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Bisphenol A (BPA), used in polycarbonate plastics and epoxy resins, has a widespread exposure to humans. BPA is of concern for developmental exposure resulting in immunomodulation and disease development due to its ability to cross the placental barrier and presence in breast milk. BPA can use various mechanisms to modulate the immune system and affect diseases, including agonistic and antagonistic effects on many receptors (e.g., estrogen receptors), epigenetic modifications, acting on cell signaling pathways and, likely, the gut microbiome. Immune cell populations and function from the innate and adaptive immune system are altered by developmental BPA exposure, including decreased T regulatory (Treg) cells and upregulated pro- and anti-inflammatory cytokines and chemokines. Developmental BPA exposure can also contribute to the development of type 2 diabetes mellitus, allergy, asthma and mammary cancer disease by altering immune function. Multiple sclerosis and type 1 diabetes mellitus may also be exacerbated by BPA, although more research is needed. Additionally, BPA analogs, such as bisphenol S (BPS), have been increasing in use, and currently, little is known about their immune effects. Therefore, more studies should be conducted to determine if developmental exposure BPA and its analogs modulate immune responses and lead to immune-related diseases.
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toxics
Review
Developmental Bisphenol A Exposure Modulates
Immune-Related Diseases
Joella Xu 1, Guannan Huang 2and Tai L. Guo 1, *
1Department of Veterinary Biosciences and Diagnostic Imaging, Interdisciplinary Toxicology Program,
University of Georgia, Athens, GA 30602-7382, USA; joella@uga.edu
2Department of Environmental Health Sciences, University of Georgia, Athens, GA 30602-7382, USA;
guhuang@uga.edu
*Correspondence: tlguo1@uga.edu; Tel.: +1-706-542-1358; Fax: +1-706-542-0051
Academic Editor: Shu-Li Wang
Received: 8 August 2016; Accepted: 12 September 2016; Published: 26 September 2016
Abstract:
Bisphenol A (BPA), used in polycarbonate plastics and epoxy resins, has a widespread
exposure to humans. BPA is of concern for developmental exposure resulting in immunomodulation
and disease development due to its ability to cross the placental barrier and presence in breast
milk. BPA can use various mechanisms to modulate the immune system and affect diseases,
including agonistic and antagonistic effects on many receptors (e.g., estrogen receptors), epigenetic
modifications, acting on cell signaling pathways and, likely, the gut microbiome. Immune
cell populations and function from the innate and adaptive immune system are altered by
developmental BPA exposure, including decreased T regulatory (Treg) cells and upregulated pro- and
anti-inflammatory cytokines and chemokines. Developmental BPA exposure can also contribute to
the development of type 2 diabetes mellitus, allergy, asthma and mammary cancer disease by altering
immune function. Multiple sclerosis and type 1 diabetes mellitus may also be exacerbated by BPA,
although more research is needed. Additionally, BPA analogs, such as bisphenol S (BPS), have been
increasing in use, and currently, little is known about their immune effects. Therefore, more studies
should be conducted to determine if developmental exposure BPA and its analogs modulate immune
responses and lead to immune-related diseases.
Keywords:
bisphenol A; immunotoxicity; developmental; epigenetics; microbiome; multiple sclerosis;
diabetes; allergy; asthma; mammary cancer; bisphenol S
1. Introduction
Bisphenol A (BPA) is used in polycarbonate plastics and epoxy resins, such as food containers
and can linings, with human exposure levels measurable in more than 90% of human urine samples in
a 2003–2004 national survey and in a more recent 2007–2009 Canadian survey [
1
,
2
]. With such a high
frequency of exposure in humans, there has been an increasing amount of research published on BPA
exposure in utero and through lactation for many possible developmental and reproductive effects,
which can lead to an altered immune system and disease development.
BPA exposure is considered mainly from food. The estimated exposure levels are from
0.01–13
µ
g/kg/day in children and about 4.2
µ
g/kg/day for adults [
3
]. However, BPA in fasting adults
did not decrease over time with concentrations greater than 12 ng/mL still present in urine after fasting
for 6 or 9.5 h [
4
]. This suggests that BPA exposures from nonfood sources and/or bioaccumulation in
human tissue are important factors for BPA exposure. Additionally, BPA has been detected in fetal
cord blood (from 0.14–9.2 ng/g), fetal liver (from 1.3–50.5 ng/g), amniotic fluids (from 0.36–5.62 ng/g),
placental tissue (up to 273.9 ng/g) and breast milk (up to 1.16 µg/kg) [3,5].
Toxics 2016,4, 23; doi:10.3390/toxics4040023 www.mdpi.com/journal/toxics
Toxics 2016,4, 23 2 of 23
Due to BPA’s ability to bind to estrogen receptors, BPA is classified as an endocrine-disrupting
chemical (EDC). EDCs can decrease the survival of immune cells as seen from animal studies and may
suppress type 1 helper (Th1) cell immunity or type 2 helper (Th2) cell immunity, leading to a shift in
immune balance; an increase in the Th1 response results in a pro-inflammatory response, while a Th2
shift will result in an anti-inflammatory response [
6
]. The shift in T helper cell populations (Th1, Th2,
Th17, etc.) can alter immune responses to antigens and disease profile, contributing to autoimmune
diseases (e.g., multiple sclerosis) and allergic diseases (e.g., asthma) [7].
Studies on BPA’s effect on the immune system are mainly from adult exposure and
in vitro
studies
of differentiated cell lines. However, BPA can affect nuclear receptors and non-nuclear receptors in
murine placenta with sex-dependent differences, and it passes through the placenta to the fetus likely
via passive diffusion [
8
,
9
]. Additionally, developmental BPA exposure has been shown to alter the
immune responses and risks for some immune-related diseases in offspring.
2. Mechanisms of Immune Modulation and Disease Exacerbation Following Developmental
BPA Exposure
2.1. Receptor Modification
BPA’s effects on the immune system are likely due to its agonistic and antagonistic effects
on receptors. BPA can modulate the immune response through binding to various receptors,
including nuclear and non-nuclear receptors. Some of the main receptors bound by BPA are estrogen
receptors (ERs), estrogen-related receptors (ERRs), aryl hydrocarbon receptor (AhR), peroxisome
proliferator-activated receptors (PPARs) and toll-like receptors (TLRs) [
10
,
11
]. Of these receptors, ERs,
ERRs and TLRs are expressed in the majority of immune cells; dendritic cells (DCs), macrophages,
B cells and the T cell subsets Th17 and Treg express AhR; and PPARs are expressed in macrophages,
DCs, T cells and B cells [
10
,
12
,
13
]. This allows BPA to act on the receptors of many different immune
cells of the innate and adaptive immune systems. However, these results are currently based on
adult exposure, and only a few studies have examined ER or ERR modification following prenatal or
perinatal exposure.
Activation of ERs can shift the Th1/Th2 balance to a Th2 profile with increased anti-inflammatory
cytokines and inhibited antigen-presenting cell (APC) activation, T cell proliferation and
pro-inflammatory cytokine secretion when there is a high level of endogenous estrogen. Low or
moderate levels of estrogen lead to a shift towards a Th1 profile with ER binding resulting in increased
pro-inflammatory cytokines, APC activation and T cell proliferation [
14
]. The amount of endogenous
estrogen, the amount of BPA that it is exposed to and levels of other hormones, including progesterone,
will all determine whether the shift from EDC exposure increases the Th1 or Th2 response. Due to the
importance of hormone levels, sex and age also play a key role in the outcome from BPA exposure on
the immune system.
The sex-specific effects were seen in a study by Miao et al. [
15
] in which F344 rats exposed to BPA
perinatally had increased ER
α
expression in the F0 and F1 females, while the F0 and F1 males had
decreased ER
α
expression. Miao et al. [
15
] also found perinatal BPA exposure to F344 rats resulted in a
dose-dependent decrease in IL-2, IL-12, IFN-
γ
and TNF-
α
in the F0 and F1 generations. This decrease
is likely due to BPA’s ability to alter ER
α
expression, which has been indicated to modulate expression
of IL-2 and IFN-
γ
and other nuclear and hormone receptors [
15
,
16
]. These cytokines are important for
the inflammatory response and T cell response, particularly the Th1 response.
While BPA’s affinity for ERRs is greater than ERs, less research has been done on BPA’s
immunomodulation through ERR interaction [
17
,
18
]. ERRs can bind estrogen response elements (EREs)
and the ERR-response element (ERRE) resulting in crosstalk between ERs and ERRs [
17
]. Additionally,
ERRs regulate oxidative metabolism and mitochondrial biogenesis in many cells including T cells
and macrophages [
19
,
20
]. Of particular importance to the adaptive immune system, ERR
α
regulates
T effector cell function and is needed for T effector cell activation and differentiation [
21
]. In Jurkat
cells, a leukemic T cell line, it was found that BPA increased ERR
α
expression in a concentration-related
Toxics 2016,4, 23 3 of 23
manner, which suggested that BPA could alter T cell function through modulating ERR expression [
20
].
Developmental BPA exposure can also alter ERR levels, as seen from low dose (2 and 20
µ
g/kg) prenatal
BPA exposure altering prefrontal cortex and hypothalamus ERR
γ
gene expression in a sex-specific
manner (increasing in males, while decreasing in females) [
22
]. ERRs are also involved in diseases,
for example increased expression contributing to breast cancer proliferation and alleviating EAE,
which could be a mechanism for BPA to alter immune-related diseases, as discussed later [19,21].
