International Journal of Molecular Sciences

Research

17 pages, 2781 KiB

Open AccessArticle

The Prognostic Impact of the Aryl Hydrocarbon Receptor (AhR) in Primary Breast Cancer Depends on the Lymph Node Status

by Udo Jeschke, Xi Zhang, Christina Kuhn, Stéphan Jalaguier, Jacques Colinge, Kristina Pfender, Doris Mayr, Nina Ditsch, Nadia Harbeck, Sven Mahner, Sophie Sixou and Vincent Cavaillès

Int. J. Mol. Sci. 2019, 20(5), 1016; https://doi.org/10.3390/ijms20051016 - 26 Feb 2019

Cited by 23 | Viewed by 3348

Abstract

Increasing evidence implicates the aryl hydrocarbon receptor (AhR) as a possible regulator of mammary carcinogenesis. This study aims to clarify its prognostic impact in breast cancer (BC). Meta-analyses performed at the mRNA level demonstrated that the predictive value of AhR expression in BC [...] Read more.

Increasing evidence implicates the aryl hydrocarbon receptor (AhR) as a possible regulator of mammary carcinogenesis. This study aims to clarify its prognostic impact in breast cancer (BC). Meta-analyses performed at the mRNA level demonstrated that the predictive value of AhR expression in BC depends on the lymph node (LN) status. AhR expression and sub-cellular location were then analyzed by immunohistochemistry in 302 primary BC samples. AhR was expressed in almost 90% of cases with a predominant nuclear location. Nuclear and cytoplasmic AhR levels were significantly correlated and associated with the expression of RIP140 (receptor-interacting protein of 140 kDa), an AhR transcriptional coregulator and target gene. Interestingly, total and nuclear AhR levels were only significantly correlated with short overall survival in node-negative patients. In this sub-group, total and nuclear AhR expression had an even stronger prognostic impact in patients with low RIP140-expressing tumors. Very interestingly, the total AhR prognostic value was also significant in luminal-like BCs and was an independent prognostic marker for LN-negative patients. Altogether, this study suggests that AhR is a marker of poor prognosis for patients with LN-negative luminal-like BCs, which warrants further evaluation. Full article

(This article belongs to the Special Issue Aryl Hydrocarbon Receptor in Biology and Toxicology)

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19 pages, 3240 KiB

Open AccessArticle

Inducible Loss of the Aryl Hydrocarbon Receptor Activates Perigonadal White Fat Respiration and Brown Fat Thermogenesis via Fibroblast Growth Factor 21

by Nathaniel G. Girer, Dwayne Carter, Nisha Bhattarai, Mehnaz Mustafa, Larry Denner, Craig Porter and Cornelis J. Elferink

Int. J. Mol. Sci. 2019, 20(4), 950; https://doi.org/10.3390/ijms20040950 - 22 Feb 2019

Cited by 17 | Viewed by 5037

Abstract

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor highly expressed in hepatocytes. Researchers have employed global and liver-specific conditional Ahr knockout mouse models to characterize the physiological roles of the AHR; however, the gestational timing of AHR loss in these models [...] Read more.

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor highly expressed in hepatocytes. Researchers have employed global and liver-specific conditional Ahr knockout mouse models to characterize the physiological roles of the AHR; however, the gestational timing of AHR loss in these models can complicate efforts to distinguish the direct and indirect effects of post-gestational AHR deficiency. Utilizing a novel tamoxifen-inducible AHR knockout mouse model, we analyzed the effects of hepatocyte-targeted AHR loss in adult mice. The data demonstrate that AHR deficiency significantly reduces weight gain and adiposity, and increases multilocular lipid droplet formation within perigonadal white adipose tissue (gWAT). Protein and mRNA expression of fibroblast growth factor 21 (FGF21), an important hepatokine that activates thermogenesis in brown adipose tissue (BAT) and gWAT, significantly increases upon AHR loss and correlates with a significant increase of BAT and gWAT respiratory capacity. Confirming the role of FGF21 in mediating these effects, this phenotype is reversed in mice concomitantly lacking AHR and FGF21 expression. Chromatin immunoprecipitation analyses suggest that the AHR may constitutively suppress Fgf21 transcription through binding to a newly identified xenobiotic response element within the Fgf21 promoter. The data demonstrate an important AHR-FGF21 regulatory axis that influences adipose biology and may represent a “druggable” therapeutic target for obesity and its related metabolic disorders. Full article

