Role of the Arylhydrocarbon Receptor (AhR) in the Pathology of Asthma and COPD

Department of Dermatology, Graduate School of Medical Sciences, Kyushu University School of Medicine, 3-1-1, Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan.
Journal of Allergy 01/2012; 2012:372384. DOI: 10.1155/2012/372384
Source: PubMed
ABSTRACT
The dioxins and dioxin-like compounds in cigarette smoke and environmental pollutants modulate immunological responses. These environmental toxicants are known to cause lung cancer but have also recently been implicated in allergic and inflammatory diseases such as bronchitis, asthma, and chronic obstructive pulmonary disease (COPD). In a novel pathway of this response, the activation of a nuclear receptor, arylhydrocarbon receptor (AhR), mediates the effects of these toxins through the arachidonic acid cascade, cell differentiation, cell-cell adhesion interactions, cytokine expression, and mucin production that are implicated in the pathogenesis and exacerbation of asthma/COPD. We have previously reported that human bronchial epithelial cells express AhR, and AhR activation induces mucin production through reactive oxygen species. This review discusses the role of AhR in asthma and COPD, focusing in particular on inflammatory and resident cells in the lung. We describe the important impact that AhR activation may have on the inflammation phase in the pathology of asthma and COPD. In addition, crosstalk of AhR signaling with other ligand-activated transcription factors such as peroxisome proliferator-activated receptors (PPARs) has been well documented.

Full-text

Available from: Takahito Chiba
Hindawi Publishing Corporation
Journal of Allergy
Volume 2012, Article ID 372384, 8 pages
doi:10.1155/2012/372384
Review A rticle
Role of the Arylhydrocarb on Receptor (AhR) in the Pathology of
Asthma and COPD
Takahito Chiba,
1
Junichi Chihara,
2
and Masutaka Furue
1, 3
1
Department of Dermatology, Graduate School of Medical Sciences, Kyushu University School of Medicine, 3-1-1, Maidashi,
Higashi-Ku, Fukuoka 812-8582, Japan
2
Department of Clinical and Laboratory Medicine, Akita University School of Medicine, Akila 010-8502, Japan
3
Research and Clinical Center for Yusho and Dioxin, Kyushu University Hospital, Fukuoka 812-8582, Japan
Correspondence should be addressed to Takahito Chiba, allheartakita@yahoo.co.jp
Received 17 September 2011; Accepted 18 October 2011
Academic Editor: Brian Oliver
Copyright © 2012 Takahito Chiba et al. This 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.
The dioxins and dioxin-like compounds in cigarette smoke and environmental pollutants modulate immunological responses.
These environmental toxicants are known to cause lung cancer but have also recently been implicated in allergic and inflammatory
diseases such as bronchitis, asthma, and chronic obstructive pulmonary disease (COPD). In a novel pathway of this response,
the activation of a nuclear receptor, arylhydrocarbon receptor (AhR), mediates the eects of these toxins through the arachidonic
acid cascade, cell dierentiation, cell-cell adhesion interactions, cytokine expression, and mucin production that are implicated in
the pathogenesis and exacerbation of asthma/COPD. We have previously reported that human bronchial epithelial cells express
AhR, and AhR activation induces mucin production through reactive oxygen species. This review discusses the role of AhR in
asthma and COPD, focusing in particular on inflammatory and resident cells in the lung. We describe the important impact
that AhR activation may have on the inflammation phase in the pathology of asthma and COPD. In addition, crosstalk of AhR
signaling with other ligand-activated transcription factors such as peroxisome proliferator-activated receptors (PPARs) has been
well documented.
1. Introduction
Both allergic asthma and COPD are defined as airway
inflammatory diseases; however, the inflammatory mech-
anism is dierent for each disease. Nocuous agents such
as PCBs, B[a]P, and dioxin-like compounds in cigarette
smoke and environmental pollutants have the potential
to induce inflammation or exacerbate chronic bronchitis,
asthma, COPD, and lung cancer [14]. In addition to airway
epithelial cells, many inflammatory cells, including Th2 cells,
eosinophils, and basophils, play a major pathophysiological
role in asthma and COPD [58]. Cigarette smoke and
environmental pollutants activate these inflammatory cells,
and they contribute to the activation of growth factors and
cytokines. For example, exposure to some types of noxious
agents increases the rate of TGF-α,TGF-β,IL-1β,IL-6,IL-
8, and IFN-γ gene expression [912]. While the molecular
signaling mechanism for this transcriptional modulation of
cytokines remains to be determined, it has been recently
recognized that these eects are mainly mediated through
the binding of noxious agents to the AhR. All major human
cell types express AhR, including pulmonary tissue [13, 14].