2.2. Epigenetics
Most EDCs including BPA do not directly affect DNA by altering the DNA sequence or causing
mutations. Instead, studies show that epigenetic changes are taking place with many EDCs including
BPA [
6
,
23
,
24
]. These types of changes have the potential to affect immune cells directly by altering the
transcription and translation of immune function-related genes or indirectly by increasing the risk for
diseases, such as cancer [2426].
DNA methylation, histone modification and RNA interfering are the three most studied types of
epigenetic modifications [
27
]. DNA methylation results in a more compact and inactive chromatin
with less transcription. Histone modifications can result in a more tightly bound nucleosome and
less transcription or a more loosely bound nucleosome and more transcription, depending on the
modification. The two main types of histone modifications are acetylation, which upregulates
transcription, and methylation, which may upregulate or downregulate transcription based on the site
of the modification. RNA interfering involves silencing from post-transcriptional RNA, with miRNA
being the most studied of these RNAs [27].
Developmental BPA exposure can modify the epigenome through all three mechanisms [
23
,
24
].
Although studies focusing on epigenetic effects on the immune system are lacking, other studies on
BPA’s ability to alter the epigenome show that immune gene transcription and translation are likely
also changed. For example, prenatal BPA can alter DNA methylation patterns in different mouse fetal
tissues including fetal liver tissue [
28
]. Additionally, Dhimolea et al. [
23
] found DNA methylation
and histone modification patterns of the mammary gland epigenome and, specifically, genes involved
in cancer (e.g., p. 57), in rats following prenatal BPA exposure change over time differently from
control rats. A cohort study of prepubescent Egyptian girls found that higher BPA levels in urine
correlate with more hypomethylated genes involved with immunity and inflammation, indicating that
BPA increases immune and inflammatory response through epigenetics [
29
]. Nonetheless, whether
epigenetic alterations affect immune genes after developmental exposure in humans has yet to be
researched. While further studies are needed to determine BPA’s effect on the immune system from
epigenetic alteration, this reported evidence suggests epigenetics as a mechanism for developmental
BPA exposure altering the immune system.
2.3. Microbiome
One of BPA’s main routes of exposure is oral, resulting in exposure of the gut-associated lymphoid
tissue (GALT). The GALT contains both innate and adaptive immune cells that interact with intestinal
epithelial cells and microbiota [
30
,
31
]. This raises the possibility that BPA can affect the immune system
through interaction with the gut microbiota.
Dysbiosis, a microbial imbalance or maladaptation, has been associated with an increase in
disease risk including type 1 diabetes (T1D), but the mechanisms are still unclear [
32
]. Environmental
exposures to different chemicals can cause dysbiosis in infants and increase their risk for diseases [
31
].
To date, there are no studies on BPA’s effect on the gut microbiota. Furthermore, the mechanisms
of how environmental exposures to chemicals such as BPA may affect the microbiota and possibly
cause dysbiosis that leads to immune dysfunction and disease are still unclear. It is known that the
early developmental stages are critical for metabolic maturation, and alterations of the gut microbiota
during this period can lead to obesity with an increased risk for diseases like T1D, heart disease and
cancer [
33
]. Dysbiosis also likely results in increased permeability of the intestinal epithelial layer,
Toxics 2016,4, 23 4 of 23
leading to a leaky gut, which often precedes inflammatory diseases, such as T1D [
34
], but more studies
are needed to determine the interaction between the microbiome and the intestinal epithelial layer [
34
].
Braniste et al. [
35
] found that BPA exposure alters the intestinal barrier permeability and function
leading to inflammation, which possibly resulted from alterations in the gut microbiota. Due to the
close relationship between the GALT and the gut microbiota, these studies suggest that BPA exposure
disrupts gastrointestinal function and affects gut microbiota composition, and further research would
provide better insight.
2.4. Cell Signaling Pathways
BPA can act through cell signaling pathways to alter the immune system and increase disease
risk [
36
]. Early growth response gene-2 (EGR2) and signal transducer and activator of transcription 3
(STAT3) are two examples of cellular processes that BPA can activate to alter immune functions such as
inflammation [
37
,
38
]. EGR2 is involved in development of Treg cells, dendritic cells and Th17 cells and
suppresses naive CD4
+
T cells [
39
]. In Treg cells, ERG2 activation increases IL-10 production, while
in Th17 cells, ERG2 activation decreases IL-17 production. Additionally, dendritic cell activation of
ERG2 decreases IL-12, IFN-
γ
and antigen uptake [
39
]. EGR2 also regulates LAG3
+
Treg cells and is
required for T cell anergy [
40
]. ERG2 modulation of immune cells suggests that BPA activation of this
cellular pathway can alter immune responses, leading to ERG2-related diseases including lupus-like
syndrome, seen in C57BL/6 mice, and allergic airway diseases, seen in BALB/c mice [40,41].
STAT3 is required for IL-27-mediated EGR-2 induction [
40
]. Activation of STAT3 downstream
effects depends on the microenvironment. STAT3 regulates tumor-associated inflammation, and
its activation downregulates the Th1 response by upregulating Foxp3
+
Treg cells [
42
,
43
]. STAT3
regulation of inflammation during M. tuberculosis infection differs from tumor-associated inflammation
by downregulating Foxp3
+
Treg cells and macrophage inflammatory response and modulating
Th cell response [
44
,
45
]. STAT3 can be activated by immune cytokines (e.g., IL-10) and EDCs
including
BPA [38,42,46].
While studies have shown the activation of STAT3 and EGR2 by BPA,
the molecular mechanisms of how these cellular pathways are activated by BPA are unclear.
However, the immunomodulation by BPA affecting these pathways can result in increased disease
risks, such as cancer [
47
]. Additionally, other signaling pathways, such as NF-
κ
B and ERK 1/2
phosphorylation in macrophages, can be altered by BPA to dysregulate immune cell function and
cytokine production [4850].
3. Immune System Alteration Following Developmental BPA Exposure
3.1. Innate Immune System
The alteration of the innate immune response from BPA exposure can be seen from zebrafish
embryos, which lack an adaptive immune system at early ages. Zebrafish embryos exposed to varying
concentrations of BPA (0.44–4400 nM) developed an innate immune response resulting from oxidative
stress as seen from increased reactive oxygen species (ROS) and downstream effects of upregulated
TLRs, cytokines and chemokines, inducible nitric oxide synthase (iNOS) and nitric oxide (NO) [
51
].
This study shows that BPA can affect the innate immune system and signaling for upregulated
pro-inflammatory (e.g., INF-
γ
) and anti-inflammatory markers (e.g., IL-10). In addition, this study
suggests that BPA alters macrophages and neutrophils as seen from the upregulated expression of
cytokines and chemokines produced from these cells.
Studies using macrophage cell lines and a perinatally-exposed diabetic mouse model have shown
that the number of macrophages is decreased from BPA exposure with higher apoptotic cells [
52
54
].
Macrophage functions are also altered by BPA as seen from both cell models and developmental
mouse studies. BPA can decrease phagocytosis activity of macrophages, which possibly reduces
the immune defense against pathogens [
49
,
52
,
54
]. Additionally, BPA can increase inflammation
by increasing macrophage production of pro-inflammatory cytokines (e.g., TNF-
α
) and decreasing
anti-inflammatory cytokines (e.g., IL-10) [
48
,
49
,
52
]. However, BPA has also been found to decrease
Toxics 2016,4, 23 5 of 23
macrophage pro-inflammatory cytokine production at very high concentrations, which are less
physiologically relevant, suggesting that the amount of BPA that it is exposed to determines its
effects on macrophages [50,54,55].
Eosinophils, which are involved in allergy and asthma development, can also be altered from
developmental BPA exposure. BPA in combination with allergen exposure (e.g., OVA) differently
modifies eosinophil production by increasing eosinophils from early life exposure and decreasing
eosinophils from late life exposure as discussed in the section below on allergies and asthma [
56
58
].
These studies suggest that not only the doses of BPA that it is exposed to, but also that the windows of
exposure play a role in the modulation of the innate immune system.
3.2. Adaptive Immune System
BPA exposure has been found to decrease Treg cells, which are important for immune cell balance,
resulting in an altered Th1/Th2 response [
10
]. Prenatal BPA exposure in both male and female
mouse offspring can increase CD3
+
CD4
+
(T helper) and CD3
+
CD8
+
(cytotoxic T cells) splenic T cell
populations [
59
]. Increases of these T cell populations could be a result from decreased Treg cells, which
are important for regulating T helper and cytotoxic T cell functions. The unregulated increase in these
T cell populations (e.g., autoreactive CD8
+
and CD4
+
T cells) increases the risk for immune-related
diseases [6062].
Chick embryos exposed to BPA exhibited altered structures of the thymus, where T cells develop,
and bursa of Fabricius, where B cells develop in birds [
63
]. However, no studies yet have examined
the effects of prenatal or perinatal BPA exposure on bone marrow, where B cells develop in mammals.
Structural alteration of organs where T and B cells develop can negatively affect the adaptive immune
cell development and may result in altered cell populations and/or functions [
64
,
65
], which may
further increase susceptibility to infections and diseases [60,66].
