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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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... Unfortunately, there is still a lack of extensive and conclusive studies in humans showing the effects of this xenoestrogen on brain health and neurological development [74]. As mental and behavioral problems in children are now a very serious public health problem, it is imperative to pay attention not only to their increasing frequency but also to their exposure to all environmental factors, including bisphenol A. ...
... BPA, by affecting a change in gene transcription, disrupts the immune system through, among other things, the expression of sex genes. Thus, it induces an autoinflammatory response and deregulation of immunoglobulin T-reg [24,74]. It may also contribute to other mechanisms that promote autoimmune expression and progression [74]. ...
... Thus, it induces an autoinflammatory response and deregulation of immunoglobulin T-reg [24,74]. It may also contribute to other mechanisms that promote autoimmune expression and progression [74]. ...
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BPA has demonstrated enormous multisystem and multi-organ toxicity shown mainly in animal models. Meanwhile, the effects of its exposure in humans still require years of observation, research, and answers to many questions. Even minimal and short-term exposure contributes to disorders or various types of dysfunction. It is released directly or indirectly into the environment at every stage of the product life cycle, demonstrating its ease of penetration into the body. The ubiquity and general prevalence of BPA influenced the main objective of the study, which was to assess the toxicity and health effects of BPA and its derivatives based on the available literature. In addition, the guidelines of various international institutions or regions of the world in terms of its reduction in individual products were checked. Bisphenol A is the most widely known chemical and perhaps even the most studied by virtually all international or national organizations, but nonetheless, it is still controversial. In general, the level of BPA biomonitoring is still too high and poses a potential threat to public health. It is beginning to be widely argued that future toxicity studies should focus on molecular biology and the assessment of human exposure to BPA, as well as its substitutes. The effects of its exposure still require years of observation, extensive research, and answers to many questions. It is necessary to continue to deepen the knowledge and interest of many organizations, companies, and consumers around the world in order to make rational purchases as well as future choices, not only consumer ones.
... Enhancement of the immune-stimulating effects of the estrogens. T cell aggregation, effects on prolactin levels and cytochrome P450, and promoting reactive oxygen species formation are the other components of BPA induced autoimmunity (6). Given the higher prevalence of autoimmune thyroid disease in women, the potential role of BPA's estrogenic effects in its pathogenesis is a compelling area of study. ...
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Objective The precise mechanism underlying autoimmune thyroiditis is still unclear. The female preponderance suggests the role of estrogens in autoimmunity, and there is strong evidence about this role. Bisphenol A (BPA), a widely used endocrine disruptor, may have estrogenic effects and affect autoimmunity through estrogenic and non-estrogenic mechanisms. We aimed to determine the relationship between serum BPA levels and thyroid autoimmunity. Methods We performed a cross-sectional case-control study involving 143 autoimmune thyroiditis patients and 95 age-matched healthy controls. Serum BPA levels were measured using ELISA method.. Results BPA levels were not significantly different between autoimmune thyroiditis and control groups. The percentage of antibody-positive patients, thyroid function, thyroid antibody levels, or BMI were not different between BPA quartiles. Also, there was no correlation between BPA levels and thyroid autoantibody levels. Conclusion Serum BPA levels were not significantly different in autoimmune thyroiditis. Also, we could not show any relationship between BPA, thyroid function tests, and thyroid antibody levels.
... Bisphenol A (BPA) is an organic, synthetic chemical that is utilized in the manufacturing of epoxy resins and polycarbonate plastics. It has been detected in a multitude of everyday products, including beverage and food packaging, plastic utensils, flame retardants, home electronics, thermal paper, dental sealants and composites, and other medical devices [18][19][20][21]. The environmental fate of BPA includes its release into the environment and subsequent distribution and accumulation in different ecosystems. ...
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Given its simplicity, Caenorhabditis elegans appears to be a promising model for future research on endocrine disruptors, including bisphenol A and its supposedly safer alternatives. The aim of this study was to investigate the impact of embryonic exposure of C. elegans to different concentrations (0.5, 1.0, and 5 µM) of bisphenol A and its analogs (bisphenol S, bisphenol F, and bisphenol AF) on selected biological characteristics of the nematode C. elegans and to compare them with an unexposed control group. Embryonal exposure of C. elegans to bisphenol A, as well as bisphenol S, F, and AF at concentrations of 0.5, 1.0, and 5 µM resulted in a significant influence on the percentage of hatched eggs and habituation to anterior stimuli (with significant results ranging from p ≤ 0.05 to p ≤ 0.001). The growth of C. elegans was also significantly impaired by bisphenol A, S, and AF in some concentrations (with p-values ranging from p ≤ 0.05 to p ≤ 0.001). Our findings confirm prior research that bisphenol A and its supposedly safer analogs exert a detrimental effect on diverse biological processes. Therefore, bisphenol A analogs should be employed with caution, particularly until a comprehensive risk assessment has been conducted.
