tyrosine is

Bisphenol A; A Potrntial Threat As Thyroid Disruptor |

first iodized to monoiodotyrosine (MIT) and then to diiodotyrosine (DIT). Then the iodotyrosine
residues become coupled with one another.

Figure 1.Biosynthesis of thyroid hormones (Guyton and Hall, XIth edn.)

On stimulation of TSH the apical surface of the thyroid cells sends out pseudopod
extensions that close around small portions of the colloid to form pinocytic vesicles that enter the
apex of the thyroid cell. Then lysosomes in the cell cytoplasm immediately fuse with these
vesicles to form digestive vesicles containing digestive enzymes from the lysosomes mixed with
the colloid. Multiple proteases among the enzymes digest the thyroglobulin molecules and
release thyroxine and triiodothyronine in free form. These then diffuse through the base of the
thyroid cell into the surrounding capillaries. Thus, the thyroid hormones are released into the
blood (Guyton and Hall, XIth edn.).

Bisphenol A; A Potrntial Threat As Thyroid Disruptor |

Figure 2. Mechanisms for iodine transport, thyroxine and triiodothyronine formation, and their
release into the blood. MIT, monoiodotyrosine; DIT, diiodotyrosine; T3,
triiodothyronine; T4, thyroxine; TG, thyroglobulin.(Guyton and Hall, XIth edn.)

8. Molecular Signaling involved in Thyroid Hormone Action

The functions of T3 are mediated by several isoforms of nuclear thyroid receptors (TRs),
encoded by two separate genes (alpha and beta respectively). TRs belong to the nuclear receptor
superfamily which also includes receptors for steroid hormones. The TRα locus generates TRα1
and several related proteins, TRα2, TRα3, and TR delta αs, which result from alternative splicing
of the TRα primary transcript. The TRβ locus generates TRβ1, TRβ2, TRβ3, and TR delta βs by
using different promoters and alternative splicing. TRβ1, TRβ2, and TRβ3 have an identical
ligand binding domain (LBD). The expression of TRβ2 is restricted to some specific organs,
including the pituitary and hypothalamus, where it appears to play a key role in the regulation of
TSH synthesis and secretion. The tissue distributions of TRα1, TRβ1, and TRβ3 are relatively
ubiquitous and the expression of these proteins begins early in development. Unliganded TR are
9

Bisphenol A; A Potrntial Threat As Thyroid Disruptor |

bound to DNA at thyroid hormone response elements (TRE) predominantly as homodimers or as
heterodimers with retinoid X-receptors (RXR), and are associated with a complex of proteins
containing co-repressor proteins. Ligand binding promotes co-repressor dissociation and binding
of a co-activator. The LBD is comprised mostly of α-helices. The ligand is completely buried in
the receptor and forms part of its hydrophobic core.
Many crucial processes of vertebrate body such as reproduction and differentiation are
regulated by the actions of small, lipophilic hormones including the steroids, retinoids, and
thyroid hormones. These are sensed by nuclear hormone receptors that bind to specific hormone
and function as ligand regulated transcription factors. Each nuclear hormone receptor binds to
specific sites on the DNA and modulates the expression of specific sets of target genes.
Nuclear hormone receptors can exert both positive and negative effects on transcription.
These bimodal transcriptional properties are manifested through the ability of these receptors to
associate with auxiliary regulator proteins, known as co-repressors and co-activators, which
mediate the involved transcriptional response. For TRs and retinoid X-receptors can function as
transcriptional silencers in the absence of hormone, a context in which these receptors bind to a
class of co-repressor proteins denoted SMRT (Silencing Mediator of Retinoic acid and Thyroid
hormone receptor)/NCoR (Nuclear receptor Co-repressor) (also known as TRAC and RIP13).
Binding of hormone converts TRs and RXRs into strong transcriptional activators, a process that
is accomplished by the release of the SMRT/NCoR co-repressors and the subsequent association
of the receptors with a new set of proteins that function as transcriptional co-activators.