3.3. Cytokine/Chemokine, Antibody Production and Host Resistance
Alteration of cytokines and chemokines by BPA might result from alterations in the number of
immune cells, expression of genes or receptor modifications in immune cells. Due to BPA’s effect on
ER, cytokines and chemokines are likely affected in both the innate and adaptive immune system.
Holladay et al. [
67
] observed that C57BL/6 male offspring perinatally exposed to 1.0 mg/kg BPA had
a trend of upregulated cytokines and chemokines towards a Th1 and Th17 response at 20 weeks old;
however, this study lacked enough mice for statistical analysis, and the dose was high. Similar results
were found from measuring the immune response in 300 and 3000
µ
g/kg prenatally BPA exposed
male offspring in mice that were immunized with hen egg-white lysozyme (HEL) protein at eight and
11 weeks old when both INF-
γ
and IL-4, Th1 and Th2 cytokines, respectively, were increased along
with increased anti-HEL IgG titers; however, the Th1 response had a higher increase [59].
In another study that measured markers for allergy and inflammatory processes in human cord
blood and compared the amount of maternal urinary BPA concentration during the first trimester,
it was found that thymic stromal lymphopoietin (TSLP), IL-33 and IgE levels were elevated in a
non-linear manner in both males and females exposed to BPA during fetal development, suggesting
that both low and high exposure levels of BPA during the first trimester might result in allergies or
inflammatory diseases [
68
]. The non-linear response seen in this study is common for many EDCs,
including BPA, and has resulted in increased concerns over human exposure, which tends to be lower
than the doses used in experiments [
69
,
70
]. Together, these studies suggest that developmental BPA
exposure can alter the production of mediators important for immune function, which can shift the
immune response in a non-monotonic manner.
Male mice prenatally exposed to BPA had decreased Treg cells along with increased Th1 and
Th2 cytokine markers INF-
γ
and IL-4, respectively, after being challenged with L. major protozoa
infection [
71
]. In contrast, perinatally-exposed female Wistar rats exhibited no change in INF-
γ
,
IL-4 or anti-OVA antibody titers following ovalbumin (OVA) antigen challenge; however, Treg cells,
Toxics 2016,4, 23 6 of 23
T helper cells and dendritic cells were significantly decreased in the spleen and mesenteric lymph
nodes (MLN) [
72
]. In the same study, female offspring following challenge with nematode intestinal
infection showed no change in IgE, but increased survival of larvae from decreased neutrophils and
myeloperoxidase (an enzyme produced by neutrophils), along with increased Th2 cytokines IL-13
and IL-4, as well as pro-inflammatory cytokines growth-related oncogene and INF-
γ
, in the small
intestine [
72
]. The differences between these results suggested the antigen-specific effects of BPA
in altering the immune system, which could be a downstream effect from decreased Treg cells by
disrupting the immune cell balance after BPA exposure.
In contrast, perinatally BPA exposed male and female mice showed no difference in virus-specific
IgG levels, cytotoxic T cells, T helper cells or Treg cells following challenge with influenza A virus
infection; however, a decrease in cytokines and chemokines produced by neutrophils and macrophages
similar to the other host resistance studies as discussed above was observed during early infection [
73
].
This suggests that the adaptive immune response to viral infection is not affected by BPA exposure, but
the innate immune response may be delayed as seen from downregulated cytokines and chemokines
produced by neutrophils and macrophages during early infection. The differences in BPA’s effect on
T cells between these studies could be from different antigens used, species/strains used, sexes of
animals used and from different doses. Additionally, the different host resistance tests that measured
innate immune response tended to show a decrease in innate immune cells along with downregulation
of cytokines and chemokines produced by innate immune cells.
4. Diseases Related to Immune System Alteration Following Developmental BPA Exposure
4.1. Multiple Sclerosis
Multiple sclerosis (MS) is a chronic autoimmune disease resulting from demyelination of nerve
cells. T cells, antibodies and inflammatory responses all contribute to MS development. CD8+T cells
and macrophages are the predominant immune cells involved in human MS lesions. BPA is likely
to have neurotoxic effects, which can result in exacerbation of neurological diseases and disorders.
Neurotoxic mechanisms of chemicals are suggested to include oxidative stress, epigenetic effects,
endocrine disruption and, possibly, lipophilic exogenous chemicals crossing the blood brain barrier
(BBB) and allowing the entry of hydrophilic chemicals; BPA has been shown to cause endocrine
disruption and epigenetic modification and is lipophilic, enabling BPA to cross the BBB [
53
,
74
].
Moreover, ER
β
knockout mice have deficits in synaptic plasticity and in neurogenesis, and perinatal
BPA exposure inhibits ER
β
expression and can activate the N-methyl-D-aspartate (NMDA) receptor
in hippocampal cells from mice [
75
]. Whether BPA affects MS warrants further study, since there
is a paucity of research published on BPA’s effect on this disease (Table 1). Animal models include
autoimmune encephalomyelitis (EAE) for mammals, virus-induced demyelination (Theiler’s murine
encephalomyelitis virus (TMEV)) for mice and toxin-induced demyelination for mammals [76].
Krementsov et al. [
77
] have reported that perinatal exposure to BPA at a dose that produces
similar amounts of accumulation as humans resulted in no significant changes in EAE severity from
the control in male and female mice on a phytoestrogen-free diet. Moreover, perinatally-exposed
adult female C57BL/6J mice, but not SJL/JCrHsd mice, on a phytoestrogen-free diet had decreased
IL-17 production [
77
], which suggested that BPA might be protective, because a reduction in IL-17
ameliorated this disease in mice and, possibly, in humans [
78
]. IL-17 is a pro-inflammatory cytokine
that promotes inflammation in MS lesions and autoimmunity, and downregulation of IL-17 can
ameliorate MS [
78
,
79
]. Modulation of IL-17 could mean ERG2 is an important part of MS development
from BPA exposure, since downregulation of ERG2 has been seen with more severe EAE in mice and
in MS patients [39].
On the other hand, Brinkmeyer-Langford et al. [
80
] using the TMEV model of this disease found
a significantly increased onset of disease after perinatally exposing male and female mice to BPA.
These perinatally BPA exposed mice also had less antibody production to the virus along with increased
Toxics 2016,4, 23 7 of 23
inflammation of the spinal cord, increased inflammatory colitis, downregulation of anti-inflammatory
genes and upregulated IFN-
γ
, which all lead to a pro-inflammatory response and disease onset [
80
].
The opposite results in these two studies may be due to the different multiple sclerosis mouse models
and/or phytoestrogen levels in the diet. While both MS models have their pros and cons, EAE is
mainly CD4
+
T cell mediated, while TMEV is mainly macrophage mediated and more similar to MS
disease development in humans [
76
]. This would suggest that BPA’s differential effects based on
models may be from BPA altering macrophage function to induce disease in the TMEV model, but not
affecting the CD4+T cells in the EAE model. Further research directly measuring these immune cells
in these animal models would provide a clearer answer on whether BPA can increase MS risk.
Table 1. Summary of animal multiple sclerosis studies on BPA exposed offspring.
Multiple
Sclerosis
Disease Models
Animal Model Exposure
Windows BPA Dose Routes of
Administration Diet Effects Reference
Autoimmune
Encephalomyelitis
(EAE)
Male and
Female Mice
(C57BL/6J and
SJL/JCrHsd)
Gestation
and
Lactation
10 µg/mL 1% ethanol in
drinking water
AIN-93G
(casein-based
phytoestrogen-free)
No Effect on EAE
or INF-γ;
decreased IL-17
in females
[77]
Theiler’s
Murine
Encephalomyelitis
Virus (TMEV)
Male and
Female Mice
(SJL)
Gestation
and
Lactation
10 µg/kg
BW
Charcoal-stripped
corn oil via
gavage
Not Specified
Earlier onset of
disease; increased
inflammation;
decreased
antibodies
to virus
[80]
BPA: bisphenol A; BW: body weight.
4.2. Type 1 Diabetes Mellitus
T1D is an autoimmune disease involving the destruction of pancreatic
β
-cells. Worldwide, there
is an annual increase in T1D incidence by 3%–5% with over a million people affected by this disease in
the United States alone [
56
]. There has been a parallel increase in EDC exposure and incidence of T1D.
Exposure to BPA has been associated with an increased incidence of T1D in adult animals and diabetes
in humans [
81
,
82
]. Whether BPA can increase the risk for T1D from perinatal or prenatal exposure is
still uncertain. So far, there has only been two studies published using a T1D mouse model of females
exposed perinatally only or throughout life (Table 2), which found that BPA increased the percent
diabetes at 20 and 25 weeks of age, respectively, while also increasing apoptosis of macrophages,
β
-cells and
α
-cells in pancreatic islets and increasing Foxp3
+
Treg cells [
52
,
83
]. Increased apoptosis of
β
-cells,
α
-cells and macrophages is a common factor involved with T1D disease development [
57
,
58
].
As discussed earlier, macrophage function was also altered with decreased phagocytic activity, which
could result in increased inflammation due to less clearance of apoptotic cells [
52
]. Additionally, BPA
altered splenocyte cytokine production including decreased IL-10, which was likely a mechanism of
increased T1D development from BPA exposure [
52
]. In the perinatal exposure only study, however,
these effects were only seen at a very high dose (10 mg/L; about 3000
µ
g/kg/day), while lower doses
(about 30 and 300
µ
g/kg/day) did not show much effect, although the effects were seen at a lower
dose (1 mg/L) in the lifelong study.
