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

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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.
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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 BPAs 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-
priatepolarizationofTcellsandcytokineprolesandshiing
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.BPAsroleasbothahaptenandestrogenic
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 BPAs 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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... BPA is a monomer used in the production of epoxy resins, polycarbonate plastics, polyacrylate, and polyesters, and can be used in the manufacture of various products, such as baby bottles, plastic bottles, food containers' coating, dental fillings, toys, utensils, medical tubes, and thermal paper, having a more significant presence in the electronics and food industries [4,9,10]. ...
... The Food and Drug Administration (FDA) considers the compound a food additive for this migratory characteristic. The primary exposure to the compound is through its ingestion, precisely because of BPA's characteristic of migrating from plastic to food [9,10,12]. ...
... The constant presence of products containing BPA is of great importance, as it means that, currently, there are more potential sources of exposure than at any other time, with the compound being detectable worldwide at nanomolecular levels in human serum. The exposure is not only through ingestion of contaminated food and liquids but also through dermal contact with thermal papers found on receipts and labels, which contain a high concentration of free BPA; moreover, inhalation can also represent a source of exposure to the compound [9,11,12,18,19]. ...
Article
Background Plastic polymers are omnipresent, and life without them is virtually impossible. Despite the advantages provided by the material, conventional plastic also has harmful effects on the environment and human health. Plastics release microplastics and compounds, such as BPA, which is a xenoestrogen and once absorbed by the body, have an affinity for estrogen receptors α and β, acting as an agonist on human cells, being an endocrine disrupter able to cause various diseases and acting as a potential neoplastic inducer. BPS and BPF are BPA’s analogs, a proposed solution to solve its harmful effects incorporated into the market. The analogs can be found in daily use products and are used in several industrial applications. Objectives In the present work, the researchers aimed to develop a revisional study of BPA's harmful effects on human health, focusing on its carcinogenic potential, discussing its mechanisms of action, as well as its analogs effects, and identifying if they are a viable alternative to BPA's substitution in plastic polymers' production. Methods In this review, articles published in the last 15 years related to the different aspects of conventional plastics and BPA were analyzed and revised with precision. The subjects ranged from conventional plastics and the problems related to their large-scale production, BPA, its negative aspects, and the feasibility of using its analogs (BPS and BPF) to replace the compound. The articles were extensively reviewed and concisely discussed. Results This study demonstrated that BPA has a high carcinogenic potential, with known mechanisms to trigger breast, ovarian, prostate, cervical, and lung cancers, thus elucidating that its analogs are also xenoestrogens, that they can exert similar effects to BPA and, therefore, cannot be considered viable alternatives for its replacement. Conclusion This study suggests that new research should be carried out to develop such alternatives, allowing the substitution of plastic materials containing BPA in their composition, such as developing economically viable and sustainable biodegradable bioplastics for socio-environmental well-being.
... BPA interacts not only with the hormone system but also with the immune system, and the effect of this xenoestrogen may manifest even after years of exposure or as a result of its accumulation in the body. The expanding global presence of BPA in many forms, ranging from food containers to toys, medical devices, and others, may be a secondary cause for disturbances that eventually result in miscarriage in women (Elobeid and Allison 2008;Keri et al. 2007;Kharrazian 2014;Lathi et al. 2014;Richter et al. 2007;Rutkowska and Rachon 2014;Soto et al. 1995). ...
... The high levels of BPA determined in the serum of women with miscarriage in the present study suggest that this xenoestrogen may play a role in the process of miscarriage. Similar to estrogens, BPA can interact with the endocrine system and modulate its functions by binding to membrane and/or nuclear estrogen receptors, often affecting human health, especially the reproductive process and fetal development (Kharrazian 2014;Lathi et al. 2014). Zbucka-Krętowska et al. (2018) described for the first time the inhibitory effect of BPA on fatty acid amide hydrolase, which may cause an increase in the level of endocannabinoids in pregnant women. ...
