The Potential Roles of Bisphenol A (BPA) Pathogenesis in Autoimmunity

Abstract

Bisphenol A (BPA) is a monomer found in commonly used consumer plastic goods. Although much attention in recent years has been placed on BPA's impact as an endocrine disruptor, it also appears to activate many immune pathways involved in both autoimmune disease development and autoimmune reactivity provocation. The current scientific literature is void of research papers linking BPA directly to human or animal onset of autoimmunity. This paper explores the impact of BPA on immune reactivity and the potential roles these mechanisms may have on the development or provocation of autoimmune diseases. Potential mechanisms by which BPA may be a contributing risk factor to autoimmune disease development and progression include its impact on hyperprolactinemia, estrogenic immune signaling, cytochrome P450 enzyme disruption, immune signal transduction pathway alteration, cytokine polarization, aryl hydrocarbon activation of Th-17 receptors, molecular mimicry, macrophage activation, lipopolysaccharide activation, and immunoglobulin pathophysiology. In this paper a review of these known autoimmune triggering mechanisms will be correlated with BPA exposure, thereby suggesting that BPA has a role in the pathogenesis of autoimmunity.

Full text

Review Article
The Potential Roles of Bisphenol A (BPA) Pathogenesis in
Autoimmunity
Datis Kharrazian1,2
11001 Canvasback Court, Carlsbad, CA 92011, USA
2Division of Sciences, Bastyr University California, 4106 Sorrento Valley Boulevard, San Diego, CA 92121, USA
Correspondence should be addressed to Datis Kharrazian; datis@gmail.com
Received  November ; Revised  January ; Accepted  February ; Published  April 
Academic Editor: Aristo Vojdani
Copyright ©  Datis Kharrazian. is is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Bisphenol A (BPA) is a monomer found in commonly used consumer plastic goods. Although much attention in recent years
has been placed on BPA’s impact as an endocrine disruptor, it also appears to activate many immune pathways involved in both
autoimmune disease development and autoimmune reactivity provocation.e c urrent s cienticliterature is void of research papers
linking BPA directly to human or animal onset of autoimmunity. is paper explores the impact of BPA on immune reactivity and
the potential roles these mechanisms may have on the development or provocation of autoimmune diseases. Potential mechanisms
by which BPA may be a contributing risk factor to autoimmune disease development and progression include its impact on
hyperprolactinemia, estrogenic immune signaling, cytochrome P enzyme disruption, immune signal transduction pathway
alteration, cytokine polarization, aryl hydrocarbon activation of - receptors, molecular mimicry, macrophage activation,
lipopolysaccharide activation, and immunoglobulin pathophysiology. In this paper a review of these known autoimmune triggering
mechanisms will be correlated with BPA exposure, thereby suggesting that BPA has a role in the pathogenesis of autoimmunity.
1. Introduction
Bisphenol A [,  bis(-hydroxyphenyl) propane; BPA] is a
monomer used in the manufacture of polycarbonate plastics.
BPA is used in diverse forms of plastic products in the food
and electronic industries and in various types of commonly
used consumer goods, such as plastic containers, utensils,
toys, water bottles, and fax paper. BPA has been shown
to leach out of products, and high levels of the monomer
have been identied in human and animal samples []. e
extensive use of BPA-containing products has resulted in high
human exposure worldwide [], with studies reporting that
more than  percent of the US population has detectable lev-
els in urine samples []. It appears that increased temperature
leaches BPA into food and water products as does acidic pH
of liquids []. Additionally, dermal contact with sales receipts
and printer paper containing BPA compounds can lead to
BPA exposure [].
BPA has been studied extensively as an endocrine disrup-
tor, and numerous papers have shown how BPA may impact
perinatal, childhood, and adult health []. BPA has the ability
to bind to estrogen receptors and promote both agonist and
antagonist activity [].Italsohastheabilitytobindtoaryl
hydrocarbon receptors and exert diverse adverse endocrine
eects on human physiology []. Its impact on hormone
signaling and endocrine dysfunction continues to be an area
of research.