4.3. Type 2 Diabetes Mellitus
Increasing evidence suggest that type 2 diabetes (T2D) is also related to immune dysfunction [
84
].
Increasing exposure to EDCs is suspected as a contributive factor to T2D along with known causes,
such as obesity, decreased insulin sensitivity and disrupted
β
-cell mass and function [
85
,
86
]. Chronic
inflammation produced by obesity plays a key role in T2D development with altered immune cell
populations (e.g., CD4+Tregs) and insulin resistance contributing to the disease development [84].
Toxics 2016,4, 23 8 of 23
Table 2. Summary of animal diabetes (type 1 and type 2) studies on BPA exposed offspring.
Diabetes
Disease Model Animal Model Exposure
Windows BPA Dose Routes of
Administration Diet Effects Reference
Type 1 Diabetes
Female NOD/ShiLtJ
Mice Offspring
Gestation and
Lactation 0.1, 1 or 10 mg/L
Deionized
autoclaved
drinking water
2919X (minimal
phytoestrogen
content)
Increased insulitis, diabetes, Treg
cells and apoptosis of β-cells,
α-cells and macrophages in
highest dose only
[83]
Type 1 Diabetes
Female NOD/ShiLtJ
Mice Offspring
From Gestation to
End of Study 1 mg/L
Deionized
autoclaved
drinking water
2919X (minimal
phytoestrogen
content)
Increased insulitis, diabetes and
apoptosis pancreatic cells
macrophages; decreased
phagocytic macrophages, IL-10,
IL-4 and TNF-α
[52]
Type 2 Diabetes Male and Female
Human Infants 1st Trimester
0.34 to >1.7 µg/L
(measured,
not dosed)
Measured
exposure from
environment, etc.
Not Specified Lower adiponectins in male
cord blood [85]
Type 2 Diabetes Male Wistar
Rat Offspring
Gestation and
Lactation 50 µg/kg Gavage; dissolved
in corn oil Not Specified Increased insulin and insulin
resistance; reduced glycogen [87]
Type 2 Diabetes Male and Female
Wistar Rat Offspring
Gestation and
Lactation
50, 250 or
1250 µg/kg
Gavage; in corn oil
Standard or
high-fat diet
Low dose only: increased body
weight and insulin; altered β-cell
function; high-fat diet and male
had a greater effect
[88]
Type 2 Diabetes Male and Female
OF-1 Mice Offspring
Prenatal (GD9-16) 10 or 100 µg/kg
S.C. injection; in
tocopherol-stripped
corn oil
Soy/alfalfa-free
Low dose, males only: increased
insulin, insulin sensitivity and
glucose intolerance; altered
β-cell function
[89]
Type 2 Diabetes Male and Female
CD-1 Mice Offspring
Gestation and
Lactation About 0.25 µg/kg In food
Phytoestrogen-free
until weaning then
LFD and half mice
after 9 weeks old
high-fat diet
No effect on glucose tolerance [90]
Type 2 Diabetes Male OF-1
Mice Offspring Prenatal (GD9-16) 10 µg/kg
S.C. injection; in
tocopherol-stripped
corn oil
Soy/alfalfa-free
No effect for insulin sensitivity;
glucose intolerance;
increased NEFA
[86]
Treg cells: T regulatory cells; GD: gestation day; LFD: low butter-fat diet; S.C.: subcutaneous; NEFA: non-esterified fatty acids.
Toxics 2016,4, 23 9 of 23
A birth cohort study observed a correlation between higher BPA levels in Canadian mother’s urine
during the first trimester and lower adiponectin levels in cord blood at term birth of male metabolic
syndrome and T2D in adulthood [
85
]. While this cohort had a large participation (2001 women),
the ethnic groups were limited with mainly Caucasian women participating. Another potential bias
could result from only one time point for measuring BPA exposure, since infants were likely exposed
to varying amounts throughout infants, but not female infants; low adiponectin levels at birth are a
risk for insulin resistance gestation.
In agreement with the cohort study, animal studies also show a higher risk for male offspring,
but not as much for female offspring, as seen by increased body weight, increased insulin levels and
insulin resistance from BPA exposure [
87
,
88
]. Although glucose levels and glucose tolerance only tend
to be affected in males on phytoestrogen-free diets and in both sexes on high-fat diets following BPA
exposure, T2D is characterized more by increased insulin levels and insulin resistance [
86
90
]. BPA
exposure alters
β
-cell mass and function by reducing
β
-cell turnover and proliferation and increasing
β
-cells containing swollen mitochondria and rough endoplasmic reticulum in male offspring and in
both sexes on a high-fat diet [86,88].
Both animal studies and the previously-mentioned infant cohort study identify prenatal and
perinatal BPA exposure as a risk factor for T2D development in males on phytoestrogen-free diets and
in both sexes on a high-fat diet (Table 2; Figure 1). The immune system plays an important role in T2D.
Obesity increases the accumulation of pro-inflammatory immune cells (e.g., macrophages, cytotoxic
T cells and Th1 cells), while decreasing Foxp3
+
CD4
+
Treg cells [
84
]. Inflammation resulting from the
increased pro-inflammatory cell environment disrupts insulin action and produces insulin resistance
and
β
-cell dysfunction [
84
]. As discussed, developmental BPA exposure can increase the Th1 response
and reduce Treg cells, which is likely a mechanism for the increased T2D seen in these studies.
Toxics 2016, 4, 23 10 of 24
In agreement with the cohort study, animal studies also show a higher risk for male offspring,
but not as much for female offspring, as seen by increased body weight, increased insulin levels and
insulin resistance from BPA exposure [87,88]. Although glucose levels and glucose tolerance only
tend to be affected in males on phytoestrogen-free diets and in both sexes on high-fat diets following
BPA exposure, T2D is characterized more by increased insulin levels and insulin resistance [86–90].
BPA exposure alters β-cell mass and function by reducing β-cell turnover and proliferation and
increasing β-cells containing swollen mitochondria and rough endoplasmic reticulum in male
offspring and in both sexes on a high-fat diet [86,88].
Both animal studies and the previously-mentioned infant cohort study identify prenatal and
perinatal BPA exposure as a risk factor for T2D development in males on phytoestrogen-free diets
and in both sexes on a high-fat diet (Table 2; Figure 1). The immune system plays an important role
in T2D. Obesity increases the accumulation of pro-inflammatory immune cells (e.g., macrophages,
cytotoxic T cells and Th1 cells), while decreasing Foxp3
+
CD4
+
Treg cells [84]. Inflammation resulting
from the increased pro-inflammatory cell environment disrupts insulin action and produces insulin
resistance and β-cell dysfunction [84]. As discussed, developmental BPA exposure can increase the
Th1 response and reduce Treg cells, which is likely a mechanism for the increased T2D seen in
these studies.
Figure 1. Proposed mechanisms for increased type 2 diabetes risk following developmental bisphenol
A (BPA) exposure.
Additionally, some epidemiological studies found higher BPA and chlorinated BPA levels
during adulthood correlated with increased type 2 diabetes risk [82,91,92]. However, some other
epidemiological studies in adults found no correlation, which was likely due to differences in genetic
susceptibility modulating BPA’s effects and other confounding factors [92–95]. These adult
Figure 1.
Proposed mechanisms for increased type 2 diabetes risk following developmental bisphenol A
(BPA) exposure.
Toxics 2016,4, 23 10 of 23
Additionally, some epidemiological studies found higher BPA and chlorinated BPA levels
during adulthood correlated with increased type 2 diabetes risk [
82
,
91
,
92
]. However, some other
epidemiological studies in adults found no correlation, which was likely due to differences in
genetic susceptibility modulating BPA’s effects and other confounding factors [
92
95
]. These adult
epidemiological studies show the importance of measuring genetic susceptibility in future studies to
examine the relationship between developmental BPA exposure and T2D development, which has
also been highlighted in an animals study [96].
4.4. Allergies and Asthma
About one generation after widespread use of BPA, childhood asthma prevalence started
increasing [
97
]. Allergies and asthma generally result from an imbalance in the Th1/Th2 ratio with a
shift towards a Th2 response [
98
]. Additionally, newborns tend to have a Th2-biased immune system,
so chemicals such as BPA that increase the Th2 response likely increase the risk for allergies and asthma
in childhood [
97
]. Immune cells involved in the pathogenesis of allergies and asthma include T cells,
mast cells, eosinophils, macrophages and B cells [
98
,
99
]. Although epidemiological studies have not
made a clear conclusion concerning BPA increasing the risk of allergy and asthma, BPA exposure likely
increases risk by altering immune cell function and cytokine production towards a Th2 response [
100
].
Animal studies using ovalbumin (OVA) to elicit an allergic immune response after either perinatal
or prenatal BPA exposure have found different results depending on the method of OVA sensitization,
sex and time of exposure. Overall, for female developmental exposure in rodents, BPA shows a
trend for increased risks of allergies and asthma after sensitization with antigen, while male rodent
offspring have a mixed response depending on the route and timing of antigen exposure (Table 3).