(This article belongs to the Special Issue Aryl Hydrocarbon Receptor in Biology and Toxicology)

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13 pages, 2831 KiB

Open AccessCommunication

NAP Family CG5017 Chaperone Pleiotropically Regulates Human AHR Target Genes Expression in Drosophila Testis

by Angelina A. Akishina, Julia E. Vorontsova, Roman O. Cherezov, Mikhail S. Slezinger, Olga B. Simonova and Boris A. Kuzin

Int. J. Mol. Sci. 2019, 20(1), 118; https://doi.org/10.3390/ijms20010118 - 29 Dec 2018

Cited by 3 | Viewed by 3204

Abstract

To study the regulatory mechanism of the Aryl hydrocarbon receptor (AHR), target genes of transcription are necessary for understanding the normal developmental and pathological processes. Here, we examined the effects of human AHR ligands on male fecundity. To induce ectopic human AhR gene [...] Read more.

To study the regulatory mechanism of the Aryl hydrocarbon receptor (AHR), target genes of transcription are necessary for understanding the normal developmental and pathological processes. Here, we examined the effects of human AHR ligands on male fecundity. To induce ectopic human AhR gene expression, we used Drosophila melanogaster transformed with human AhR under the control of a yeast UAS promoter element capable of activation in the two-component UAS-GAL4 system. We found that exogenous AHR ligands decrease the number of Drosophila gonadal Tj-positive cells. We also found both an increase and decrease of AHR target gene expression, including in genes that control homeostasis and testis development. This suggests that gonadal AHR activation may affect the expression of gene networks that control sperm production and could be critical for fertility not just in Drosophila but also in humans. Finally, we found that the activation of the expression for some AHR target genes depends on the expression of testis-specific chaperone CG5017 in gonadal cells. Since CG5017 belongs to the nucleosome assembly protein (NAP) family and may participate in epigenetic regulation, we propose that this nucleotropic chaperone is essential to provide the human AHR with access to only the defined set of its target genes during spermatogenesis. Full article

(This article belongs to the Special Issue Aryl Hydrocarbon Receptor in Biology and Toxicology)

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27 pages, 6936 KiB

Open AccessArticle

Expression, Localization, and Activity of the Aryl Hydrocarbon Receptor in the Human Placenta

by Anaïs Wakx, Margaux Nedder, Céline Tomkiewicz-Raulet, Jessica Dalmasso, Audrey Chissey, Sonja Boland, Françoise Vibert, Séverine A. Degrelle, Thierry Fournier, Xavier Coumoul, Sophie Gil and Ioana Ferecatu

Int. J. Mol. Sci. 2018, 19(12), 3762; https://doi.org/10.3390/ijms19123762 - 27 Nov 2018

Cited by 26 | Viewed by 5103

Abstract

The human placenta is an organ between the blood of the mother and the fetus, which is essential for fetal development. It also plays a role as a selective barrier against environmental pollutants that may bypass epithelial barriers and reach the placenta, with [...] Read more.

The human placenta is an organ between the blood of the mother and the fetus, which is essential for fetal development. It also plays a role as a selective barrier against environmental pollutants that may bypass epithelial barriers and reach the placenta, with implications for the outcome of pregnancy. The aryl hydrocarbon receptor (AhR) is one of the most important environmental-sensor transcription factors and mediates the metabolism of a wide variety of xenobiotics. Nevertheless, the identification of dietary and endogenous ligands of AhR suggest that it may also fulfil physiological functions with which pollutants may interfere. Placental AhR expression and activity is largely unknown. We established the cartography of AhR expression at transcript and protein levels, its cellular distribution, and its transcriptional activity toward the expression of its main target genes. We studied the profile of AhR expression and activity during different pregnancy periods, during trophoblasts differentiation in vitro, and in a trophoblast cell line. Using diverse methods, such as cell fractionation and immunofluorescence microscopy, we found a constitutive nuclear localization of AhR in every placental model, in the absence of any voluntarily-added exogenous activator. Our data suggest an intrinsic activation of AhR due to the presence of endogenous placental ligands. Full article