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Full-text available
Humans are exposed to a number of environmental pollutants every day. Among them, endocrine disruptors are particularly harmful to human health. Bisphenol A (BPA) is a xenoestrogen that has been shown to disrupt the endocrine system and cause reproductive toxicity. In this study, we aimed to verify the potential relationship between BPA and miscarriage involving the formation of neutrophil extracellular traps (NETs). Blood samples were collected from healthy women and women who had miscarriage in the first trimester of pregnancy. The serum levels of cytoplasmic anti-PR3 antibody and perinuclear anti-MPO antibody were determined using an immunoenzymatic method. The concentrations of key proinflammatory proteins TNF-α and MCP-1, as well as NADPH oxidase subunits NOX1 and NCF2, were also measured in the serum samples. The serum concentration of BPA was determined using gas chromatography. The results showed that the concentrations of BPA were significantly elevated in the serum of women who had miscarriage compared to the control group, with the highest concentration found in the “NETs-positive” group. The levels of MCP-1 and TNF-α were significantly higher in the “NETs-positive” group compared to the “NETs-negative” and control group. The levels of NOX1 and NCF2 were also higher in the “NETs-positive” group compared to the “NETs-negative” group. The study showed that BPA could play a role in the course of miscarriage through the formation of NETs. The results indicate the need to limit the exposure of women planning pregnancy to xenoestrogens, including BPA.
... Bisphenol A (BPA) is a toxic chemical used in manufacturing of a wide variety of products including, plastic bottles, toys, water bottles, fax paper, and canned food containers. The extensive use of this substance exposes human and animals to its toxic effects (Groff 2010) that disturb endocrine and immune systems through activating many immune pathways involved in autoimmune diseases (Kharrazian 2014). Bisphenol A has a structural similarity to estrogen; thus, it exhibits high-affinity binding to estrogen receptors affecting the reproductive system, as well as the metabolism (Szymanska et al. 2018). ...
... BPA is known as endocrine disruptor mimicking estrogenic activity; it can induce immune dysregulation by affecting the immune cell signaling pathways and the immune responses. In support with these finding, Kharrazian (2014) had reported that BPA promotes signaling of T cell in autoimmune diseases and can stimulate the macrophage production of TNF-α. Increased production of TNF-α was linked to gastric ulcer and cancer as it contributes to mucosal injury (Sugimoto et al. 2007). ...
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This study evaluated the protective potentials of Moringa oleifera leaf alcoholic extract (MOLE) against bisphenol A (BPA)-induced stomach ulceration and inflammation in rats. Control rats received olive oil. Second group administered MOLE (200 mg/kg bwt) by oral gavage. Third group was given BPA (50 mg/ kg bwt) for 4 weeks. Fourth group administrated BPA and MOLE simultaneously. Fifth group was given MOLE for 4 weeks then administered BPA and MOLE for another 4 weeks. Bisphenol A induced gastric ulceration and decreased the volume of gastric juice, prostaglandin E2 (PGE2), reduced glutathione (GSH) and interleukin 10 (IL-10) contents, superoxide dismutase (SOD) activity, and proliferating cell nuclear antigen (PCNA) protein in stomach tissues, while increased the titratable acidity, malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) contents, and caspase-3 and NF‑κB proteins in stomach tissue. However, MOLE ameliorated BPA-induced gastric ulceration and significantly increased the volume of gastric juice, PGE2, GSH and IL-10 contents, SOD activity, and PCNA protein while significantly decreased titratable acidity, MDA, TNF-α and IL-6 contents, and of NF‑κB and caspase-3 proteins in gastric tissue. This study indicated that MOLE protected stomach against BPA-induced gastric injury via its anti-oxidant, anti-apoptotic, and anti-inflammatory activities.
... Accumulating evidence suggests that the increased prevalence of autoimmunity in industrial areas may be attributed only to the exposure to "endocrine disrupting chemicals" [78]. BPA has been linked to the pathophysiology of autoimmune diseases [79]. Perinatal exposure to BPA predisposes mouse pups to the development of asthma [80]. ...