... It is a bisphenol compound structurally characterized as 4,4'-methanediyldiphenol ( Figure 3A). BPA plays multiple roles in the ecosystem, functioning as an exogenous estrogen, an environmental contaminant, a xenobiotic, and an endocrine disruptor [51,52]. Extensively utilized in the production of polycarbonate plastics, epoxy resins, and non-polymers, BPA can interact with nuclear receptors, thereby disrupting the normal function of the endocrine system. ...
Preprint
Air pollution, particularly airborne particulate matter (PM), poses a significant threat to public health globally. It is crucial to comprehend the association between PM-associated toxic components and their cellular targets in humans to understand the mechanisms by which air pollution impacts health and to establish causal relationships between air pollution and public health consequences. Although many studies have explored the impact of PM on human health, the understanding of the association between toxins and the associated targets remain limited. Leveraging cutting-edge deep learning technologies, we developed tipFormer (toxin-protein interaction prediction based on transformer), a novel deep-learning tool for identifying toxic components capable of penetrating human cells and instigating pathogenic biological activities and signaling cascades. Experimental results show that tipFormer effectively captures interactions between proteins and toxic components. It incorporates dual pre-trained language models to encode protein sequences and chemicals. It employs a convolutional encoder to assimilate the sequential attributes of proteins and chemicals. It then introduces a learning module with a cross-attention mechanism to decode and elucidate the multifaceted interactions pivotal for the hotspots binding proteins and chemicals. Experimental results show that tipFormer effectively captures interactions between proteins and toxic components. This approach offers significant value to air quality and toxicology researchers by allowing high-throughput identification and prioritization of hazards. It supports more targeted laboratory studies and field measurements, ultimately enhancing our understanding of how air pollution impacts human health.
... Furthermore, BPA exposure throughout life could affect cognitive functions, inducing alterations in the central nervous system (Cheng et al. 2021), development of autoimmune diseases due to alterations in estrogenic immune signaling, cytochrome P450 enzymes and macrophage activation (Kharrazian 2014). ...
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The exposome encompasses the total exposure an individual experiences throughout their life, comprising components influenced by the person's genetic, epigenetic and intrinsic and age-related traits (healthy ENDO-exposome), as well as diet, environmental factors and pollutants, habits, and socio-cultural and socio-economic aspects (ECTO-exposome). These elements interact and impact the organism, potentially leading to diseases (unhealthy ENDO-exposome). Metabolic diseases and cancer are a priority for research due to their rising prevalence. Different life stages create windows of susceptibility to external exposures. The ECTO-exposome that leads to metabolic diseases and cancer can occur from pre-birth in utero to postnatal periods, including infancy, childhood, adolescence, and adulthood. Additionally, we propose the concept of the ‘exposome loop’, which is defined as the response of an unhealthy ENDO-exposome to the ECTO-exposome.
... This chemical can leach into food, leading to negative health effects. Research demonstrates that BPA generates reactive oxygen species, causing oxidative damage to the liver, kidneys, and testes in animal studies, and vitamin C can exacerbate this damage [58]. Therefore, it is advisable to avoid consuming vitamin-C-enriched beverages from plastic bottles. ...
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Meals served to children should not only satisfy hunger and taste preferences but also be nutritionally adequate. Nutrition in early childhood is critical, as children spend a significant portion of their day in kindergarten or preschool, making these settings key contributors to their overall dietary intake. With the rising prevalence of nutrition-related health conditions among children, early interventions are essential for developing and establishing lifelong healthy eating habits. This study assessed the nutritional value and quality of children’s diets in two distinct settings: kindergartens in Wroclaw, Poland, and preschools in Sydney, Australia, evaluating their alignment with the planetary health diet. The research analysed 10-day menu cycles from five kindergartens in Wroclaw and the contents of lunchboxes from five preschools in Sydney’s Upper North Shore area. A total of 100 menus were reviewed in Poland, while 100 children’s lunchboxes were assessed in Australia. Different analytical methods were employed: the Diet 6D software program for the Polish menus and the Food Consumption Score for the Australian lunchboxes. Both methods revealed dietary imbalances, such as excessive intake of protein, vitamin A, salt, and sugar, alongside deficiencies in calcium, vitamin C, and vitamin D. The study concluded that children’s diets should adhere to nutritional guidelines, meeting both Polish and Australian standards, and align with the principles of the planetary health diet. To achieve this, nutritional education is essential for kindergarten staff in Poland, while targeted educational interventions are needed for parents and children in both Poland and Australia, promoting health and environmental sustainability through better nutrition.