The liver, adipose tissue, and skin are the major storage sites
of AhR ligands in humans [15]. These AhR ligands are also
concentrated in bronchial epithelial cells, suggesting that the
respiratory s ystem is sensitive to AhR ligands [16].
The AhR is a ligand-activated transcription factor, and
after ligation of dioxins to the AhR, the receptor translocates
from the cytosol to the nucleus, where it heterodimerizes
with the ARNT. It then binds to a DRE, an enhancer sequence
of several drug-metabolizing enzymes, such as CYP1A1 [17].
AhR-induced CYP1A1 activation is important for detoxica-
tion. CYPs convert B[a]P and dioxin-like compounds into
physiologic metabolites that exert e ects on cell growth,
dierentiation, and migration. A number of researchers have
demonstrated the molecular aspects of the AhR pathway by
using selective agonists such as TCDD or B[a]P among PAHs.
Page 1
2 Journal of Allergy
In this review article, we summarize cur rent findings
regarding the functional role of AhR molecules in airway
inflammation and focus on bronchial epithelial cells, fibrob-
lasts, granulocytes, and lymphocytes. Understanding the
eects of AhR on these cells would be a breakthrough in our
understanding of the pathology and treatment of asthma and
COPD.
2. Airway Inflammatory Effect through
AhRActivationinAsthmaandCOPD
2.1. Airway Epithelial Cells. Airway epithelial cells are able to
modify allergic airway inflammation by virtue of their ability
to produce a variety of inflammatory mediators [18, 19]. One
such mediator is the moderate bronchial mucin-containing
mucus, which normally protects the airway from exogenous
substances. Hypermucosis in the airway, however, is asso-
ciated with several respiratory diseases, including asthma
and COPD. Mucus hypersecretion in the airway increases
coughing and expectoration of sputum. Clara cells in the
airway can secrete a wide var iety of glycoproteins, such as
mucins and SP-D, and are ver y sensitive to AhR stimulation
[20, 21]. Wong et al. recently have reported TCDD, an AhR
agonist, increased expression of inflammatory cytokines,
MUC5AC, and MMPs via AhR signaling in a Clara-cell-
derived cell line [21]. Mucus production is typically mediated
by cytokine or lipid mediator release, or an increase of ROS
[2224]. Studies using AhR agonists and inhibitors have
demonstrated that AhR activation induces the production
of cytokines such as TGF-α,TNF-α, and MMP through
receptors in human hematocytes and epithelial cells [21, 25
27]. Wong et al. also reported an increase of COX-2 and IL-
1β mRNA expression in response to AhR activation [21]. The
production of prostanoids such as PGE
2
, which is derived
from COX-2, can activate mucin production in the airway
[22]. Although prostaglandins derived from COX-2 pathway
activation may be responsible for AhR-induced mucin
production in the bronchial epithelial cells, the mechanism
of their action remains to be determined. Therefore, it is of
paramount interest to investigate the mechanism by which
AhR activation induces mucin production. In an earlier
study, we reported findings similar to those by Wong et
al. In our study, we found that AhR activation upregulates
the expression of MUC5AC and mucin secretion in a NCI-
H292 cell line that was derived from a bronchiolar Clara
cell [14](Figure 1). Moreover, we concurrently showed that
AhR activation induced ROS generation, and the antioxidant
agent NAC inhibited B[a]P-induced MUC5AC upregulation.
Kopf and Walker also demonstrated that TCDD-induced
AhR ac tivation increased ROS levels in endothelial cells [29].
Another prostaglandin, PGD
2,
is synthesized from arachi-
donic acid via the catalytic ac tivities of COX in epithelial
cells and mast cells. It is released into the airway follow ing
an antigen challenge during an acute allergic response [30].