... However, another study conducted in 2361 adults, aged >15 years, found that BPA was independently associated with positive anti-TPO antibodies [82]. A variety of mechanisms by which BPA may be a triggering compound to autoimmunity have been described, including its impact on hyperprolactinemia, estrogenic immune signaling, cytokine expression, and activation of macrophages, cytochrome P450 enzyme disruption, molecular mimicry to triiodothyronine, and immunoglobulin pathophysiology with increased production of IgA and IgG2a [79]. ...
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Background: Bisphenol A (BPA) is an endocrine-disrupting chemical widely used in plastic products that may have an adverse effect on several physiologic functions in children. The aim of this systematic review is to summarize the current knowledge of the impact of BPA concentrations on thyroid function in neonates, children, and adolescents. Methods: A systematic search of Medline, Scopus, Clinical Trials.gov, Cochrane Central Register of Controlled Trials CENTRAL, and Google Scholar databases according to PRISMA guidelines was performed. Only case-control, cross-sectional, and cohort studies that assessed the relationship between Bisphenol A and thyroid function in neonates and children aged <18 years were included. Initially, 102 articles were assessed, which were restricted to 73 articles after exclusion of duplicates. A total of 73 articles were assessed by two independent researchers based on the title/abstract and the predetermined inclusion and exclusion criteria. According to the eligibility criteria, 18 full-text articles were selected for further assessment. Finally, 12 full-text articles were included in the present systematic review. Results: The presented studies offer data that suggest a negative correlation of BPA concentrations with TSH in children, a gender-specific manner of action, and a potential effect on proper neurodevelopment. However, the results are inconclusive with respect to specific thyroid hormone concentrations and the effect on thyroid autoimmunity. Conclusion: The potential negative effect of BPA in the developing thyroid gland of children that may affect proper neurodevelopment, suggesting the need to focus future research on designing studies that elucidate the underlying mechanisms and the effects of BPA in thyroid function in early life.
... For links to epidemic issues, "animal and human research has associated BPA with many health problems including infertility, weight gain, behavioral changes, early-onset puberty, prostate and mammary gland cancers, cardiovascular effects, and diabetes" [103], plus connections with immune and autoimmune diseases [104] and cancer in general through different mechanisms [105,106]. ...
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Evidence is presented for an estrogen disruptor related meta-epidemic with three overlapping waves. The first arose in the 1930s with animal intersexes, but few apparent human effects, and involved substances such as halogenated biphenyls and DDT. The second began around 1960 and continues today, with obvious ongoing human epidemics with diverse estrogenic effects, connections to hygiene hypothesis related immune disorders that explain epidemic timing, and health benefits related to strokes, heart attacks, and cognition where alternative medical explanations are insufficient. A single novel disruptor with dual estrogenic effects explains similar timing for adverse and beneficial changes. Dual effects could also account for the obesity paradox, where excess weight improves outcomes with other diseases, since the same agent that causes obesity could also ameliorate sequelae. Bisphenol A, a common constituent of plastics, is a likely candidate, with detectable levels in humans, including fetuses, estrogen disruption in vitro, and multiple links to epidemic findings. Production and use are historically consistent with early epidemic changes. Bisphenol S, a common replacement, is probably equally harmful. First and second waves exposures overlap, and a third wave involves chronic effects and interactions.
... Since BPA is extensively present in the environment worldwide, it may contribute to the increased prevalence of autoimmune diseases. BPA may potentially induce autoimmune disorders in estrogen-target organs, such as the brain, ovary, mammary gland, uterus, testis, and epididymis, via the promotion of hyperprolactinemia, acceleration of regulatory B cell activity, disruption of Th1/Th2 homeostatic balance, suppression of regulatory T cell, increasing Th17 cells, activation of Th17 aryl hydrocarbon receptors, and amplification of antigen-presenting cells (APCs) activity (Kharrazian, 2014;Lee et al., 2003;Yoshino et al., 2004). Although several studies have linked BPA to the onset of autoimmune disease, a systems-level approach is required to understand the immune response to BPA exposure since it involves complex biological systems at the genetic, physiological, and environmental levels. ...