... In another study on female children, higher testosterone levels and higher odds of having a Tanner Stage > 1 for breast development was associated with second trimester BPA exposure, indicating that BPA may affect reproductive development during critical periods of fetal growth [138]. PRL is vital in regulating immune and inflammatory responses through multiple immune signaling pathways [63]. BPA can mimic estrogen and trigger elevated PRL levels, leading to hyperprolactinemia [125]. ...
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Bisphenol-A (BPA) is a recognized endocrine-disrupting chemical used to produce several consumer goods and products. There has been widespread exposure to BPA because of increased industrial production and use of BPA-containing products. As a result of these exposures, BPA is found in several human body fluids and can cause endocrine disruption by interfering with hormone signaling pathways and epigenetic modifications. Therefore, human reproductive health and development have been adversely affected by BPA. This review aimed to consolidate existing knowledge on the impact of BPA on human reproductive health, examining its effects on both males and females. To achieve this, we systematically searched four databases for studies that associated BPA with reproductive health (male and female), after which we retrieved the important information from the selected articles. There was an association of reproductive health diseases with high BPA exposure. In males, BPA was associated with increased sperm alterations, altered reproductive hormone levels, and testicular atrophy. In females, there was an association of BPA exposure with hormonal imbalances, reduced ovarian reserve, and increased likelihood of conditions such as fibroids, polycystic ovarian syndrome, endometriosis and infertility. BPA's pervasive presence and its harmful effects on reproductive health underscore the need for global regulation and public awareness. Although substantial evidence from animal and in vitro studies supports the detrimental effects of BPA, there is a need for more human-focused research, particularly in developing countries, to confirm these findings. This review advocates for increased regulatory measures to limit BPA exposure.
... From a toxicological point of view, BPA has been classified as an endocrine-disrupting chemical [9]. High levels of exposure to BPA can lead to metabolic diseases, such as type 2 diabetes, hypertension, and elevated cholesterol [10,11], or interference with the immune and reproductive system by hormonal interactions [12,13]. In 2006, the European Food Safety Agency (EFSA) conducted the initial risk assessment of BPA, prompting the European Commission to establish concentration limitations, particularly focusing on products intended for infants and food contact materials [14,15]. ...
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Bisphenols are widely used as monomers and additives in plastic production. Thus, bisphenol A (BPA) and its most prominent substitutes have been detected in many environmental and human samples. This study proposes an online solid-phase extraction analytical methodology coupled to liquid chromatography with tandem mass spectrometry for the determination of six bisphenols (BPA and bisphenols F (BPF), S (BPS), AF (BPAF), B (BPB), and E (BPE)) in urine samples as an efficient and automated methodology. The method was developed and validated for all bisphenols with good recoveries (92–112%) and repeatability (RSD ≤ 10%) despite the variable matrix effects, except BPAF (which would require a dedicated internal standard), achieving method quantification limits in the 0.05–2.2 ng mL⁻¹ range. The methodology was subsequently applied to 435 urine samples from a non-occupational exposure population (civil servants for the regional government) from Santiago de Compostela (Galicia, Spain). Only BPA, BPF, and BPS were positively detected; the last two presented higher detection frequencies than BPA. When the urinary concentrations are extrapolated to human intake and compared to the European Food Safety Agency (EFSA) tolerable daily intake (TDI) of 2 × 10⁻⁴ µg kg⁻¹ day⁻¹ (TDI), all BPA positively identified samples would surpass this threshold. Although no TDI exists currently for the other two identified bisphenols, it is evident that human exposure to bisphenols should be limited. Finally, the results stratification by gender revealed higher levels of exposure to BPF in the women group. Supplementary Information The online version contains supplementary material available at 10.1007/s00216-024-05386-7.
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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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The study of the liver as a lymphoid organ is a growing field fueled by our better knowledge of the different component of the immune system and how they orchestrate an immune-related response. The liver have highly specialized mechanisms of immune tolerance, mainly because is continuously exposed to microbial and environmental antigens, and dietary components from the gut. Accordingly, the liver contains specialized lymphoid subpopulations acting as antigen-presenting cells. Growing evidences show that the liver is also associated with obesity-associated diseases because of its immune-related capacity to sense metabolic stress induced by nutritional surplus. Finally, the liver produces a pletora of neo-antigens being the primary metabolic organ of the body. Common immune mechanisms play a key pathogenetic role in most of acute and chronic liver diseases and in the rejection of liver allografts. Any perturbations of liver-related immune functions have important clinical implications. This issue of the Journal of Autoimmunity is focused on the more recent advances in our knowledge related to the loss of liver tolerance, a paradox for a tolerogenic organ, that leads to overactivation of the innate and adaptive immune response and the development of autoimmune liver diseases, such as autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis. The invited expert review articles capture the underlying immunomolecular mechanisms of the development and progression of autoimmune liver diseases, the novel field of the immune-related "liver-gut" axis influences to the development of liver autoimmunity, the predominant role of genetic factors, and the increasingly effective immuno-therapeutic possibilities.