Figure 3.Pathway showing genomic action of T3 (1. T3 enters nucleus, 2. T3 binds to TR

and displaces NCoR, 3. Association with NCoA, 4.Active translation (Fauci et al. Harrison’s
Principles of Internal Medicine, 18thedn.)

10

Bisphenol A; A Potrntial Threat As Thyroid Disruptor |

 Thus, repression by nuclear hormone receptors involves a physical recruitment of
SMRT/NCoR co-repressor proteins to the target promoter. The SMRT/NCoR proteins can
recruit, in turn, an ensemble of additional polypeptides such as histone deacetylases etc. It is this
larger co-repressor complex that is thought to be the actual effector of transcriptional repression.
Repression of gene expression probably involves multiple mechanisms including both
modifications of the chromatin template and inhibitory interactions with the general
transcriptional machinery itself (Hong et al. 1998).

9. Thyroid Disruption

Thyroid function is regulated by a finely tuned negative feedback mechanism of circulating

thyroid hormones at the hypothalamic and pituitary levels, maintaining relatively stable serum
levels of thyroid hormones with each individual having his or her specific set point (Feldt-
Rasmussen et al., 1980). Alterations in the thyroid gland, binding proteins, peripheral
metabolism and clearance also affect thyroid function. The mechanisms involved in thyroid
homeostasis are thus numerous and complex, and environmental chemicals may interfere at all
levels. The large physiological range of TSH and peripheral thyroid hormones in human,
resulting in a large variation of measurements between individuals makes studies of human
populations very difficult. In addition, human exposure is constant, cumulative for persistent
chemicals, and involves a vast number of chemicals. At the level of the thyroid gland itself,
chemicals may disturb the overall activity of the gland by interference with the TSH receptor, as
thyroid-stimulating hormone (TSH) stimulates all steps of the hormone production. The function
of the sodium iodide symporter (NIS) or thyroid peroxidase (TPO) can be affected by chemicals
through stimulation or inhibition. Chemicals may also interfere with other receptors on the
thyrocyte whereby interference with intracellular mechanisms (e.g. cytokine actions) may occur
(Boas et al., 2012).

Thyroid hormones are in humans mainly bound to thyroid binding globulin (TBG),
whereas transthyretin (TTR), being the most important carrier protein in rodents, binds only a

11

Bisphenol A; A Potrntial Threat As Thyroid Disruptor |

minor proportion of the hormones. However, TTR has been proposed to be of importance by
transferring thyroid hormones over the blood–brain barrier as well as over placenta to the fetal
compartment. In contrast to TTR, to which hydroxylated PCBs can competitively bind, no EDCs
have been demonstrated to compete with thyroid hormones for binding to TBG or albumin with
significant strength (Van den Berg, 1990; Lans et al., 1994). Competitive binding of
environmental chemicals to transport proteins may result in increased bioavailability of
endogenous thyroid hormones, but feedback regulation via TSH may compensate for this change
in binding capacity of the transport proteins. Displacement of T4 from TTR by EDCs is not
believed to be a major health hazard in humans (Purkey et al., 2004). Another potential effect of
binding of EDCs to natural transport proteins may facilitate their transport to thyroid dependent
tissues such as the brain or the fetus. At target cells, thyroid hormones are probably actively
transported across the cell surface via membrane bound transporters. Interference of EDCs with
these proteins may compromise the bioavailability of thyroid hormones to the nuclear thyroid
hormone receptors (TR). Several chemicals have been shown to interact with the TR, either
directly as agonists or antagonists, or by regulating expression of the TR genes. In the brain,
thyroid hormones are involved in oligodendrocyte development and myelination as well as
extension of Purkinje cell dendrites, which is essential for normal neuronal circuit formation
(synaptogenesis) and subsequent behavioral functions. Alterations in TR expression or binding
may disturb the normal development of the central nervous system (Boas et al., 2012).