Article
Bisphenol A (BPA) is pervasive in the environment, and exposure to BPA may increase the incidence of noncommunicable diseases like autoimmune diseases and cancer. Although BPA causes immunological problems at the cellular level, no system-level research has been conducted on this. Hence, in this study, we aimed to gain a better understanding of the biological response to BPA exposure and its association with immunological disorders. For that, we explored the transcriptome and the proteomic modifications at the systems and cellular levels following BPA exposure. Our integrated multi-omics data showed the alteration of the T cell receptor (TCR) signaling pathway at both levels. The proportion of enlarged T cells increased with upregulation of CD69, a surface marker of early T cell activation, even though the number of T cells reduced after BPA exposure. Additionally, on BPA exposure, the levels of pLCK and pSRC increased in T cells, while that of pLAT decreased. Following BPA exposure, we investigated cytokine profiles and discovered that chitinase 3 Like 1 and matrix metalloproteinase 9 were enriched in T cells. These results indicated that T cells were hyperactivated by CD69 stimulation, and phosphorylation of SRC accelerated on BPA exposure. Hence, alteration in the TCR signaling pathway during development and differentiation due to BPA exposure could lead to insufficient and hasty activation of TCR signaling in T cells, which could modify cytokine profiles, leading to increased environmental susceptibility to chronic inflammation or diseases, increasing the chance of autoimmune diseases and cancer. This study enhances our understanding of the effects of environmental perturbations on immunosuppression at molecular, cellular, and systematic levels following pubertal BPA exposure, and may help develop better predictive, preventative, and therapeutic techniques.
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Introduction Trained Immunity represents a novel revolutionary concept of the immunological response involving innate immune cells. Bisphenol A is a well-known endocrine disrupter, widely disseminated worldwide and accumulated in the human body. Due to the increased interest regarding the effects of plastic-derived compounds on the immune system, our purpose was to explore whether BPA was able to induce trained immunity in human primary monocytes in vitro using low environmental concentrations. Materials and methods We extracted BPA from the serum of 10 healthy individuals through a liquid-liquid extraction followed by a solid phase extraction and measured the concentration using an HPLC system coupled to a triple quadrupole mass spectrometer. In parallel, monocytes were isolated from whole blood and acutely stimulated or trained with BPA at three different concentrations (1 nM, 10 nM, 20 nM). Pro- and anti-inflammatory cytokines (IL-1β, TNF-α, IL-6, and IL-10) production were assessed after 24 hours of acute stimulation and after Lipopolysaccharide (LPS) rechallenge. A comprehensive overview of the metabolic changes after BPA acute stimulation and trained immunity induction was assessed through extracellular lactate measurements, Seahorse XFb metabolic flux analysis and ROS production. Results Monocytes primed with BPA showed increased pro- and anti-inflammatory cytokine responses upon restimulation, sustained by the modulation of the immunometabolic circuits. Moreover, we proved the non-toxic effect of BPA at each experimental concentration by performing an MTT assay. Additionally, correlation analysis were performed between pro- and anti-inflammatory cytokines production after LPS acute stimulation or BPA-mediated trained immunity and BPA serum concentrations showing a significant association between TNF-α and BPA circulating levels. Discussion Overall, this study pointed out for the first time the immunological effects of an environmental chemical and plastic-derived compound in the induction of trained immunity in a healthy cohort.