BPAalsohasbeenshowntohavepotentialadverse
neurological eects, especially with respect to fetal brain
development and promotion of neurodegenerative diseases
[]. Mice models showing perinatal exposure to BPA inhibits
synaptogenesis and aects synaptic structural modication
aer birth []. e impact of BPA on brain health and
neurodevelopmentalsocontinuestobeanareaofresearch.
is paper explores the worldwide exposure to BPA and
its potential role in the growing epidemic of autoimmune
disease. Although no human or animal studies have been
published linking BPA to the onset of autoimmune disease,
the potential seems very high due to the physiological inu-
ences of BPA and current immunological models regarding
loss of self-tolerance and autoimmunity. In addition to known
immune mechanisms promoted by BPA that overlap with
Hindawi Publishing Corporation
Autoimmune Diseases
Volume 2014, Article ID 743616, 12 pages
http://dx.doi.org/10.1155/2014/743616

Autoimmune Diseases
Promotion of B-reg cell activity
Promotion of
T-reg suppression
Estrogenic activation of
Disruption of cytochrome
LPS promotion of
Molecular mimicry
presenting cell activity
Amplication of antigen-
BPA-binding protein
promotion of new epitope
nitrosative reactions
Activation of TH-17 ayrl
p450 activity
hydrocarbon receptors
immune responses
TH-17 activation
hyperprolactinemia
TH-1and TH-2
polarization
Potential roles
of bisphenol A
pathogenesis in
autoimmunity
F : is diagram illustrates the potential mechanisms of bisphenol A’s promotion of autoimmunity. BPA: bisphenol A; B-reg cell:
regulatory B cell; LPS: lipopolysaccharide; TH: T-helper; T-reg: regulatory T cell.
autoimmune generation, some early evidence also indicates
that BPA may contribute to mechanisms that promote auto-
immune expression and progression (Figure ).
2. BPA, Hepatic Biotransformation, and
Autoimmunity
e hepatic biotransformation of BPA depends on phase
I oxidation/reduction involving glutathione and phase II
glucuronidation, glutathione, and sulfate conjugation [].
HealthyhumansexposedtoBPAappeartohaveanaccu-
mulated body burden of BPA and monitoring studies that
measureurinaryBPAshoweditstoredinlipidreservoirs
[]. Despite proper hepatic biotransformation of BPA, the
accumulation of BPA in body reservoirs may set the stage
for immune reactivity and the onset of autoimmunity. Also,
impaired hepatic clearance of circulating immune com-
plexes in response to environmental compounds may induce
autoimmunity. In a study of mice exposed to inorganic mer-
cury, those mice that demonstrated reduced hepatic clear-
ance of immune complexes also showed increased levels and
altered quality of circulating immune complexes in mer-
cury-induced autoimmunity []. Patients with abnormal
hepatic biochemistries also have been shown to have a higher
frequency of autoimmune disease [].
A growing body of evidence shows increased toxic loads
deplete hepatic tolerance, which leads to over activation of the
innateandadaptiveimmuneresponseandthedevelopment
of autoimmune disease []. Higher BPA concentrations were
associated with increased abnormal liver function tests [].
Animal studies demonstrate that BPA has the ability to gen-
erate reactive oxygen species (ROS) and reduce antioxidant
reserves and enzymes that are critical for hepatic phase I
and II biotransformation, including glutathione, superoxide
dismutase, glutathione peroxidase, glutathione S-transferase,
glutathione reductase, and catalase activity [].
BPA disruption of cytochrome P enzymes may be
a potential mechanism for autoimmune pathophysiology.
e cytochrome P (CYP) monooxygenases play a crucial
role in the liver and various other tissues and are involved
with oxidation of organic substances and the bioactivation
of drugs and xenoestrogens [].CYPactivityisnecessary
for the conversion of xenoestrogens into inactive metabolites
that are both noninammatory and biologically inactive.
However, environmental xenoestrogens also have the poten-
tial to be metabolized into more reactive and inammatory
metabolites, thereby inducing increased ROS []. ROS are
involved in apoptosis, activation of antigen presentation cells,
and the initiation or amplication of diverse immunologic
reactions that may be involved with the pathogenesis of auto-
immune disease (Figure )[].