PGD
2
induces chemotaxis of Th2 cells, eosinophils, and
basophils as a consequence of the activation of its receptors
[31]. This suggests that PGD
2
promotes inflammation in
allergic asthma. Prostaglandins that are derived from COX-
2 pathway activation and ROS that are induced by AhR
B[a]P (μM)
Relative expression
10
0
0.01 0.1 1 1 1 1
(
)
(
)()()()
∗∗
()
0.01 0.1 11
Resveratrol
(μM)
MUC 5 AC mRNA
Figure 1: Eects of AhR agonist B[a]P on MUC5AC mRNA level in
NCI-H
292
after 12 h of incubation. MUC5AC was measured by real-
time RT-PCR. B[a]P induced MUC5AC mRNA expression in dose-
dependent manner. Pretreatment with AhR antagonist, resveratrol,
inhibited AhR-induced MUC5AC upregulation. Data are expressed
as means
± SD (n = 6).
P
< 0.05 versus control (medium alone).
∗∗
P
< 0.05 versus B[a]P 1 μM.
activation are the major inflammatory mediators capable of
inducing mucin production, inflammatory cell chemotaxis,
or inflammatory cell activation. Therefore, increased levels
of prostaglandins and ROS, either directly or through the
formation of lipid peroxidation products, may enhance the
inflammatory response in both asthma and COPD.
Neutrophils isolated from peripheral blood and BAL
fluid of asthmatic patients generate more ROS than cells
from normal patients. Additionally, the production of ROS
correlates with the degree of airway hyperresponsiveness
[32, 33]. Neutrophils and macrophages are also known to
migrate into the lungs of COPD patients [34, 35]. Indeed,
the neutrophils that mediate ROS-induced injury to the
airway epithelium are responsible for hyperresponsiveness in
human peripheral airways, suggesting that neutrophils play
an important role in the pathogenesis of asthma a nd COPD
[36]. AhR-derived inflammatory mediators in airway epithe-
lial cells, such as IL-8 and l eukotriene B4, may have a chemo-
tactic eect. We previously confirmed that normal human
epidermal keratinocytes (NHEKs) enhanced IL-8 production
through AhR activation [37](Figure 2). Martinez et al.
demonstrated that IL-8 gene expression was upregulated by
TCDD in A549 cells from a bronchial epithelial cell line
[38]. However, the y could not detect IL-8 production at
the protein level in airway epithelial cells. We were also
unable to detect IL-8 production from AhR-activation in
NCI-H292 cells using ELISA analysis (data not shown).
Although it is not clear that AhR directly modulates NF-κB,
the induction of a transcription factor for IL-8, tumor
necrosis factor, or IL-1β by AhR activation might impact IL-8
production in airway epithelial cells [21, 25, 26, 39].
Cell-cell contact molecules in the airways create a barrier
that plays an important role in the defense against bacteria.
Page 2
Journal of Allergy 3
0
300
200
100
IL-8 production (pg/mL)
20 nM 40 nM 100 nM 1 μM 10 μM
B[a]P
(
)
Figure 2: Normal human epidermal keratinocytes (NHEKs) were
exposed to B[a]P at various concentrations for 24 h, and IL-8
production in the culture supernatant was measured. B[a]P induced
IL-8 production in a dose-dependent manner. Data are expressed as
means
± SD (n = 3).
P
< 0.05 versus control (medium alone).
Loss of expression of cell-cell contact molecules, such as E-
cadherin, reduces the ability of epithelial cells to function
as a barrier and may increase the allergic response and
susceptibility to infection. Indeed, E-cadherin and α-catenin
interacted with cytosolic domain of the cadherin expression
are significantly lower in asthmatic than in nonasthmatic
subjects [40]. AhR also regulates the expression of adhe-
sion molecules and consequently controls cell-cell contact.
Exposure to TCDD from a human breast cancer cell line
downregulates E-cadherin expression [41]. Using rat liver
epithelial cells, Diet rich et al. demonstrated that TCDD
exposure inhibits the expression of γ-catenin, which links E-
cadherin to actin filaments [42]. We hypothesize that several
pathways may be involved in the production of inflammatory
cytokines and mucus in asthma and COPD, as illustrated in
Figure 3.