Human epidemiological studies tend to show increased asthma symptoms in children developmentally
exposed to BPA, but no effect on allergic responses induced by other common allergens (e.g., cat
epithelium; Table 4).
Female offspring: Airway OVA sensitization of perinatally BPA exposed female offspring
have increased lymphocytes in airways along with increased inflammation when compared to
OVA-sensitized control female offspring, but no changes in T cell subpopulations or anti-OVA IgE [
101
].
This study suggests that perinatal BPA exposure can increase the risk for asthma and allergic airway
diseases by increasing lymphocytes in airways, leading to increased lung inflammation after exposure
to aeroallergens (Figure 2A). Similarly, following a “suboptimal” peritoneal sensitization (e.g., exposing
female pups to a lower OVA dose at an earlier age), perinatal BPA exposure results in increased airway
hyperresponsiveness (AHR), bronchoalveolar lavage fluid (BALF) eosinophil and anti-OVA IgE and no
change in anti-OVA IgG1 compared to OVA-sensitized control females [
97
,
102
]. This study confirms
that developmental BPA exposure can increase female offspring’s risk for allergies and asthma after
allergen sensitization (Figure 2B).
In the above studies, increased IgE and BALF eosinophils result in AHR. In contrast, research using
a standard peritoneal sensitization procedure shows that female offspring exposed perinatally to BPA
have decreased eosinophils [
101
,
103
]. Additionally, BPA’s modulation of anti-OVA IgE is not consistent,
with increased amounts, decreased amounts and no change seen by various studies [
101
,
103
105
].
However, a trend for increased allergy and asthma risks for perinatal BPA exposed female offspring
is still seen (Figure 2C). Perinatal BPA exposure increases IFN-
γ
, activated T cells, neutrophils and
IL-13 in female offspring, which can potentially enhance an allergic response [
103
105
]. However,
whether these changes increase lung inflammation is unclear, with some studies suggesting increased
lung inflammation while others showing no change in both lung inflammation and AHR [
101
,
103
,
104
].
In summary, all three models of sensitization suggest that developmental BPA exposure increases
allergy and asthma risk in female offspring, with early exposure to allergens being the most sensitive
exposure window.
Toxics 2016,4, 23 11 of 23
Table 3. Summary of allergy/asthma animal studies on BPA exposed offspring.
OVA
Sensitization
Animal
Model/Sex
Exposure
Windows BPA Dose Routes of
Administration Diet Effects Reference
Airway
Sensitization
Male and Female
C57BL/
6 Offspring
GD6-PND21 0.5, 5, 50 or
500 µg/kg
Peanut oil
via gavage
AIN76-semi-PD1RR
chow
(phytoestrogen-free)
Increased airway lymphocytes and lung inflammation
in females; decreased airway neutrophils and lung
inflammation in males; no effect on IgE, T cell
subpopulations or BALF cytokines
[101]
“Suboptimal”
Peritoneal
Sensitization
BALB/c offspring Gestation and
Lactation 5 or 10 µg/mL
Drinking water
Phytoestrogen-free
Increased AHR, BALF eosinophils and IgE; no effect
for IgG1 [97]
BALB/c offspring Prenatal, perinatal
or postnatal 5µg/mL
Drinking water
Phytoestrogen-free
Increased AHR and BALF eosinophils from prenatal
and perinatal; no effect for postnatal only exposure [102]
Peritoneal
Sensitization
Female C57BL/
6 Offspring GD6-PND21 0.5, 5, 50 or
500 µg/kg
Peanut oil via
gavage
AIN76-semi-PD1RR
chow
(phytoestrogen-free)
Decreased airway eosinophils and IgE; no effect
on AHR [101]
Male and Female
BALB/c Offspring
Gestation and
Lactation
50 ng, 50 µg or
50 mg/kg diet In food AIN-93G
(phytoestrogen-free)
Increased IgE, IL-13 and INF-γ; decreased BALF
leukocytes, eosinophils, IL-17 and CysLTs; decreased
macrophages, PMN and lung inflammation in males;
in females only: decreased BALF IL-4, IL-13 and TNF-
α
,
increased lung RANTES and no effect on
lung inflammation
[103]
BALB/cByJ
Offspring
One week after
mating period
until birth
or PND21
5µg/mL
Drinking water
C1000
(phytoestrogen-free)
Prenatal: no effect on AHR or airway inflammation;
perinatal: increased lung inflammation, IgE and IL-13 [104]
Female Wistar
rats offspring GD15-PND21 0.5, 5 or
50 µg/kg
4% ethanol in
corn oil
via oral
Rodent Diet 2018
(<20 pmol
estrogen content)
Increased IgG, activated T cells, splenocyte proliferation,
INF-γ, neutrophils and IL-10 (colon); no effect for IgE,
Treg cells or IL-10 (spleen); decreased TGF-β(colon)
[105]
Gavage
Sensitization
Male heterozygous
offspring of
OVA-TCR-Tg
crossed
with BALB/c
Gestation and
Lactation
0, 0.1
or 1 ppm BPA In Food Not Specified
Increased IL-13, INFγ, anti-OVA IgG1 and anti-OVA
IgG2a; no change in IL-4; decreased OVA-specific T cells
and Treg response to OVA
[99]
BPA: bisphenol A; OVA: ovalbumin; GD: gestation day; PND: postnatal day; BALF: bronchoalveolar lavage fluid; AHR: airway hyperresponsiveness; CysLT: cysteinyl leukotriene;
PMN: polymorphonuclear neutrophil; Treg: T regulatory cells.
Toxics 2016,4, 23 12 of 23
Table 4. Summary of allergy/asthma epidemiological studies from BPA exposed infants/children.
Sex/Age Time of BPA Measurement BPA Measured BPA Levels
Assessed From Effects Reference
Male and Female Infants
1st Trimester 0.8 µg/L Median urine
concentration
Non-monotonic increase of TSLP, IL-33 and
IgE in cord blood [68]
Male and
Female Children
16 weeks gestation, 26 weeks
gestation and birth 2.4 µg BPA/g creatinine Median urine
concentration
Increased wheeze risk of 6 months old,
but not 3 years [106]
Male and
Female Children
3rd trimester, 3, 5 and
7 years old
1.8 ng/mL (3rd trimester),
3.8 ng/mL (3 years),
3.1 ng/mL (5 years),
2.7 ng/mL (7 years)
Median urine
concentration
Higher prenatal BPA levels inversely
correlated with wheeze at 5 years and
bronchodilator response; postnatal exposure
increased wheeze, airway inflammation and
aeroallergen sensitization at 7 years
[107]
Male and
Female Children 12 and 32 weeks gestation 2.4 µg BPA/g creatinine Median urine
concentration
Increased wheeze, respiratory tract infection
and bronchitis risk from 6 months–7 years
old; no change in atopy/IgE levels
[108]
Male and
Female Children
16 weeks gestation, 26 weeks
gestation and birth 2.4 µg BPA/g creatinine Median urine
concentration
Decreased lung function at 4 years, but not
5 years; 16 week BPA only: increased
wheeze and persistent wheeze risk
[109]
BPA: bisphenol A; TSLP: thymic stromal lymphopoietin.
Toxics 2016,4, 23 13 of 23
Toxics 2016, 4, 23 14 of 24
Figure 2. Allergy and asthma risks following developmental bisphenol A (BPA) exposure in female
rodents. (A) Increased allergic airway and asthma risks result from developmental BPA and
aeroallergen exposures; (B) increased airway hyperresponsiveness and allergy risks result from
developmental BPA and early life antigen exposures; (C) lung inflammation may result from
developmental BPA and late antigen exposures, but this is uncertain.
Male offspring: Unlike female offspring, perinatal BPA exposure has a protective effect in
airway-sensitized male offspring (Figure 3A). This is reflected by decreased airway neutrophils and
lung inflammation, with no change in T cell subpopulations, BALF cytokines or anti-OVA IgE in male
offspring exposed to BPA [101]. This study has indicated that BPA’s downregulation of neutrophils
causes the decrease in lung inflammation in this model.
Conversely, “suboptimal” sensitization results in an increased risk for allergies and asthma after
both prenatal and perinatal BPA exposure in male offspring similar to female offspring (Figure 3B).
Both increased BALF eosinophils and anti-OVA IgE increase AHR [97,102]. It seems that the
“suboptimal” model is more sensitive for BPA exposed male offspring, as similar results are also seen
in the female offspring. While the standard peritoneal sensitization shows no effect in
prenatally-exposed BPA male offspring, perinatally BPA exposed male offspring exhibit mixed
results with some studies seeing an increase in lung inflammation and inflammatory factors (e.g.,
IL-13), while others show decreased lung inflammation and inflammatory factors
(e.g., eosinophils) [103,104].
Additionally, BPA exposed male offspring show a decreased Treg response to OVA while
increased Th1 and Th2 responses, including increased IL-13, INF-γ, anti-OVA IgG1 and anti-OVA
IgG2a following OVA sensitization by gavage, suggesting increased allergy and asthma risk
(Figure 3C) [99]. These studies show that the route and timing of antigen/allergen exposure would
determine whether BPA exposed male offspring are at an increased or decreased risk for allergies
and asthma. The differences seen in the males versus the females are likely due to the differences in
hormone levels (e.g., estrogen).