Impairment of hepatic biotransformation of CYP expres-
sion may lead to ROS pathophysiology of autoimmunity. ROS
have the ability to induce autoreactive molecules that may be
involved with both the onset and the exacerbation of auto-
immunity []. CYP enzymes are involved with metabolizing
xenobiotics and producing ROS that may play a role in the
pathophysiology of autoimmune disease.
In a study of mice ospring, BPA exposure to  and
 mg/L of drinking water induced cytochrome CYP
downregulation leading to potential proteomic alterations in
immune function []. ese mechanisms demonstrate the
potentialforBPAtodisruptproperCYPactivityandpoten-
tially induce hepatotoxicity by promoting oxidative stress
[]. Increased production of ROS has demonstrated the abi-
lity to promote autoimmunity []. BPA activity has com-
plex immune-activating reactions throughout the body. e
impact of BPA on CYP enzyme expression may be a

Autoimmune Diseases 
Xenoestrogen
activity
yroid endocrine
disruptor
Bisphenol A
Hepatic phase I
Oxidation/reduction
glutathione
Glutathione
Glucuronidation conjugation Sulfation
GSH GSSG
Immunoreactive
metabolite
Systemic immune
activation
Autoimmunity
Hepatic phase II
Intestinal 𝛽-glucuronidase Water-solu bl e metabolite
Excreted in urine, sweat, and feces
Activate NF-𝜅B
Endocrine
disruptor
F : is diagram illustrates the hepatic biotransformation
of bisphenol A. GSH: reduced glutathione; GSSG: oxidized glu-
tathione.
BPA BPA
Liver
Disruption of cytochrome p450 enzymes
Reactive
oxygen
species
Activation of diverse
immunological stimulating reactions
Autoimmunity
F : is diagram illustrates how bisphenol A can activate
autoimmunity by disrupting cytochrome P enzymes. BPA:
bisphenol A.
contributing mechanism to BPA autoimmune pathophysiol-
ogy (Figure ).
3. BPA Impact on Prolactin Synthesis
and Autoimmunity
Although the peptide hormone prolactin is known primarily
for its role in lactation, it also plays a critical role in modu-
lating immune and inammatory responses through various
immune signaling pathways []. Prolactin has been shown
to play signicant roles in antigen presenting functions and
in the initiation of the response against major histocompat-
ibilitycomplex(MHC)presentingself-antigensasfoundin
autoimmunity [].
A review of hyperprolactinemia and autoimmunity has
found increased prolactin levels associated with production
of anti-DNA antibodies, islet cell antibodies, thyroglobulin
antibodies, thyroid peroxidase antibodies, adrenocortical
antibodies, and transglutaminase antibodies with individuals
suering from systemic lupus erythematosus (SLE), diabetes
mellitus type , Hashimoto’s disease, Addison’s disease, and
celiac disease []. Prolactin has profound immunologi-
cal stimulating, enhancing, and proliferative responses to
antigens and mitogens by promoting increased cytokine
activity and immunoglobin production. It also interferes
with B cell tolerance and has autoimmune promoting eects
[].
BPA is an endocrine disruptor with powerful eects on
the pituitary lactotroph cells, which are estrogen responsive
and promote prolactin release. In vitro and in vivo studies
have found that BPA mimics estradiol and induces hyper-
prolactinemia []. erefore, BPA has potential impacts on
autoimmune disease activation via its impact on increasing
the immunostimulatory response of prolactin (Figure ).
A link between BPA exposure and increased prolactin
levels was found in women workers in occupational settings
within one year. ey demonstrated marked prolactin level
increases and a multivariate analysis found BPA exposure
was an independent risk factor for increased serum prolactin
levels [].
e correlation between hyperprolactinemia and autoim-
mune disease promotion has been reported in the literature
in multiple papers during the past  years []. Additionally,
recent evidence has found that BPA has major stimulatory
impacts on prolactin release. ese correlations strongly
suggest that BPA may promote autoimmune pathophysiolog y
by increasing prolactin release that then promotes immune-
stimulating activity.