2.2. Fibroblast or Airway Smooth Muscle. Chronic asthmatic
patients w ho are unresponsive to treatment experience
progressive and irreversible changes in pulmonary function.
These changes, known as “airway remodeling, are associated
with structural alterations, such as subepithelial fibrosis,
smooth muscle or goblet cell hyperplasia, and airway hyper-
responsiveness [43]. In chronic asthma patients, fibrosis is
due to increased deposition of extracellular matrix. Increases
in airway smooth muscle mass are thought to be caused by
faster proliferation, mitogenic, or inflammatory stimuli [44].
Some of the factors contributing to these eects are TGF,
FGF, EGF, and PDGF. TGF-β is one of these contributors and
is a major eector cytokine that can increase deposition by
fibroblasts and airway smooth muscle hypert rophy. Guo et al.
reported that levels of RNA for TGF-β2andTGF-β2-related
genes increased in AhR-knockout smooth muscle cells [45].
This suggests that AhR may repress the TGF-β- signaling
pathway, resulting in an anti-inflammatory eect unlike
in rodent lung cells. On the other hand, cigarette smoke,
via AhR, can induce cyclooxygenase and PGE
2
in human
lung fibroblasts [46]. PGE
2
significantly enhances cigarette
smoke extract-treated neutrophil chemotaxis and adhesion
to airway epithelial cells [47]. In fact, the concentration
of PGE
2
in the sputum of COPD patients is correlated
with the number of infiltrating neutrophils [ 47]. Neutrophil
activation through AhR signaling plays a causal role in
pathogenesis and exacerbation of COPD.
2.3. Granulocytes with Focus on Eosinophils. Eosinophils play
an essential role in the pathology of asthma because they
contribute to tissue injury, vascular leakage, mucus secre-
tion, and tissue remodeling by releasing cytotoxic granule
proteins, ROS, and lipid mediators [48]. Because eosinophils
are the final eector cells in allergic inflammation, it is
important to study the process by w hich nuclear receptors,
such as AhR, activate eosinophils in order to understand
the pathogenesis of allergic diseases. For example, PPARs
are among the important ligand-activated transcription
factors that regulate the expression of genes involved in
many cellular functions, including dierentiation, immune
responses, and inflammation [49, 50]. The PPAR subfamily
consists of 3 isotypes: PPARα,PPARβ/δ,andPPARγ,allof
which have been identified in eosinophils. These nuclear
receptors form heterodimers with retinoid X receptors, bind
to a specific DNA sequence (PPRE), and activate target gene
transcription. In vivo and in vitro evidence suggests that
PPARα and PPARγ expression in granulocytes and dendritic
cells plays a critical role as an inflammatory suppressive
regulator in allergic diseases. Treatment with the PPARγ
agonist, rosiglitazone, decreases the clinical severity of skin
lesions in atopic dermatitis and airway inflammation in
asthmatic patients [51, 52]. We previously demonstrated
that the PPARγ agonist troglitazone reduced IL-5-stimulated
eosinophil survival, eotaxin-directed eosinophil chemotaxis,
and f unctional augmentation of eosinophil adhesion in a
concentration-dependent manner. These changes occurred
without reducing the quantitative expression of β2 integrins
[53, 54](Figure 4). It has been lately shown that PPARγ
induction is suppressed during the activation of the AhR
by TCDD [55]. In addition, Cho et al. demonstrated
that CYP1B1 upregulation induced the inhibition of AhR
expression in 10T1/2 cells derived from preadipocyte lines.
Moreover, the reduced AhR expression was accompanied by
an increase in P PARγ expression [56]. These results suggest
that the AhR signal may repress migration, degranulation,
and cellular adhesion of eosinophils. This may impair the
antiallergic eects induced by PPARγ.Wewereabletocon-
firm AhR expression in human eosinophils using RT-PCR
(data not shown). Clarification of the interaction between
AhR and PPARγ signals should broaden our understanding
not only of the functional role of eosinophils but also of
asthma regulation.