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The term interferon describes a family of proteins consisting of three major types (I, II, and III) which differ in their primary protein sequences, cognate receptors, genetic loci, and cell types responsible for their production. The interferons, including types I and II, overlap significantly in the genes they control resulting in a shared spectrum of diverse biological effects which includes regulation of both the innate and adaptive immune responses. As such, the interferons are major effectors in the pathogenesis of autoimmunity, especially systemic autoimmunity. The type I IFNs, because they are produced during the early stages of the innate immune response, are thought to play the foremost role in autoimmune responses. However, numerous studies have found that the single type II IFN, IFN-γ, plays an essential role in the development and severity of systemic autoimmunity, particularly systemic lupus erythematosus. This is supported by animal studies where IFN-γ is uniformly required in both spontaneous and induced models of lupus. Although expression of IFN-γ in cells of the innate immune system is almost immediate after activation, expression in adaptive immunity requires a complex orchestration of cellular interactions, signaling events, and epigenetic modifications. The multifaceted nature of IFN-γ in adaptive immunity identifies numerous possible therapeutic targets that, because of the essential contribution of IFN-γ to systemic autoimmunity, have the potential for producing benefits.
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There is growing evidence that bisphenol A (BPA) may adversely affect humans. BPA is an endocrine disruptor that has been shown to be harmful in laboratory animal studies. Until recently, there were relatively few epidemiological studies examining the relationship between BPA and health effects in humans. However, in the last year, the number of these studies has more than doubled. A comprehensive literature search found 91 studies linking BPA to human health; 53 published within the last year. This review outlines this body of literature, showing associations between BPA exposure and adverse perinatal, childhood, and adult health outcomes, including reproductive and developmental effects, metabolic disease, and other health effects. These studies encompass both prenatal and postnatal exposures, and include several study designs and population types. While it is difficult to make causal links with epidemiological studies, the growing human literature correlating environmental BPA exposure to adverse effects in humans, along with laboratory studies in many species including primates, provides increasing support that environmental BPA exposure can be harmful to humans, especially in regards to behavioral and other effects in children.
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Development of the chemical industry leads to the development of new chemical compounds, which naturally do not exist in the environment. These chemicals are used to reduce flammability, increase plasticity, or improve solubility of other substances. Many of these compounds, which are components of plastic, the new generation of cosmetics, medical devices, food packaging and other everyday products, are easily released into the environment. Many studies have shown that a major lipophilicity characterizes substances such as phthalates, BPA, TBBPA and PCBs. This feature allows them to easily penetrate into living cells, accumulate in the tissues and the organs, and affect human and animal health. Due to the chemical structures, these compounds are able to mimic some endogenous hormones such as estradiol and to disrupt the hormone homeostasis. They can also easily pass the placental barrier and the blood-brain barrier. As numerous studies have shown, these chemicals disturb the proper functions of the nervous system from the earliest moments of life. It has been proven that these compounds affect neurogenesis as well as the synaptic transmission process. As a consequence, they interfere with the formation of the sex of the brain, as well as with the learning processes, memory and behavior. Additionally, the cytotoxic and pro-apoptotic effect may cause neurodegenerative diseases. This article presents the current state of knowledge about the effects of phthalates, BPA, TBBPA, and PCBs on the nervous system.
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Bisphenol A (4,40-isopropylidenediphenol, BPA) is known to adversely affect various organs. The liver is reported to be affected by BPA in animal studies. However, there are few studies in humans on the effects of BPA on the liver. Therefore, we evaluated the relationship between urinary BPA levels and liver function in elderly subjects using repeated measurements. From 2008 to 2010, a total of 560 elderly subjects residing in Seoul were each evaluated up to three times. At the first visit, demographic data, environmental exposure and lifestyle information were obtained from a systemised questionnaire. At each visit, blood and urine samples were collected and stored for analysis. Linear mixed and GLIMMIX model analyses were performed after adjusting for age, sex, Body Mass Index, alcohol consumption, urinary cotinine concentrations, exercise frequency, and low-density lipoprotein cholesterol level. The mean urinary BPA concentration was 1.13 μg/g creatinine. Significant relationships were observed between urinary BPA and aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase after adjusting for potential confounders (p<0.05). When subjects were grouped according to urinary BPA concentrations divided by the median value, higher urinary BPA concentrations were associated with increased abnormal liver function (OR 2.66; 95% CI 1.15 to 5.90). Community-level exposure to BPA was associated with abnormal liver function in the elderly, indicating that more stringent control of BPA is necessary to protect susceptible populations.
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