4. BPA and Estrogenic Activation of
Immune Responses
In addition to the impact of BPA on prolactin release through
its estrogenic inuence on pituitary cells, BPA also appears
to directly aect immune cell signaling pathways and thus
immune responses []. BPA is classied as an endocrine
disruptor in the form of a xenoestrogen and has the potential
to mimic estrogen activity throughout the body []. is
is important because increased circulating estrogens have
demonstrated relationships with greater autoimmune activity
[]. Furthermore, epidemiological evidence suggests that
the signicant increase in the prevalence of autoimmune
disease may in part be attributed to environmental estrogens
(xenoestrogens). A review of the role of estrogens provides
reasonable evidence of an association between xenoestrogen
exposure and autoimmune disorders [].
Various estrogen-promoted mechanisms have been
found to trigger autoimmune reactivity. e reticulum trans-
membrane protein UNCB, which is essential for track-
ing toll-like receptors (TLRs) from endoplasmic reticulum
andisfoundtoplayaroleinautoimmunity,hasbeenshown
to be upregulated by estrogenic signaling []. Estrogen acti-
vity has also been shown to directly and indirectly stimulate

Autoimmune Diseases
Pituitary
Lactotroph
Prolactin
Interference
Cytokine activity
Proliferative response to
antigens and mitogens
Autoimmune disease promotion
with B cell
tolerance
cells
BPA
F : is diagram illustrates how bisphenol A can activate hyperprolactinemia and increase immunostimulatory responses, promoting
autoimmunity. BPA: bisphenol A.
activation-induced deaminase (AID), leading to immune
hyperstimulation. AID plays an important role in immune
tolerance and the actual elimination of autoantibodies that
may impact autoimmune reactivity []. Estrogen activity
appears to promote signaling of T cell activation in autoim-
munity []. Estradiol impacts macrophage production of
tumor necrosis factor alpha []. Treatment of immune cells
with estradiol has been shown to increase levels of B cell
activating factor (BAFF) mRNA and protein that are asso-
ciated with increasing severity of autoimmune disease expres-
sion []. Estrogen activity appears to impact dendritic cell
dierentiation and interferon production []. In summary,
estrogen activity appears to have diverse and complex modu-
latory and stimulating roles in the immune system [].
Many of these immune-stimulating responses that per-
petuate chronic inammation and autoimmunity may also
be potentiated by the estrogenic activity of BPA []. BPA
stimulates cell proliferation and induced expression of estro-
gen responsiveness. It also stimulates uterine, vaginal, and
mammary growth and dierentiation in vivo []. BPA treat-
ment in mice induced splenocyte proliferation, a shi of cyto-
kine proles from - to - activity, and hyperstimulation
of cellular immunity similar to patterns associated with -
dominant autoimmune disease []. Overall, BPA has multi-
ple estrogenic mechanisms in promoting abnormal immune
responses that include altering T cell subsets, B cell functions,
and dendritic cell activity and inducing abnormal immune
signalingviaitsdisruptiveimpactonestrogenreceptor
signaling , aryl hydrocarbon receptor signaling , and abnormal
signaling of peroxisome proliferator-activated nuclear recep-
tors []. ese BPA estrogenic impacts on virtually all the
major cells of the immune system and critical signaling path-
ways may be one way in which BPA promotes pathogenesis
of autoimmunity (Figure ).
5. BPA Impact on Immune Signaling Pathways
BPA has hapten and estrogenic activity, both of which play
roles in activating hyperactive immune responses that may
occur in autoimmune pathophysiology.
BPA exposure leads to aquatic animal hemocyte immune
dysfunction, potentially increasing its role in induced auto-
immunity through immune dysregulation. BPA injected
into mussels leads to signicant lysosomal membrane desta-
bilization and a dramatic decrease in phosphorylation of
the stress-activated p mitogen-activated protein kinases
(MAPKs) and CREB-like transcription factor (cAMP-
responsive element-binding protein) in mussels []. ese
results indicate BPA-induced alteration of hemocyte signal
transducers and activator of transcription (STAT). ese
MAPKandSTATpathwaysarecrucialinnormalsignalingto
prevent upregulation of autoreactive T cells found to induce
autoimmune inammatory reactivity [].