(This article belongs to the Special Issue Aryl Hydrocarbon Receptor in Biology and Toxicology)

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18 pages, 3192 KiB

Open AccessArticle

Genome-Wide Transcriptional and Functional Analysis of Human T Lymphocytes Treated with Benzo[α]pyrene

by Marie Liamin, Hélène Le Mentec, Bertrand Evrard, Laurence Huc, Frédéric Chalmel, Elisa Boutet-Robinet, Eric Le Ferrec and Lydie Sparfel

Int. J. Mol. Sci. 2018, 19(11), 3626; https://doi.org/10.3390/ijms19113626 - 17 Nov 2018

Cited by 13 | Viewed by 4012

Abstract

Polycyclic aromatic hydrocarbons (PAHs) are widely distributed environmental contaminants, known to affect T lymphocytes. However, the molecular targets and pathways involved in their immunotoxic effects in human T lymphocytes remain unknown. Here, we analyzed the gene expression profile of primary human T lymphocytes [...] Read more.

Polycyclic aromatic hydrocarbons (PAHs) are widely distributed environmental contaminants, known to affect T lymphocytes. However, the molecular targets and pathways involved in their immunotoxic effects in human T lymphocytes remain unknown. Here, we analyzed the gene expression profile of primary human T lymphocytes treated with the prototypical PAH, benzo[α]pyrene (B[α]P), using a microarray-based transcriptome analysis. After a 48 h exposure to B[α]P, we identified 158 genes differentially expressed in T lymphocytes, including not only genes well-known to be affected by PAHs such as the cytochromes P450 (CYP) 1A1 and 1B1, but also others not previously shown to be targeted by B[α]P such as genes encoding the gap junction beta (GJB)-2 and 6 proteins. Functional enrichment analysis revealed that these candidates were significantly associated with the aryl hydrocarbon (AhR) and interferon (IFN) signaling pathways; a marked alteration in T lymphocyte recruitment was also observed. Using functional tests in transwell migration experiments, B[α]P was then shown to significantly decrease the chemokine (C-X-C motif) ligand 12-induced chemotaxis and transendothelial migration of T lymphocytes. In total, this study opens the way to unsuspected responsive pathway of interest, i.e., T lymphocyte migration, thus providing a more thorough understanding of the molecular basis of the immunotoxicity of PAHs. Full article

(This article belongs to the Special Issue Aryl Hydrocarbon Receptor in Biology and Toxicology)

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18 pages, 2935 KiB

Open AccessArticle

Comparative In Vitro and In Silico Analysis of the Selectivity of Indirubin as a Human Ah Receptor Agonist

by Samantha C. Faber, Anatoly A. Soshilov, Sara Giani Tagliabue, Laura Bonati and Michael S. Denison

Int. J. Mol. Sci. 2018, 19(9), 2692; https://doi.org/10.3390/ijms19092692 - 10 Sep 2018

Cited by 27 | Viewed by 4400

Abstract

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that modulates gene expression following its binding and activation by structurally diverse chemicals. Species differences in AhR functionality have been observed, with the mouse AhR (mAhR) and human AhR (hAhR) exhibiting significant differences [...] Read more.

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that modulates gene expression following its binding and activation by structurally diverse chemicals. Species differences in AhR functionality have been observed, with the mouse AhR (mAhR) and human AhR (hAhR) exhibiting significant differences in ligand binding, coactivator recruitment, gene expression and response. While the AhR agonist indirubin (IR) is a more potent activator of hAhR-dependent gene expression than the prototypical ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), it is a significantly less potent activator of the mAhR. DNA binding analysis confirmed the greater potency/efficacy of IR in stimulating transformation/DNA binding of the hAhR in vitro and domain-swapping experiments demonstrated that the enhanced response to IR was primarily due to the hAhR ligand binding domain (LBD). Site-directed mutagenesis and functional analysis studies revealed that mutation of H326 and A349 in the mAhR LBD to the corresponding residues in the hAhR LBD significantly increased the potency of IR. Since these mutations had no significant effect on ligand binding, these residues likely contribute to an enhanced efficiency of transformation/DNA binding by IR-bound hAhR. Molecular docking to mAhR LBD homology models further elucidated the different roles of the A375V mutation in TCDD and IR binding, as revealed by [³H]TCDD competitive binding results. These results demonstrate the differential binding of structurally diverse ligands within the LBD of a given AhR and confirm that amino acid differences within the LBD of AhRs contribute to significant species differences in ligand response. Full article