Article
The widespread consumption of nanoplastics (NPs) and bisphenol A (BPA) affected the aquatic ecosystem and imposed risks to the safety of aquatic organisms. This study was aimed at assessing the ecotoxicological effects of single and combined exposure to BPA and polystyrene nanoplastics (PSNPs) on the channel catfish (Ictalurus punctatus). A total of 120 channel catfish were separated into four groups with triplicate (each contains 10 fish) and exposed to chlorinated tap water (control group), PSNP single exposure (0.3 mg/L), BPA single exposure (500 μg/L) and PSNPs (0.3 mg/L) + BPA (500 μg/L) co-exposure for 7 days. Our results showed a relatively higher intestinal accumulation of PSNPs in co-exposure group, compared to PSNP single exposure group. Histopathological analysis showed that single exposure to PSNPs and BPA caused breakage of intestinal villi and swelling of hepatocytes in channel catfish, while the co-exposure exacerbated the histopathological damage. In addition, co-exposure significantly increased SOD, CAT activities and MDA contents in the intestine and liver, inducing oxidative stress. In terms of immune function, the activities of ACP and AKP were significantly decreased. The expressions of immune-related genes such as IL-1β, TLR3, TLR5, hepcidin and β-defensin were significantly up-regulated, and the expression of IL-10 was down-regulated. Additionally, the co-exposure significantly altered the composition of the intestinal microbiota, leading to an increase in the Shannon index and a decrease in the Simpson index. In summary, this study revealed that mixture exposure to PSNPs and BPA exacerbated toxic effects on histopathology, oxidative stress, immune function and intestinal microbiota in channel catfish. It emphasized the threat of NPs and BPA to the health of aquatic organisms and human food safety, with a call for effective ways to regulate the consumption of these anthropogenic chemicals.
Article
Aims: Investigate the immunomodulatory effects of bisphenols in the THP-1 cell line and peripheral blood mononuclear cells in response to lipopolysaccharide (LPS) activation or to phorbol 12-myristate 13-acetate (PMA) and ionomycin. Background: We have previously demonstrated the usefulness of the evaluation of RACK1 expression as a link between endocrine disrupting activity and the immunotoxic effect of xenobiotics. We demonstrated that while BPA and BPAF reduced RACK1 expression, BPS was able to increase it. Objective: Bisphenol A (BPA) is one of the most commonly used chemicals in the manufacturing of polycarbonate plastics and plastic consumer products. Its endocrine disrupting (ED) potential and changes in European regulations have led to replacing BPA in many uses with structurally similar chemicals, like bisphenol AF (BPAF) and bisphenol S (BPS). However, emerging data indicated that bisphenol analogues may not be safer than BPA both in toxic effects and ED potential. Methods: THP-1 cell line and peripheral blood mononuclear cells were activated with lipopolysaccharide (LPS) or with phorbol 12-myristate 13-acetate (PMA) and ionomycin. Results: BPA and BPAF decreased LPS-induced expression of surface markers and the release of pro-inflammatory cytokines, while BPS increased LPS-induced expression of CD86 and cytokines. BPA, BPAF, and BPS affected PMA/ionomycin-induced T helper differentiation and cytokine release with gender-related alterations in some parameters investigated. Conclusion: Data confirm that bisphenols can modulate immune cell differentiation and activation, further supporting their immunotoxic effects.
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Bisphenol A (BPA) can induce complex regulatory mechanisms in many aquatic organisms, and it is difficult to find a suitable analytical method to efficiently enrich key genes responding to BPA exposure. In this study, zebrafish embryo transcriptomic data were obtained from two types of different BPA exposure methods. After BPA exposure, three differential gene enrichment methods were used jointly to identify up-regulated genes or pathways in zebrafish embryo larvae. The results showed that the systemic lupus erythematosus signaling pathway was significantly enriched in all BPA exposure groups. It was also noteworthy that most of the up-regulated genes in systemic lupus erythematosus signaling were histones. In conclusion, this study suggested that autoimmunity signaling was the most common important pathway in zebrafish embryo-larvae response to different BPA exposures, and histones may play a key role in response to low-concentration BPA.