In addition to turning on gene expression of autoreactive
T cells, alterations in these MAPK and STAT signaling path-
ways lead to chronic activation of antigen-presenting cells
(APCs), loss of regulatory T cells (CD+CD+), apoptosis
of APCs, and inhibition of innate and adaptive immunity
wind-up found in the pathogenesis of autoimmunity [].
e signaling pathways that are activated by BPA exposure
have been shown to be the exact signaling pathways of mole-
cular processes in autoimmune disease pathophysiology [].

Autoimmune Diseases 
Estrogen BPA
Estrogen receptor
Transcription
Protein
Autoimmunity
Stimulates AID
Stimulates BAFF
Stimulates dendritic cells
Stimulates AhR signaling
Stimulates T cell activation
Stimulates macrophage production of TNF-𝛼
messenger
activation
F : is diagram illustrates how bisphenol A can bind to estrogen receptors and promote estrogenic-mediated autoimmunity.
AID: activation-induced deaminase; BAFF: B cell activating factor; BPA: bisphenol A; TNF-alpha: tumor necrosis factor alpha; AhR: aryl
hydrocarbon.
BPA
Estrogen receptor
cAMP MAPK
STAT
Autoi mmunity
Chronic activation of
Loss of regulatory T cells
antigen-presenting cells
F : is diagram illustrates how bisphenol A can promote
autoimmunity by cellular transcription activation. BPA: bisphenol
A; cAMP: adenosine 󸀠󸀠-cyclic monophosphate; MARK: mitogen-
activated protein kinase; STAT: signal transducer and activator of
transcription.
erefore, BPA activity as either an estrogenic endocrine
disruptor or hapten-activating structure seems to specically
disrupt immune signaling pathways found in autoimmune
disease (Figure ).
6. BPA and Cytokine Expression
Cytokines have been shown to play a key role in the patho-
genesisofautoimmunedisease.eshiofcytokinesinto-
/- dominance and the IL-/IL- (-) axis has been
showntoplaypivotalrolesinthemodelofautoimmunityand
the breakdown of self-tolerance []. BPA has been shown to
impact the dierentiation processes of the dendritic cells that
may cause unintended ac tivation of the immune system in the
absence of pathological conditions, thus promoting inappro-
priatepolarizationofTcellsandcytokineprolesandshiing
the immune system into an overzealous immunological state
[]. Additionally, BPA exposure prenatally to mice with oral
feeding induced upregulation of - responses in adulthood
[].
e impact of BPA on na¨
ıve immune systems using T cell
receptor transgenic mice followed by measurement of cyto-
kine responses to antigens suggest that BPA can augment -
 reactions when administered orally in low doses (.mg to
. mg/kg weight) in water. Specically BPA increased anti-
gen-specic interferon gamma production leading to exag-
gerated T cell activation and polar - and - shis
[]. ese mechanisms associated with interferon have been
shown to play powerful eector roles in the pathogenesis of
autoimmunity, especially system autoimmunity such as sys-
temic lupus erythematosus [].
Animal studies have also shown that BPA exposure pro-
motes cytokine inammatory shis associated with potential
autoimmune development. BPA administered to mice in
drinking water produced signicant shis of lymphocytes
subpopulations. e production of inammatory - type
cytokines (IFN-gamma) was induced while - cytokine
(IL-) was suppressed with BPA treatment, promoting the
transcription of IRF-. e mRNA expression of GATA-
was inhibited in BPA-treated groups in dosages of ., .,
and  mg/mL for  weeks []. ese responses indicated
that BPA has the potential to induce - polar shis of
transcription factor that lead to exaggerated cellular immune
responses leading to an exaggerated - immune response.
e suppression of GATA- transcription factors and T cell
polarization favoring a - bias has been shown to be an
immune mechanism of multiple sclerosis autoimmunity in
animals [].