Figure 2.
Allergy and asthma risks following developmental bisphenol A (BPA) exposure in
female rodents. (
A
) Increased allergic airway and asthma risks result from developmental BPA
and aeroallergen exposures; (
B
) increased airway hyperresponsiveness and allergy risks result
from developmental BPA and early life antigen exposures; (
C
) lung inflammation may result from
developmental BPA and late antigen exposures, but this is uncertain.
Male offspring: Unlike female offspring, perinatal BPA exposure has a protective effect in
airway-sensitized male offspring (Figure 3A). This is reflected by decreased airway neutrophils and
lung inflammation, with no change in T cell subpopulations, BALF cytokines or anti-OVA IgE in male
offspring exposed to BPA [
101
]. This study has indicated that BPA’s downregulation of neutrophils
causes the decrease in lung inflammation in this model.
Conversely, “suboptimal” sensitization results in an increased risk for allergies and asthma after
both prenatal and perinatal BPA exposure in male offspring similar to female offspring (Figure 3B). Both
increased BALF eosinophils and anti-OVA IgE increase AHR [
97
,
102
]. It seems that the “suboptimal”
model is more sensitive for BPA exposed male offspring, as similar results are also seen in the female
offspring. While the standard peritoneal sensitization shows no effect in prenatally-exposed BPA male
offspring, perinatally BPA exposed male offspring exhibit mixed results with some studies seeing an
increase in lung inflammation and inflammatory factors (e.g., IL-13), while others show decreased
lung inflammation and inflammatory factors (e.g., eosinophils) [103,104].
Additionally, BPA exposed male offspring show a decreased Treg response to OVA while increased
Th1 and Th2 responses, including increased IL-13, INF-
γ
, anti-OVA IgG1 and anti-OVA IgG2a
following OVA sensitization by gavage, suggesting increased allergy and asthma risk (Figure 3C) [
99
].
These studies show that the route and timing of antigen/allergen exposure would determine
whether BPA exposed male offspring are at an increased or decreased risk for allergies and asthma.
The differences seen in the males versus the females are likely due to the differences in hormone levels
(e.g., estrogen).
Toxics 2016,4, 23 14 of 23
Toxics 2016, 4, 23 15 of 24
Figure 3. Allergy and asthma risks following developmental bisphenol A (BPA) exposure in male
rodents. (A) Decreased lung inflammation results from developmental BPA and aeroallergen
exposures; (B) increased airway hyperresponsiveness and allergy risks result from developmental
BPA and early life antigen exposures; (C) increased allergy risks result from developmental BPA and
oral antigen exposures.
Epidemiological studies: Human exposure to BPA during any of the three trimesters results in
increased asthma biomarkers and symptoms (Figure 4). However, allergy sensitivities to antigens
other than aeroallergens as measured by IgE-specific seroatopy are not affected [107,108]. Higher
BPA levels result in increased TSLP, IL-33 and IgE from cord blood, which are biomarkers for
allergies and asthma development later in life [68]. Additionally, increased BPA exposure increases
asthma outcomes, including wheeze, persistent wheeze, respiratory tract infection and bronchitis, up
to the age of seven years old and decreases lung function until four years of age [108,109]. These
cohort studies suggest that asthma risk increases in children who have a higher than average prenatal
BPA exposure. Although most epidemiological studies show exacerbation of asthma symptoms from
higher prenatal BPA exposure, Donohue et al. [107] found that higher prenatal BPA levels result in a
protective effect by decreasing wheeze. The difference in asthma outcome seen from prenatal BPA
exposure by Donohue et al. [107] could be due to the cohort design differences or difference in sample
populations. However, Donohue et al. [107] also found increased risks of asthma, wheeze, airway
inflammation and aeroallergen sensitization from higher postnatal BPA levels up to seven years old.
Figure 3.
Allergy and asthma risks following developmental bisphenol A (BPA) exposure in male
rodents. (
A
) Decreased lung inflammation results from developmental BPA and aeroallergen exposures;
(
B
) increased airway hyperresponsiveness and allergy risks result from developmental BPA and
early life antigen exposures; (
C
) increased allergy risks result from developmental BPA and oral
antigen exposures.
Epidemiological studies: Human exposure to BPA during any of the three trimesters results in
increased asthma biomarkers and symptoms (Figure 4). However, allergy sensitivities to antigens
other than aeroallergens as measured by IgE-specific seroatopy are not affected [
107
,
108
]. Higher BPA
levels result in increased TSLP, IL-33 and IgE from cord blood, which are biomarkers for allergies
and asthma development later in life [
68
]. Additionally, increased BPA exposure increases asthma
outcomes, including wheeze, persistent wheeze, respiratory tract infection and bronchitis, up to the
age of seven years old and decreases lung function until four years of age [
108
,
109
]. These cohort
studies suggest that asthma risk increases in children who have a higher than average prenatal BPA
exposure. Although most epidemiological studies show exacerbation of asthma symptoms from higher
prenatal BPA exposure, Donohue et al. [
107
] found that higher prenatal BPA levels result in a protective
effect by decreasing wheeze. The difference in asthma outcome seen from prenatal BPA exposure by
Donohue et al. [
107
] could be due to the cohort design differences or difference in sample populations.
However, Donohue et al. [
107
] also found increased risks of asthma, wheeze, airway inflammation
and aeroallergen sensitization from higher postnatal BPA levels up to seven years old.
Toxics 2016,4, 23 15 of 23
Toxics 2016, 4, 23 16 of 24
Figure 4. Asthma risk increases following developmental bisphenol A (BPA) and aeroallergen
exposures in humans.
4.5. Mammary Cancer
Both the innate and adaptive immune systems play important roles for primary and recurring
mammary cancer prevention along with tumor growth and metastasis [42,43,110]. Additionally, in
utero exposure to endocrine disruptors has long-term effects on mammary tissue, and the fetal
origins of cancer hypothesis has developed from studies focusing in EDCs including BPA [111]. Most
research on developmental BPA exposure and cancers focuses on mammary cancer due to BPA’s
interaction with ERs [112,113]. However, alteration of the immune system by BPA may increase the
risk of other cancers, including an increase in hepatic adenomas, as seen by Weinhouse et al. [112].
Developmental BPA exposure can alter mammary tissue structure and development and increase
hormone responses through ERs, leading to increased risk of mammary cancer [114,115].
Additionally, prenatal and perinatal BPA exposure can alter mediators related to immunity and
defense in the mammary gland, increasing the susceptibility of mammary gland cancer cell
transformation in female offspring [114,116,117]. BPA alters mammary gland ER expression by
decreasing ERα, while increasing ERβ. Perinatal BPA exposure also decreases chemokines that
further result in decreased attraction of immune cells, such as neutrophils and lymphocytes to
mammary gland tissue to remove abnormal cells [114]. Decreased inflammation can decrease
immune defense against pre-cancerous and cancerous cells [118]. Furthermore, immune cell and
cytokine dysfunction resulting from developmental BPA exposure can increase the risk for
mammary cancer [114].
5. Bisphenol S: An Alternative for BPA
Bisphenol analogs, such as bisphenol S (BPS), have been increasing in use as BPA use decreases.
BPS was found in 81% of analyzed urine samples from the U.S. and seven Asian countries with
concentrations up to 21.0 ng/mL from a 2010–2011 study [119]. Although BPS has a widespread use,
there is a lack of research on any developmental effects on the immune system from BPS exposure.
However, BPS also seems to have a low-dose effect similar to BPA and has been found to adversely
affect neurogenesis of zebrafish and Wistar rats [120,121]. BPS can also alter gene transcription in a
human osteosarcoma cell line related to immunity (e.g., downregulating CCL2) [122]. However,
Figure 4.
Asthma risk increases following developmental bisphenol A (BPA) and aeroallergen
exposures in humans.
4.5. Mammary Cancer
Both the innate and adaptive immune systems play important roles for primary and recurring
mammary cancer prevention along with tumor growth and metastasis [
42
,
43
,
110
]. Additionally,
in utero exposure to endocrine disruptors has long-term effects on mammary tissue, and the fetal
origins of cancer hypothesis has developed from studies focusing in EDCs including BPA [
111
]. Most
research on developmental BPA exposure and cancers focuses on mammary cancer due to BPA’s
interaction with ERs [
112
,
113
]. However, alteration of the immune system by BPA may increase the
risk of other cancers, including an increase in hepatic adenomas, as seen by Weinhouse et al. [
112
].
Developmental BPA exposure can alter mammary tissue structure and development and increase
hormone responses through ERs, leading to increased risk of mammary cancer [
114
,
115
]. Additionally,
prenatal and perinatal BPA exposure can alter mediators related to immunity and defense in the
mammary gland, increasing the susceptibility of mammary gland cancer cell transformation in female
offspring [
114
,
116
,
117
]. BPA alters mammary gland ER expression by decreasing ER
α
, while increasing
ERβ. Perinatal BPA exposure also decreases chemokines that further result in decreased attraction of
immune cells, such as neutrophils and lymphocytes to mammary gland tissue to remove abnormal
cells [
114
]. Decreased inflammation can decrease immune defense against pre-cancerous and cancerous
cells [
118
]. Furthermore, immune cell and cytokine dysfunction resulting from developmental BPA
exposure can increase the risk for mammary cancer [114].