2.4. Lymphocytes. Allerg ic asthma is associated with dis-
ruption of the immune system, particularly an imbalance
of Th1 and Th2 cells. It is well known that Th2 cells
play a key role in the regulation of inflammatory reactions
through the release of Th2 cytokines. AhR is known to exert
an influence on allergic immunoregulation. In fact, Tauchi
et al. reported that mice with constitutive AhR activation
Page 3
4 Journal of Allergy
B[a]P
TCDD
Dioxins
AhR
DRE
CYP1
Arnt
Transcription
AhR
Arnt
Onset and/or exacerbation
of asthma or COPD
Airway epithelial cells
MMPs
ROS
COX
Arachidonic acid
Mucin
production
downregulation?
PGE
2
NF-κB
E-cadherin
IL-8
TNF-α?
TGF-α?
Figure 3: Schematic diagram of the proposed crosstalk AhR-signaling pathway and inflammatory eects in airway epithelial cells.
0
100
Troglitazone
3 30 3000
50
Eotaxin (10 nM)
(μM)
(+)
(+)
(+)
(+)
IL-5 (
)
IL-5 (+)
Eotaxin-stimulated cells (%)
(a)
0
3 30 300
0
50
Troglitazone
(μM)
IL-5 (
)
IL-5 (+)
Annexin + PI-cells (%)
(b)
Figure 4: (a) Eect of PPARγ agonist troglitazone on eosinophil chemotaxis stimulated with eotaxin. Purified eosinophils were preincubated
with increasing concentrations of troglitazone for 1 h. Migration assays were performed using Boyden chambers. Chemotactic response to
eotaxin alone was considered to be 100%, and reactions to lower concentrations are presented relative to eotaxin alone. Data are expressed
as mean
± SD. Troglitazone inhibited the eotaxin-directed eosinophil chemotaxis in a dose-dependent manner (n = 4).
P
< 0.05
versus eotaxin alone. (b) Eect of troglitazone on eosinophil survival determined by staining with Annexin V-FITC and propidium iodine.
Eosinophils were incubated with and w ithout troglitazone in the presence of 1 ng/mL IL-5 for 48 h. Eosinophils were treated with Annexin
V to stain early-phase apoptotic cells and with propidium iodine (PI) to stain the late-phase cells. The bar graph shows a dose-dependent
eect of troglitazone on IL-5-induced eosinophil survival (n
= 4). Data are expressed as mean ± SD.
P
< 0.05 versus without troglitazone.
Page 4
Journal of Allergy 5
developed severe skin lesions that were similar to the lesions
seen in atopic dermatitis. The lesions were accompanied by
high ser u m levels of IgE and increased production of IL-
4 and IL-5 from stimulated splenic lymphocytes [57]. In
addition, AhR expression in splenic B cells was enhanced
by the presence of lipopolysaccharide, which is known to
exacerbate asthma and COPD [58]. PAH and TCDD increase
IgE production in cocultures with purified B cells [59]. These
results provide further evidence that AhR may play a complex
role in the humoral immunological balance in airway allergic
pathogenesis.
Th17 cells have been recently classified as a subtype
of helper T cells that are characterized by the production
of IL-17 [60]. AhR activation promotes the development
of Th17 cells and results in increased pathology in animal
models of multiple sclerosis [61]. Th17 cells found in the
skin, gastrointestinal tract, and bronchial tubes are involved
in inflammatory conditions, such as inflammatory bowel
disease and asthma [62]. The IL-17 produced by Th17 cells
is a potent activator of NF-κB, thereby, increasing the levels
of inflammatory cytokines such as IL-8, IL-6, TNF-α,G-
CSF, and GM-CSF [63]. Therefore, although Th17 plays
a role in regulating neutrophil and macrophage inflam-
mation, it is not known whether IL-17 induced by AhR
activation contributes to the de velopment of asthma or
COPD. Clinically, IL-17 levels in BAL fluid, sputum, and
peripheral blood from patients with allergic asthma are
higher than those in healthy controls [64, 65]. A knockout
mouse model of the IL-17 receptor showed reduced OVA-
induced airway hyperresponsiveness and eosinophil infiltra-
tion. Additionally, the levels of IgE and Th2 cytokines in
knockout mice were not as highly elevated as they were in
wild-type mice [66]. Furthermore, stimulation with IL-17
increased the concentration of biologically active MMP-9 in
mouse airways. IL-17 protein, as represented by neutrophilic
inflammation, has been detected in COPD patients, but at
a lower level than observed in a sthma patients [67]. Human
lymphocytes, however, may behave dierently. For example,
AhR agonists appear to favor IL-22 but not IL-17 production
in humans [68]. These studies suggest a role of AhR-induced
Th17 in promoting allergic or inflammatory airway diseases,
but there are interesting dierences between human and
mouse T cells. These dierences suggest that the response to
AhR activation may vary according to cell type, maturation,
and dierentiation process.