Furthermore, thyroid hormones are metabolized in the liver by sulphation and conjugation
by UDPGTs, and stimulation of these enzymes by EDCs may lead to faster clearance of the
thyroid hormones. Due to the physiological feedback regulation between TSH and peripheral
hormones, the effects of EDCs are not easily predictable or detectable, as no ‘exposure free’ state
exists in humans. Unfortunately, very few human studies include long term health effects of
thyroid related outcomes such as neurological development or growth in their outcomes. Despite
the compensating capacity of the thyroid gland the combined long-term effects of numerous
EDCs, some of which accumulate with time, which may potentially result in hypothyroidism
(Boas et al., 2012).

In brief, the basic areas of interference with thyroid metabolism include: (1) inhibition of
iodide uptake at the cellular membrane of the thyrocyte via blockage of the NIS transporter; (2)

12

Bisphenol A; A Potrntial Threat As Thyroid Disruptor |

synthesis inhibition via thyroperoxidase; (3) binding of transport protein TTR in the
bloodstream; (4) altered hepatic phase 2 catabolism by glucuronosyltransferase and
sulfotransferase metabolism of T3 and T4; (5) alteration of deiodinase-regulated T4 metabolism;
and (6) alterations of transport across cellular membranes and alteration of cellular receptors
(TSH receptor) (Patrick, 2009).

10. BPA and T3- Comparison of Structure

If we compare the structures of natural T3 hormone and exogenous BPA we can note a
striking resemblance between the two of them. Both the structures show the presence of two
benzene rings linked by carbon in BPA and by oxygen atom in T3. BPA has two hydroxyl groups
whereas T3 has one hydroxyl and one alanine group. BPA is seen to displace [125I]T3 from
endogenous TR (extracted from rat liver) with an inhibition constant Ki=200μM. Scatchard
analysis revealed that presence of BPA decreased the value for the association constant (Ka)
from 0.44 to 0.28x10-9 M (Moriyama et al., 2002).

Figure 4. Comparison of chemical structure of BPA and T3 (Moriyama et al., 2002)

13

Bisphenol A; A Potrntial Threat As Thyroid Disruptor |

 11. Mechanism of Thyroid Disruption induced by BPA

BPA binds to TR and can act as an antagonist to inhibit transcriptional activity stimulated
by thyroid hormone T3 (Moriyama et al., 2002; Zoeller, 2005). The halogenated derivatives of
BPA viz. tetrabromobisphenol A and tetrachlorobisphenol A, commonly used as flame retardants
for building materials, paints, textiles, electronic equipment and other items, have been shown to
inhibit binding of T3 to TR. In fact, both agonist and antagonist activities of halogenated BPA
derivatives at TR have been reported (Rubin, 2011).

Various experiments were carried out to study the effect of BPA on thyroid action. An
experiment was performed by using TSA201 cells, which are a derivative of human embryonic
kidney 293 cells. A recombinant TR was constructed by combining ligand binding domain of
TRα1or TRβ with DNA binding domain of one of the yeast transcription factor, namely Gal4,
whose corresponding gene is UAS-E1BTATA-Luc. Gal4 gene codes for luciferase enzyme,
firefly luciferase is a member of the acyl-adenylate/thioester-forming superfamily of enzymes
that catalyzes the oxidation of firefly luciferin with molecular oxygen to emit light. Thus
Luciferase is used as a sensitive genetic reporter in this experiment.The experiment showed that
BPA could inhibit the transcription of Gal4 gene mediated by Gal4-TRα1 and Gal4-TRβ with
increasing concentration of BPA (Moriyama et al., 2002).

Figure 5. Representation of Luciferase activity with growing BPA concentration

14

Bisphenol A; A Potrntial Threat As Thyroid Disruptor |

 Effect of BPA on different physiological T3 concentrations was also studied by addition of
gradually increasing amounts of T3. In the presence of a fixed concentration of BPA, when
increased amounts of T3 was introduced to the medium, and then the transcriptional activity was
assayed, it was shown that BPA could suppress the activity mediated by Gal4-TRα1 as compared
to the respective control level which is kept unhindered from Bisphenol A. Similar results were
obtained when Gal4-TRβ was used instead of Gal4-TRα1 (Moriyama et al., 2002).