5. Bisphenol S: An Alternative for BPA
Bisphenol analogs, such as bisphenol S (BPS), have been increasing in use as BPA use decreases.
BPS was found in 81% of analyzed urine samples from the U.S. and seven Asian countries with
concentrations up to 21.0 ng/mL from a 2010–2011 study [
119
]. Although BPS has a widespread
use, there is a lack of research on any developmental effects on the immune system from BPS
exposure. However, BPS also seems to have a low-dose effect similar to BPA and has been found
to adversely affect neurogenesis of zebrafish and Wistar rats [
120
,
121
]. BPS can also alter gene
transcription in a human osteosarcoma cell line related to immunity (e.g., downregulating CCL2) [
122
].
Toxics 2016,4, 23 16 of 23
However, research on developmental BPS exposure’s effects on the immune system is needed to draw
a conclusion.
6. Discussion
BPA alteration of the immune response varies by exogenous and endogenous factors, such as
diet, estrogen levels and genetic differences [
95
,
96
]. This can result in a Th1 or Th2 shift, although a
Th1 shift towards a pro-inflammatory response is more likely. BPA reduction of Treg cells is likely
one of the main reasons that both Th1 and Th2 cells can increase from BPA exposure, which can lead
to altered immune function and disease development. BPA can also increase the risk for diseases by
reducing the number of APCs, such as macrophages. Moreover, studies performed after weaning
when BPA was no longer present have shown the lasting alteration of immune function.
BPA’s main mechanisms of immunomodulation and disease development are through interactions
with both nuclear and non-nuclear receptors, but primarily ERs and ERRs. Additionally, developmental
BPA exposure can alter gene transcription through epigenetic mechanisms and likely also alters
transcription and translation of genes related to the immune system. More research examining
the effect from developmental exposure to BPA on the epigenome with relation to immunity is
needed. A third possible mechanism of immunomodulation is via interaction with microbes in the
gut microbiome. The importance of the gut microbiota in immunity and disease has been emerging
recently. There have yet to be any studies examining if BPA alters the gut microbiota causing dysbiosis.
Due to the close proximity of the GALT and gut microbiota, dysbiosis may also be a mechanism of
developmental BPA exposure in immunomodulation, though no conclusions can be made yet.
Alteration of the immune system may result in neurological diseases from BPA exposure due to its
ability to cross the BBB. There is some research relating BPA’s effect on multiple sclerosis, but the results
show either no effect (in the T helper cell-mediated disease model) or an exacerbated effect (in the
macrophage-mediated disease model). These studies indicate that primary immune cells mediating
this disease in humans affect whether BPA can exacerbate multiple sclerosis. More studies are needed
to understand the etiology of MS.
Diabetes is another diverse disease, the immune alterations of which can increase the risk for
both type 1 and type 2 diabetes. BPA exacerbated T1D development in prenatally-exposed females.
This effect was due to BPA reducing macrophage cells,
β
-cells and
α
-cells, which all result in increased
T1D risk. However, the increased risk seen in females was only at a high dose not as relevant for
human exposure and only observed at a more relevant dose when BPA exposure was throughout life.
In addition, whether males are at risk has not yet been researched. As for T2D, an increased risk has
been shown for T2D development after prenatal and perinatal exposure to BPA in male offspring and
in both sexes on a high-fat diet. While females did not show an increase for T2D risk in the absence of a
high-fat diet, feeding a high-fat diet models human T2D development better than from genetic diversity
alone [
123
]. BPA’s increase of T2D risk results from an increase in a pro-inflammatory response and
dysregulated β-cell function, which produces insulin resistance, further increasing diabetes risk.
As for asthma and allergy development after developmental BPA exposure, BPA likely increases
asthma risk. However, allergy risk seems to only increase in rodent studies and not in epidemiological
studies. Furthermore, developmental BPA exposure has a protective effect on lung inflammation
in male rodent offspring, which indicates a protection against asthma and allergic airway diseases.
This was opposite from male children, which had increased asthma symptoms. The differences
are likely due to the differences in the species, such as genetics and hormone concentrations.
Developmental BPA also can increase cancer risk for different cancers, including mammary cancer
and liver cancer, by altering the immune and inflammatory response. However, it should be noted
that, unlike studies using other disease models, the inflammatory response was decreased from
developmental BPA exposure in the cancer models used. This may be due to BPA producing its
cancer-promoting effects through the STAT3 pathway [
47
], which upregulates Foxp3
+
Treg cells and
downregulates the Th1 inflammatory response in the tumor microenvironment [42].
Toxics 2016,4, 23 17 of 23
In conclusion, BPA alteration of the immune system after prenatal and perinatal exposure has
been shown to result in a shift in the response of T helper cells. This can lead to neurological and
autoimmune diseases. However, there is still a paucity of research on the final disease outcome
from developmental BPA exposure for many diseases, and this warrants further study due to BPA’s
known immune effects. In addition, the changes in the immune system and increased risk for different
diseases from developmental BPA exposure might also be a concern for BPS. BPA analogs such as
BPS have been increasing as BPA decreases in manufacturing. However, little is known about the
immunomodulatory effects of BPS, which is a concern considering the increasingly widespread use of
BPS, and more research is needed.
Acknowledgments: This study was supported by R21ES24487.
Author Contributions:
Joella Xu prepared the manuscript; Guannan Huang performed literature search, edited
the manuscript and participated in the discussion; Tai L. Guo engaged in the design of the chapter, edited the
manuscript and participated in the discussion.
Conflicts of Interest: There are no conflicts of interest to declare.
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2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access
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... It can bind to oestrogen receptors, oestrogen-related receptors, aryl hydrocarbon receptors and peroxisome proliferator-activated receptors (Acconcia et al. 2015). Owing to its ability to interact with many types of receptors, BPA has a wide impact on immune system regulation (Xu et al. 2016). Regarding the impact of BPA on the immune/allergic system, an epidemiological study showed that prenatal exposure to BPA was associated with paediatric respiratory outcomes among boys but not girls (Buckley et al. 2018). ...
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Allergic diseases are increasing worldwide, and their precise causes are not fully understood. However, this observation can be correlated with growing chemical pollution of the environment. Bisphenol A (BPA) alters the immune system, microbiota and barrier functions. Here, we studied the effect of oral BPA at levels equivalent to human exposure to understand the mechanisms of immunological, physiological and microbial action on food allergies. In a murine model of allergy, we evaluated the effect of direct oral exposure to BPA at 4 µg/kg bw/d corresponding to tolerable daily intake (TDI). We studied symptoms, intestinal physiology and humorall and cellular immune responses during food allergy. We explored the relationship between oral exposure to BPA and changes in the gut microenvironment. Markers of food allergy and intestinal permeability were increased following exposure to BPA. We also observed a modulated humorall and T-cell response with aggravation of food allergy inflammation. Moreover, BPA exposure induced gut dysbiosis and decreased microbial diversity induced by food allergy. Altogether, these results suggest that the 2015 European Food Safety Authority (EFSA) TDI should be reviewed to consider the immunotoxicity of BPA.
... Exposure of BPA can occur as early as during gestation, according to reports of BPA presence in amniotic fluid, fetal serum, and breast milk [20,21]. In this regard, there is an existing concern about the effects that BPA could exert on a developing organism, including the immune system [22][23][24]. Several studies indicate that estrogen and progesterone stimulate the expression of the vascular endothelial growth factor (VEGF) in breast cancer and tumors [25]. ...
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... The data also suggest that human exposure to BPA elevate the risk of obesity, diabetes, and heart diseases [102,126]. BPA binds to various receptors, which regulate transcription factors, produce epigenetic alterations, impact glucose metabolism, initiation, and progression of numerous cancers, alter immunological functions, gut microbiome, and damage to genetic material [4,89,128]. Low concentration of BPA cause problems related to reproduction, immune system modulation, hormone-dependent malignancies, and metabolism [81]. ...
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Bisphenol A (BPA) environmental exposure during the life stage of an organism can influence immune cell development and may cause disease in later life. The harmful health impacts of BPA exposure pinpoint multiple mechanisms for BPA-induced toxicity, further exacerbated by reports of a biphasic response. BPA exposure and its chronic negative consequences, as well as their links to endocrine disruption and epigenetic changes, reveal that shifts in DNA methylation patterns, histone modifications, and microRNA alteration modify the epigenome in a tissue-specific manner. BPA has immunotoxic properties observed during in vitro and in vivo studies. It is reported that BPA exhibits adverse health effects due to immunotoxicity, which may lead to immune disorders. In vitro and in vivo study confirms that bisphenol impairs both innate and adaptive immune mechanism which in turn interferes with cellular and humoral activities. The present review focus upon BPA mediated disturbances in the immune system including immune cells development, inflammation, its related pathways and ability to impair mature immune system.
... Down regulation of Regulatory T cells and upregulation of cytokines was observed upon exposure to BPA. Onset of type 1 diabetes in females and deferred onset of diabetes in males are due to immune function stimulated by BPA (Xu et al., 2019(Xu et al., , 2016. Decrease in pro-inflammatory gut microbiome and anti-inflammation factors was observed in males and females. ...