3. Conclusion
We reviewed studies on the relationship between AhR
function and airway inflammation, as it is important in the
initial phase of asthma/COPD. In addition to studying the
toxicological eects, we wish to promote studies focused
on the immune regulation of endogenous AhR pathways.
Moreover, it s eems increasingly apparent that AhR acts
by competing with other nuclear receptors in a complex
manner. Further investigation may yield a novel treatment
strategy for AhR-associated lung diseases.
Abbreviations
PCBs: Polychlorinated biphenyls
B[a]P: Benzopyrene
COPD: Chronic obstructive pulmonary disease
TGF-α: Transforming growth factor alpha
AhR: Arylhydrocarbon receptor
ARNT: AhR nuclear translocator
DRE: Dioxin response element
CYP1A1: Cytochrome P450 1A1
TCDD: 2,3,7,8-tetrachlorodibenzo-p-dioxin
ROS: Reactive oxygen species
TNF-α: Tumor necrosis factor alpha
MMP: Matrix metalloproteases
COX-2: Cyclooxygenase-2
PGE
2
: Prostaglandin E
2
PGD
2
: Prostaglandin D
2
MUC5AC: Oligomeric mucus/gel forming
BAL: Bronchoalveolar lavage
PPARs: Peroxisome proliferator-activated receptors
PPRE: PPARs response element
IgE: Immunoglobulin E
G-CSF: Granulocyte colony-stimulating factor
FGF: Fibroblast growth factor
EGF: Epidermal growth factor
PDGF: Platelet-derived growth factor.
Acknowledgments
This work was supported by the Environment Technology
Development Fund of the Ministry of the Environment of
Japan and in part by the Ministry of Health, Labour, and
Welfare of Japan.
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  • Source
    • "However, for HCB and p,p'-DDE maternal pre-pregnancy BMI was higher in the third tertiles compared to the first To our knowledge, only a few studies have examined developmental exposures to PCBs in relation to wheezing and asthma, and their results have varied, with some reporting positive associations (Grandjean et al. 2010; Stolevik et al. 2011) while another reported an inverse association (Weisglas-Kuperus et al. 2000; Weisglas-Kuperus et al. 2004 The suspected influence of the dioxin-like PCBs on immunoregulation is, at least partly, thought to be related to interactions with the aryl hydrocarbon receptor (AhR). AhR-mediated responses with dioxin and dioxin-like compounds are thought to contribute to asthma pathogenesis through increased expression of inflammatory cytokines, including tumor necrosis factor-α and interleukin-1 beta, which in turn can induce mucin production, cell chemotaxis, and immunoglobulin E (IgE) production (Chiba et al. 2012). Whether AhR-mediated responses are relevant to effects of developmental exposures to dioxin-like PCBs is unclear. "
    [Show abstract] [Hide abstract] ABSTRACT: Previous findings suggest that developmental exposures to persistent organochlorine pollutants (POPs) may be detrimental for the development of the immune system in the offspring. Whether these suspected immunoregulatory effects persist beyond early childhood remains unclear. The objective of this study was to evaluate the association between maternal serum concentrations of POPs and the risk of asthma in offspring after 20 years of follow-up. A birth cohort with 965 women was formed in 1988-1989 in Århus, Denmark. Concentrations of six polychlorinated biphenyls (PCBs) (congeners number 118, 138, 153, 156, 170, 180), hexachlorobenzene (HCB), and dichlorodiphenyldichloroethylene (p,p'-DDE) were quantified in maternal serum (n = 872) collected in gestation week 30. Information about offspring use of asthma medications was obtained from the Danish Registry of Medicinal Product Statistics. Maternal serum concentrations of HCB and dioxin-like PCB-118 were positively associated with offspring asthma medication use after 20 years of follow-up (p for trend < 0.05). Compared with subjects in the first tertile of maternal concentration, those in the third tertile of PCB-118 had an adjusted hazard ratio (HR) of 1.90 (95% CI: 1.12, 3.23). For HCB the HR for the third versus the first tertile of maternal concentration was 1.92 (95% CI: 1.15, 3.21). Weak positive associations were also estimated for PCB-156 and the non-dioxin like PCBs (PCB-138, 153, 170, 180). No associations were found for p,p'-DDE. Maternal concentrations of PCB-118 and HCB were associated with increased risk of asthma in offspring followed through 20 years of age.