A study comparing the eect of BPA exposure on cyto-
kine activity in adulthood and prenatally demonstrated that
in adulthood exposure to BPA signicantly promoted anti-
gen-stimulated production of IL-, IL-, and IL-, but
not IFN-gamma. However, mice exposed prenatally to BPA
showed increased production of not only IL- but also
IFN-gamma. e percentages of T regulatory function
(CD+CD+) were decreased in both groups exposed to
BPA [].LossofregulatoryTcellfunctionpromotesabnor-
mal cytokine shis that occur in autoimmune diseases [].
Suppression of regulatory T cell function leading to impaired

Autoimmune Diseases
TH-1
TH-2
TH-17
T-reg
Suppress
BPA
Naive T cell
IFN
IL-4
IL-13
IL-17
Activate
Polarization
Autoimmunity
F : is diagram illustrates how bisphenol A can induce T cell shis, promoting autoimmunity. BPA: bisphenol A; IFN: interferon; IL:
interleukin; TH: T-helper; T-reg: regulatory T cell.
Autoi mmunity
Potentiation of
nitrosative reactivity
BPA
LPS
of LPS
Bacterial translocation
F : is diagram illustrates how bisphenol A can promote
lipopolysaccharide inammatory sequelae. BPA: bisphenol A; LPS:
lipopolysaccharide.
cytokine modulation may be part of the immunopathology of
BPA autoimmune development.
e delicate interplay between -, -, and -
expressionappeartobeakeyfactorinautoimmunepatho-
physiology. Evidence indicates that BPA may induce polarity
in this delicate balance and trigger inammatory reactions,
potentially leading to loss of self-tolerance as noted in sub-
sequent paragraphs. e impact of BPA on the pathogenesis
of abnormal cytokine shis most likely occurs from complex
web-likereactions.BPA’sroleasbothahaptenandestrogenic
endocrine disruptor appears to promote multiple interwoven
pathways involved in adverse cytokine shis that may play a
role in autoimmune pathogenesis (Figure ).
7. BPA and Lipopolysaccharide-Induced
Nitric Oxide Production
Bacterial translocation of lipopolysaccharides (LPS) has the
ability to activate oxidative and nitrosamine stress pathways
associated with the inammatory responses and pathophys-
iology of autoimmune responses []. BPA directly impacts
LPSactivationofthesepathways,andtheroleofBPAonLPS
activation could likewise play a role in abnormal immune
reactivity [].
Autoimmunity
Promote shi
B-reg
cell
IgE
IL-4
CD4+T cells
NF-AT
Stimulates
BPA
F : is diagram illustrates how bisphenol A can impact
immunoglobulin-promotedautoimmunity. BPA: bisphenol A; B-reg
cell: regulatory B cell; IL: interleukin; IgE: immunoglobulin E; NF-
AT: Ca+/calcineurin-dependent nuclear factor binding sites.
Additionally, decreased activation of LPS-induced
inammatory reactions has also demonstrated a reduction in
inammatory sequelae of autoimmune cytokine and chemo-
kine expression. Specically, mice injected with BPA exhi-
bited increased endotoxin-induced macrophage activation,
suggesting that BPA may potentiate infectious autoimmune
inammatory reactions via enhanced tumor necrosis factor
and nitric oxide reactivity []. erefore, LPS-induced
expression of nitrosative stress reactivity may be a key factor
in BPA-promoted models of autoimmunity associated with
infectious autoimmune reactions (Figure ).
8. BPA Impacts on Antigen-Presenting
Cell Reactivity
Antigen-presenting cells such as dendritic cells and macro-
phages appear to play a potential role with BPA and autoim-
mune reactivity. Dendritic cells (DCs) are important antigen-
presenting cells that play a critical role in adaptive immunity
duetotheirabilitytoactivatena
¨
ıve T cells, which, when

Autoimmune Diseases 
BPA
BPA binds
New antigen
Antibody produced
Antibody also now
reacts to host protein
for new antigen
to host protein
BPA-binding protein
Autoimmunity
F : is diagram illustrates how bisphenol A can bind to the host protein, leading to a new epitope reaction against the host protein,
resulting in autoimmunity. BPA: bisphenol A.
overzealous, could promote autoimmune activity []. DCs
promote the expressions of -, -, or - cells that can
be switched to express autoimmune inammatory cascades
[]. DCs exposed to BPA in combination with tumor
necrosis factor alpha promote CC chemokine ligand  (CCL)
signaling, a chemokine that is known to trigger chemotaxis
of CCr expressing - and a subset of T regulatory cells,
thereby promoting higher levels of IL- relative to those of
IL-p on CD ligation and preferentially inducing -
deviation []. ese variant responses from DCs exposed to
BPA may play a role in autoimmunity.