Figure 6. Representation of Luciferase activity in two cell cultures, control and BPA treated in
presence of increasing T3 concentration

The inhibitory effect of BPA was also examined by native receptors. A T 3-responsive
reporter gene, TRE-tk-Luc, was cotransfected with full-length TRs. It was noted that increasing
concentrations of BPA significantly suppressed the transcriptional activities that were mediated
by TRα1 and TRβ1. Whereas in a reciprocal manner, another group of negatively regulated
genes were studied, those were stimulated by TRs in the absence of T3 and were repressed in
response to T3. The effects of BPA on the TSHα promoter were examined as a model of a
negatively regulated gene. BPA increased the transcriptional activity, which was already
suppressed by very less amount of T3. The stimulating effects were observed in the presence of
TRβ1 as well as TRβ2, which is expressed mainly in the pituitary and hypothalamus. (Moriyama
et al., 2002).

15

Bisphenol A; A Potrntial Threat As Thyroid Disruptor |

 12. BPA recruits N-CoR
Transcriptional repression of the positively regulated genes by unliganded TR, due to
contamination of BPA, is mediated by interacting with co-repressor proteins (CoRs). CoRs might
also be involved in the basal activation of negatively regulated genes. Presence of T 3 hormone
break these interactions between the repressors and thyroid hormone receptors and mediate
interaction with co-activators, in case of positively regulated genes. Whereas, in case of
negatively mediated genes, T3 hormone mediates association of thyroid receptors with co-
repressors, instead of co-activators.BPA being antagonistic in nature, weakens those interactions
mediated by T3 (Moriyama et al., 2002).

In case of negatively regulated genes

Figure 7. In case of negatively regulated genes presence of T3 hormone will switch off the
transcription of target genes by association of nuclear co-repressors with thyroid
hormone whereas BPA causes dissociation of nuclear co-repressors (Yoon et al., 2005).

16

Bisphenol A; A Potrntial Threat As Thyroid Disruptor |

In case of positively regulated genes

Figure 8. In case of positively regulated genes, presence of T3 will switch on the transcription of
target genes by dissociation of nuclear co-repressors from thyroid hormone whereas
BPA causes association of nuclear co-repressers (Yoon et al., 2005).

13. Conclusion

Thyroid hormone is essential for proper development in vertebrates. Its deficiency during
gestation and early postnatal development produces severe neurological, skeletal, metabolism
and growth abnormalities. It is therefore important to consider environmental chemicals that may
interfere with thyroid hormone signaling. Exposure to environmental contaminants that disrupt
thyroid hormone action may underlie the increasing incidence of human developmental disorders
worldwide. One contaminant of utmost concern presently is bisphenol A (BPA), a chemical
widely used to manufacture polycarbonate plastics and epoxy resins.
Molecular studies have revealed that TR heterodimerswith RXR (9-cis retinoic acid
receptors) and binds to thyroid response elements (TREs) in the promoters or enhancers of TH-
regulated genes. In the absence of TH,TR binds to co-repressor complexes and puts chromatin in
a ‘‘closed” state for transcription. In the presence of TH, a conformational change of TR allows
co-activator complexes to bind, which in turn initiates transcription.

17

Bisphenol A; A Potrntial Threat As Thyroid Disruptor |

 BPA may disrupt TR transcription simply by (1) binding to TR and directly inhibiting the
action of endogenous TH. Transcription may be inhibited by the recruitment of nuclear co-
repressors. (2) BPA may bind to TR and lower transcription of target TH-response genes by
inhibiting co-activator binding. (3) Alternatively, BPA may bind to TR and directly activate TH-
response genes via the recruitment of nuclear co-activators.
Further studies, such as animal experiments and epidemiological investigations will allow
proper evaluation of the effects of BPA on the human endocrine system.

Figure 9. Mechanisms of transcriptional regulation by TR (A) and potential modes of BPA (B)
interference on TH action. (Boas et al. 2012)

18

Bisphenol A; A Potrntial Threat As Thyroid Disruptor |

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