    Full-text · Article · Oct 2013 · Environmental Health Perspectives
  • Source
    • "Aryl hydrocarbon receptor (AHR), an important intracellular chemosensor responsive to both natural and man-made environmental compounds, is widely expressed in a variety of animal species and humans [1,2]. For several decades, AHR has been studied largely because of its critical role in xenobiotic-induced toxicity and carcino- genesis [3,4]. "
    [Show abstract] [Hide abstract] ABSTRACT: Aryl hydrocarbon receptor (AHR), a cytosolic ligand-activated transcription factor, belongs to the member of bHLH/PAS family of heterodimeric transcriptional regulators and is widely expressed in a variety of animal species and humans. Recent animal and human data suggested that AHR is involved in various signaling pathways critical to cell normal homeostasis, which covers multiple aspects of physiology, such as cell proliferation and differentiation, gene regulation, cell motility and migration, inflammation and others. Disregulation of these physiological processes is known to contribute to events such as tumor initiation, promotion, and progression. Increasing epidemiological and experimental animal data provided substantial support for an association between abnormal AHR function and cancer, implicating AHR may be a novel drug-interfering target for cancers. The proposed underlying mechanisms of its actions in cancer involved multiple aspects, (a) inhibiting the functional expression of the key anti-oncogenes (such as p53 and BRCA1), (b) promoting stem cells transforming and angiogenesis, (c) altering cell survival, proliferation and differentiation by influencing the physiologic processes of cell-cycle, apoptosis, cell contact-inhibition, metabolism and remodel of extracellular matrix, and cell-matrix interaction, (d) cross-talking with the signaling pathways of estrogen receptor and inflammation. This review aims to provide a brief overview of recent investigations into the role of AHR and the underlying mechanisms of its actions in cancer, which were explored by the new technologies emerging in recent years.
    Full-text · Article · May 2013 · Biochimica et Biophysica Acta
  • Source
    • "An overview of the AHRR gene structure is given inFigure S1a. Tobacco smoke is a remarkable source of polycyclic aromatic hydrocarbons (PAHs) that trigger the AHR signaling pathway222324, leading to several pathological effects in humans through AHR-dependent changes in gene expression25262728. AHRR is a known tumor suppressor, mediating detoxification of PAHs, which are the principle carcinogenic agents causing tobacco-related lung and other cancers [29]. "
    [Show abstract] [Hide abstract] ABSTRACT: Environmental factors such as tobacco smoking may have long-lasting effects on DNA methylation patterns, which might lead to changes in gene expression and in a broader context to the development or progression of various diseases. We conducted an epigenome-wide association study (EWAs) comparing current, former and never smokers from 1793 participants of the population-based KORA F4 panel, with replication in 479 participants from the KORA F3 panel, carried out by the 450K BeadChip with genomic DNA obtained from whole blood. We observed wide-spread differences in the degree of site-specific methylation (with p-values ranging from 9.31E-08 to 2.54E-182) as a function of tobacco smoking in each of the 22 autosomes, with the percent of variance explained by smoking ranging from 1.31 to 41.02. Depending on cessation time and pack-years, methylation levels in former smokers were found to be close to the ones seen in never smokers. In addition, methylation-specific protein binding patterns were observed for cg05575921 within AHRR, which had the highest level of detectable changes in DNA methylation associated with tobacco smoking (-24.40% methylation; p = 2.54E-182), suggesting a regulatory role for gene expression. The results of our study confirm the broad effect of tobacco smoking on the human organism, but also show that quitting tobacco smoking presumably allows regaining the DNA methylation state of never smokers.
    Full-text · Article · May 2013 · PLoS ONE
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