Macrophage modulation of nitric oxide release is also
critical for the regulation of apoptosis and dierentiation of
T cells that may lead to progression of autoimmune disease
[]. Additionally, BPA exposure has the ability to exert
disruptive eects on macrophages by binding to estrogen
receptors and leading to alteration of nitric oxide production
and TNF-alpha synthesis in the homeostasis of TH- and
TH- activity []. ese macrophage expressions from BPA
may promote immunological shis that occur with autoim-
munity, linking BPA’s potential role to abnormal antigen-
presenting cell responses.
9. BPA Effects on Immunoglobulin Activity
Increased immunoglobulin reactivity from endocrine dis-
ruptors such as BPA may raise concerns about immune
hyperactivity associated with autoimmune immunopathol-
ogy. e activation of immunoglobulins has a potential
to promote inammatory or anti-inammatory activities
through the activation of regulatory B (Breg) cells. Recent
research in mice has shown that when B cell expression shis
into IL- production, there are suppressive eects on inam-
matory responses. However, promotion of IgE-producing B
cells plays a direct role in promoting inammatory responses
and the development of immune upregulation associated
with most underlying inammatory conditions, such as
allergies and autoimmunity [].
Recent research has shown that BPA has a direct impact
on increasing immunoglobulin expression into the inam-
matory IgE response, thereby potentially promoting an
inammatory cascade in autoimmunity. Specically, expo-
sure to BPA was shown to increase IL- production in CD+
T cells and antigen-specic IgE levels in sera via the stimu-
lation of Ca2+/calcineurin-dependent nuclear factor of acti-
vated T cells binding sites (NF-AT) []. ese immune
responses have the ability to potentiate allergies and autoim-
mune reactions in those with autoimmunity. Increased levels
of IgE may play a direct role in promoting the inammatory
responses found in autoimmunity []. e potential for BPA
to increase IL- and promote a shi of Breg cells into IgE
production may be a mechanism for BPA autoimmune pro-
motion (Figure ).
In a murine model for SLE, animals implanted with
BPA specically demonstrated B cell activation and promo-
tion of autoimmune disease such as lupus nephritis. BPA
implantation enhanced autoantibody production by B cells
both in vitro and in vivo in murine models of SLE. e
study researchers suggested that BPA exacerbates preexist-
ing autoimmune diseases such as SLE and that continued
exposure to endocrine disruptors may potentiate the inci-
dence and severity of autoimmune diseases [].
Evidence of BPA on expressing B cell activity towards
inammatory expression and autoimmune development may
partly explain the complex immune web reactions of this
endocrine disruptor. Although inammatory immunoglob-
ulin reactivity may have a role to play in autoimmune expres-
sion,itismostlikelypartofalargercompleximmune

Autoimmune Diseases
HO COH
Bisphenol A
O
I
I
HO
I
O
OH
CH3
CH3
NH2
Triiodothyronine
F : is diagram illustrates the structural similarity between bisphenol A and triiodothyronine, leading to potential cross-reactivity.
BPA
Activate
TH-17
IL-17
IL-23
AhR receptors
F : is diagram illustrates how bisphenol A can activate autoimmunity by inducing mRNA expression on aryl hydrocarbon receptors
on TH- cells. AhR: aryl hydrocarbon; BPA: bisphenol A; IL: interleukin; TH: T-helper.