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Macrophages are critical mediators of inflammation and important regulators of developmental processes. As a key phagocytic cell type, macrophages evolved as part of the innate immune system to engulf and process cell debris and pathogens. Macrophages produce factors that act directly on their microenvironment and also bridge innate immune responses to the adaptive immune system. Resident macrophages are important for acting as sensors for tissue damage and maintaining tissue homeostasis. It is now well-established that macrophages are an integral component of the breast tumor microenvironment, where they contribute to tumor growth and progression, likely through many of the mechanisms that are utilized during normal wound healing responses. Because macrophages contribute to normal mammary gland development and breast cancer growth and progression, this review will discuss both resident mammary gland macrophages and tumor-associated macrophages with an emphasis on describing how macrophages interact with their surrounding environment during normal development and in the context of cancer.
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One of the major disappointments in human autoimmunity has been the relative failure on genome-wide association studies to provide "smoking genetic guns" that would explain the critical role of genetic susceptibility to loss of tolerance. It is well known that autoimmunity refers to the abnormal state that the dysregulated immune system attacks the healthy cells and tissues due to the loss of immunological tolerance to self-antigens. Its clinical outcomes are generally characterized by the presence of autoreactive immune cells and (or) the development of autoantibodies, leading to various types of autoimmune disorders. The etiology and pathogenesis of autoimmune diseases are highly complex. Both genetic predisposition and environmental factors such as nutrition, infection, and chemicals are implicated in the pathogenic process of autoimmunity, however, how much and by what mechanisms each of these factors contribute to the development of autoimmunity remain unclear. Epigenetics, which refers to potentially heritable changes in gene expression and function that do not involve alterations of the DNA sequence, has provided us with a brand new key to answer these questions. In the recent decades, increasing evidence have demonstrated the roles of epigenetic dysregulation, including DNA methylation, histone modification, and noncoding RNA, in the pathogenesis of autoimmune diseases, especially systemic lupus erythematosus (SLE), which have shed light on a new era for autoimmunity research. Notably, DNA hypomethylation and reactivation of the inactive X chromosome are two epigenetic hallmarks of SLE. We will herein discuss briefly how genetic studies fail to completely elucidate the pathogenesis of autoimmune diseases and present a comprehensive review on landmark epigenetic findings in autoimmune diseases, taking SLE as an extensively studied example. The epigenetics of other autoimmune diseases such as rheumatic arthritis, systemic sclerosis and primary biliary cirrhosis will also be summarized. Importantly we emphasize that the stochastic processes that lead to DNA modification may be the lynch pins that drive the initial break in tolerance.
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This review highlights some of the advances in mechanisms of allergic disease, particularly anaphylaxis, including food allergy, drug hypersensitivity, atopic dermatitis (AD), allergic conjunctivitis, and airway diseases. During the last year, a mechanistic advance in food allergy was achieved by focusing on mechanisms of allergen sensitization. Novel biomarkers and treatment for mastocytosis were presented in several studies. Novel therapeutic approaches in the treatment of atopic dermatitis and psoriasis showed that promising supplementation of the infant's diet in the first year of life with immunoactive prebiotics might have a preventive role against early development of AD and that therapeutic approaches to treat AD in children might be best directed to the correction of a TH2/TH1 imbalance. Several studies were published emphasizing the role of the epithelial barrier in patients with allergic diseases. An impaired skin barrier as a cause for sensitization to food allergens in children and its relationship to filaggrin mutations has been an important development. Numerous studies presented new approaches for improvement of epithelial barrier function and novel biologicals used in the treatment of inflammatory skin diseases. In addition, novel transcription factors and signaling molecules that can develop as new possible therapeutic targets have been reported.
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Bisphenol-A (BPA) is a ubiquitous estrogen-like endocrine disrupting compound (EDC). BPA exposure in utero has been linked to breast cancer and abnormal mammary gland development in mice. The recent rise in incidence of human breast cancer and decreased age of first detection suggests a possible environmental etiology. We hypothesized that developmental programming of carcinogenesis may involve an aberrant immune response. Both innate and adaptive immunity play a role in tumor suppression through cytolytic CD8, NK, and Th1 T-cells. We hypothesized that BPA exposure in utero would lead to dysregulation of both innate and adaptive immunity in the mammary gland. CD1 mice were exposed to BPA in utero during gestation (days 9-21) via osmotic minipump. At 6 weeks, the female offspring were ovariectomized and estradiol was given at 8 weeks. RNA and protein were extracted from the posterior mammary glands, and the mRNA and protein levels were measured by PCR array, qRT-PCR, and western blot. In mouse mammary tissue, BPA exposure in utero significantly decreased the expression of members of the chemokine CXC family (Cxcl2, Cxcl4, Cxcl14, and Ccl20), interleukin 1 (Il1) gene family (Il1β and Il1rn), interleukin 2 gene family (Il7 receptor), and interferon gene family (interferon regulatory factor 9 (Irf9), as well as immune response gene 1 (Irg1). Additionally, BPA exposure in utero decreased Esr1 receptor gene expression and increased Esr2 receptor gene expression. In utero exposure of BPA resulted in significant changes to inflammatory modulators within mammary tissue. We suggest that dysregulation of inflammatory cytokines, both pro-inflammatory and anti-inflammatory, leads to a microenvironment that may promote disordered cell growth through inhibition of the immune response that targets cancer cells.
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CD4+ T cells are crucial for directing appropriate immune responses during host defense and for the pathogenesis of inflammatory diseases. In addition to the classical biphasic model of differentiation of T-helper 1 (Th1) and Th2 cells, unexpected increases in the numbers of CD4+ T cell subsets, including Th17, Th9, T follicular-helper (Tfh) and T-regulatory (Treg) cells, have been recognized. In the present review, we focus on how these various T-helper cell subsets contribute to the pathogenesis of immune-mediated inflammatory diseases. In particular, we focus on multiple sclerosis, psoriasis and asthma as typical model diseases in which multiple T-helper cell subsets have recently been suggested to play a role. We will also discuss various unique subpopulations of T-helper cells that have been identified. First, we will introduce the heterogeneous T-helper cell subsets, which are classified by their simultaneous expression of multiple key transcription factors. We will also introduce different kinds of memory-type Th2 cells, which are involved in the pathogenesis of chronic type-2 immune related diseases. Finally, we will discuss the molecular mechanisms underlying the generation of the plasticity and heterogeneity of T-helper cell subsets. The latest progress in the study of T-helper cell subsets has forced us to reconsider the etiology of immune-mediated inflammatory diseases beyond the model based on the Th1/Th2 balance. To this end, we propose another model — the pathogenic T-helper population disease-induction model — as a possible mechanism for the induction and/or persistence of immune-mediated inflammatory diseases.
Article
Background: Despite widespread human exposure to biphenol A (BPA), limited studies exist on the association of BPA with adverse health outcomes in young children. This study aims to investigate the effect of prenatal exposure to BPA on toll-like receptor -induced cytokine responses in neonates and its association with infectious diseases later in life. Methods: Cord bloods were collected from 275 full-term neonates. Production of TNF-α, IL-6, and IL -10 were evaluated after stimulating mononuclear cells with toll-like receptor ligands (TLR1-4 and 7-8). Serum BPA concentrations were analyzed by ELISA. Bacteria from nasopharyngeal specimens were identified with multiplex PCR and culture method. Result: Result showed significant association between cord BPA concentration and TLR3 and TLR4 stimulated TNF-α response (p = 0.001) and that of TLR7-8 stimulated IL-6 response (p = 0.03). Clinical analysis did not show prenatal BPA exposure to be correlated with infection or bacterial colonization during the first year of life. Conclusion: This is the first cohort study that indicated prenatal BPA exposure to play a part in TLR- related innate immune response of neonatal infants. However, despite an altered immune homeostasis, result did not show such exposure to be associated with increased risk of infection during early infancy.Pediatric Research (2015); doi:10.1038/pr.2015.234.
Article
Context: Epidemiology studies showed inconsistent results about the relationship between Bisphenol A (BPA) exposure and risk of type 2 diabetes (T2D). Objective: To prospectively investigate associations of BPA with incident T2D risk and the longitudinal changes in glycemic traits; particularly examine the interaction between gene and BPA exposure on the associations. Design, setting and participants: A community-based study was conducted at baseline in 2009, including 2209 non-diabetic middle-aged and elderly subjects followed up for 4 years. Urinary BPA levels were measured at baseline. A genetic risk score (GRS) based on 34 T2D common variants that identified and validated in East Asians was created. Main outcome measures: Incident T2D was defined according to the 1999 WHO criteria. Fasting and 2h post-loading plasma glucose (FPG and 2h-PPG) were measured at baseline and follow-up. Results: Multivariable logistic regression analysis demonstrated no significant association of risk of incident T2D with BPA; while with increase in the weighted T2D-GRS (odds ratio [OR] = 1.89, 95% confidence interval [CI], 1.31-2.72 for each 10-points increment). Similar results were found in 4-year changes of FPG and 2h-PPG. The GRS modified the effect of BPA exposure on 4-year changes in FPG (P for interaction = 0.01). Each 1-unit of log-BPA was associated with 0.1mmol/L increase in FPG (P = 0.007) in the highest quartile of GRS; no associations were found in the lower 3 quartiles of GRS. Conclusions: The T2D genetic susceptibility significantly modulated the association of BPA exposure with longitudinal increase in FPG levels.