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Bisphenol A (BPA) is one of the highest-volume chemicals produced worldwide, and human exposure to BPA is thought to be ubiquitous. Thus, there are concerns that the amount of BPA to which humans are exposed may cause adverse health effects. We examined many possibilities for why biomonitoring and toxicokinetic studies could come to seemingly conflicting conclusions. More than 80 published human biomonitoring studies that measured BPA concentrations in human tissues, urine, blood, and other fluids, along with two toxicokinetic studies of human BPA metabolism were examined. Unconjugated BPA was routinely detected in blood (in the nanograms per milliliter range), and conjugated BPA was routinely detected in the vast majority of urine samples (also in the nanograms per milliliter range). In stark contrast, toxicokinetic studies proposed that humans are not internally exposed to BPA. Available data from biomonitoring studies clearly indicate that the general population is exposed to BPA and is at risk from internal exposure to unconjugated BPA. The two toxicokinetic studies that suggested human BPA exposure is negligible have significant deficiencies, are directly contradicted by hypothesis-driven studies, and are therefore not reliable for risk assessment purposes.
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Although autoimmune thyroid disease in males is less common, it is unclear whether estrogen contributes to the difference in susceptibility among males. To examine if circulating estradiol is related to thyroid autoimmunity in males. One thousound two hundred and sixty three males aged 15-94 years were studied. Serum levels of 17β- estradiol (E2), thyroid-stimulating hormone receptor antibody (TRAb), thyroid peroxidase antibody (TPOAb), thyroglobulin antibody (TgAb), free thyroxine (FT4) and thyroid-stimulating hormone (TSH) were measured by electrochemiluminescence immunoassay. Circulating E2 varied widely in males, ranging 18.4-403.7 pmol/L with a mean value of 136.2 ± 51.7 pmol/L. E2 increased with age (r = 0.18, P < 0.001). No relationship between E2 and BMI was found. When comparing the difference in E2 according to the test results for TRAb, TPOAb and TgAb, it was found that E2 was significantly higher in subjects with positive TRAb (TRAb-positive, E2 = 170.3 ± 59.8 pmol/L; TRAb-negative, E2 = 134.0 ± 50.6 pmol/L; P < 0.001). No difference in E2 was demonstrated according to TPOAb or TgAb results. Logistic regression analysis showed that E2 was a determinant of positive TRAb, independent of age and BMI. There was no relationship between serum E2 and TSH or FT4. However, E2 was negatively related to TSH (r = -0.45, P < 0.01) in subjects whose TSH fell below the reference range (0.3-4.2 mIU/L). Higher circulating estradiol is related to thyroid autoimmunity in males as reflected by positive TRAb.
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NOD.H-2h4 mice given NaI in their drinking water develop iodine-accelerated spontaneous autoimmune thyroiditis (ISAT) with chronic inflammation of the thyroid by T and B cells and production of anti-mouse thyroglobulin (MTg) autoantibody. CD28(-/-) NOD.H-2h4 mice, which have reduced numbers of CD4(+)Foxp3(+) regulatory T cells (Tregs), were developed to examine the role of Tregs in ISAT development. CD28(-/-) NOD.H2-h4 mice develop more severe ISAT than do wild-type (WT) mice, with collagen deposition (fibrosis) and low serum T4. CD28(-/-) mice have increased expression of proinflammatory cytokines IFN-γ and IL-6, consistent with increased mononuclear cell infiltration and tissue destruction in thyroids. Importantly, transferring purified CD4(+)Foxp3(+) Tregs from WT mice reduces ISAT severity in CD28(-/-) mice without increasing the total number of Tregs, suggesting that endogenous Tregs in CD28(-/-) mice are functionally ineffective. Endogenous CD28(-/-) Tregs have reduced surface expression of CD27, TNFR2 p75, and glucocorticoid-induced TNFR-related protein compared with transferred CD28(+/+) Tregs. Although anti-MTg autoantibody levels generally correlate with ISAT severity scores in WT mice, CD28(-/-) mice have lower anti-MTg autoantibody responses than do WT mice. The percentages of follicular B cells are decreased and those of marginal zone B cells are increased in spleens of CD28(-/-) mice, and they have fewer thyroid-infiltrating B cells than do WT mice. This suggests that CD28 deficiency has direct and indirect effects on the B cell compartment. B cell-deficient (B(-/-)) NOD.H-2h4 mice are resistant to ISAT, but CD28(-/-)B(-/-) mice develop ISAT comparable to WT mice and have reduced numbers of Tregs compared with WT B(-/-) mice.
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