Antibody also now
reacts to host protein
BPA
of LPS
LPS
BPA bonds
MAPK
Estrogen receptor
Bacterial translocation
cAMP
NF-AT
Simulates
Chronic activation of
antigen-presenting cells
Loss of regulatory T cells STAT
New antigen
Bisphenol A
Hepatic phase I
glutathione
disruptor
to host protein
Antibody
new antigen
produced for
IgE
B-reg
cell
BPA-binding protein
Promote shi
IL-4
Protein
transcription
Estrogen
Estrogen receptor
Simulates AID
Simulates BAFF
Simulates dendritic cells
Simulates AhR signaling
Simulates T cell activation
Simulates macrophage production of TNF-𝛼
messenger
activation
Hepatic phase II
Glucuronidation Glutathione
conjugation Sulfation activation
Activate NF-𝜅B
Systemic immune
Immunoreactive
metabolite
Intestinal 𝛽-glucuronidase Water-soluble metabolite
Excreted in urine, sweat, and feces
GSH GSSG
IL-4
IL-13
IL-17
IFN
cells
Pituitary
Potentiation of
nitrosative reactivity
TH-1
TH-2
TH-17
Xenoestrogen
activity
Activate
Suppress
Polarization
Naive T cell
Cytokine activity
Proliferative response to
antigens and mitogens
Endocrine
disruptor
T-reg
yroid endocrine
Oxidation/reduction
Lactotroph
Prolactin
tolerance
Interference
with B cell
CD4+T cell
F : Potential of various autoimmune mechanisms from bisphenol A.

Autoimmune Diseases 
reaction that is linked to this very reactive endocrine disrup-
tor.
10. BPA-Binding Protein: A Potential
New Epitope
BPA binds to host protein, potentially creating a new epi-
tope for immune reactivity. BPA binds to protein disul-
de isomerase (PDI), also known as BPA-binding protein
[], a multifunctional protein involved in diverse cellular
functions. is binding protein has been associated with
endocrine disruptor mechanisms involving BPA []. e
binding of environmental BPA to host protein may lead
to self-tissue, antigen-antibody interactions associated with
environmentally induced molecular mimicry. Autoimmune
molecular mimicry requires the similarities of surface topolo-
gies leading to antigenic combining sites []. e binding of
BPA to PDI in host has the potential to lead to new protein
epitope activation of autoimmunity (Figure ).
11. BPA and Autoimmune Molecular Mimicry
BPA and triio dothyronine (T) possess such a degree of mole-
cular structure similarity that BPA may act as an antagonist
compound on T receptor sites []. When compounds have
structural similarity, it may potentially lead to autoimmune
cross-reactivity with antigen-antibody complexes []. In
particular, environmental compounds such as hydrocarbon
rings found both on BPA and T with anchor ring like
similarities may induce mimicry []. A potential mechanism
for the role of BPA in autoimmunity may be structural
molecular mimicry, in particular with thyroid hormones
(Figure ).
12. BPA and TH-17 Aryl
Hydrocarbon Receptors
Aryl hydrocarbon receptors (AhR) are involved with reg-
ulating immune responses and the development of TH-
cells, which are key eector T cells in a variety of human
autoimmune diseases. [] Exposure to low dose BPA has
been shown to upregulate mRNA expressions of AhR. AhR
activation of TH- by BPA may potentiate autoimmunity.
e role of chemical contamination and its ability to prompt
AhR receptor activation of TH- have already been inves-
tigated in allergic and autoimmune diseases []. Although
direct evidence has not been investigated for the role of
BPA on AhR activation of TH- autoimmune reactivity, the
potential mechanism may exist (Figure ).
13. Conclusion
With the growing epidemic of autoimmune disease world-
wide and the extensive use of consumer goods containing
BPA, we must examine the risk of BPA as a potential
triggering compound in autoimmune disease. Although no
specic evidence has linked human or animal autoimmune
disease development to BPA exposure, many of the mecha-
nisms known to exist in autoimmune pathophysiology also
appear to exist with immune reactivity from BPA exposure
(Figure ). Further investigation needs to be conducted cor-
relating autoimmune disease development to BPA exposure.
Additionally, the impact of BPA exposure on those already
suering from autoimmunity needs to be investigated further
based on potential overlapping pathophysiology.
Conflict of Interests
e author declares that there is no conict of interests
regarding the publication of this paper.
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