(This article belongs to the Special Issue Aryl Hydrocarbon Receptor in Biology and Toxicology)

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12 pages, 1720 KiB

Open AccessArticle

Maternal Resveratrol Therapy Protects Male Rat Offspring against Programmed Hypertension Induced by TCDD and Dexamethasone Exposures: Is It Relevant to Aryl Hydrocarbon Receptor?

by Chien-Ning Hsu, Yu-Ju Lin, Pei-Chen Lu and You-Lin Tain

Int. J. Mol. Sci. 2018, 19(8), 2459; https://doi.org/10.3390/ijms19082459 - 20 Aug 2018

Cited by 36 | Viewed by 4688

Abstract

Hypertension can originate from early-life adverse environmental in utero exposure to dexamethasone (DEX) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Since DEX and TCDD are related to the aryl hydrocarbon receptor (AHR) signaling pathway, we examined whether resveratrol, an AHR modulator and antioxidant, could prevent programmed hypertension [...] Read more.

Hypertension can originate from early-life adverse environmental in utero exposure to dexamethasone (DEX) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Since DEX and TCDD are related to the aryl hydrocarbon receptor (AHR) signaling pathway, we examined whether resveratrol, an AHR modulator and antioxidant, could prevent programmed hypertension via regulating AHR signaling and oxidative stress. Groups of four-month-old male rat offspring were studied (n = 7–8 per group): control, DEX (0.1 mg/kg i.p. from a gestational age of 16 to 22 days), TCDD (200 ng/kg in four once-weekly oral doses), DEX + TCDD, and DEX + TCDD + R (resveratrol 0.05% in drinking water throughout pregnancy and lactation). Maternal TCDD exposure aggravated prenatal DEX-induced hypertension in adult male offspring, which maternal resveratrol therapy prevented. Maternal TCDD exposure aggravated DEX-induced oxidative damage in offspring kidneys, which was prevented by resveratrol therapy. Maternal resveratrol therapy decreased asymmetric and symmetric dimethylarginine (ADMA and SDMA) levels, thereby preventing combined DEX and TCDD exposure-induced programmed hypertension. Increases in renal Ahrr and Cyp1a1 expression induced by DEX + TCDD exposure were restored by resveratrol therapy. The beneficial effects of resveratrol on DEX + TCDD-induced hypertension relate to reduced renal mRNA expression of Ren, Ace, and Agtr1a expression. Thus, the beneficial effects of resveratrol on DEX + TCDD-induced hypertension include reduction of oxidative stress, restoration of nitric oxide (NO) bioavailability, blockade of the renin–angiotensin system (RAS), and antagonizing AHR signaling pathway. Full article

(This article belongs to the Special Issue Aryl Hydrocarbon Receptor in Biology and Toxicology)

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24 pages, 3839 KiB

Open AccessArticle

Towards Resolving the Pro- and Anti-Tumor Effects of the Aryl Hydrocarbon Receptor

by Supraja Narasimhan, Elizabeth Stanford Zulick, Olga Novikov, Ashley J. Parks, Jennifer J. Schlezinger, Zhongyan Wang, Fabrice Laroche, Hui Feng, Francesca Mulas, Stefano Monti and David H. Sherr

Int. J. Mol. Sci. 2018, 19(5), 1388; https://doi.org/10.3390/ijms19051388 - 07 May 2018

Cited by 45 | Viewed by 6052

Abstract

We have postulated that the aryl hydrocarbon receptor (AHR) drives the later, more lethal stages of some cancers when chronically activated by endogenous ligands. However, other studies have suggested that, under some circumstances, the AHR can oppose tumor aggression. Resolving this apparent contradiction [...] Read more.

We have postulated that the aryl hydrocarbon receptor (AHR) drives the later, more lethal stages of some cancers when chronically activated by endogenous ligands. However, other studies have suggested that, under some circumstances, the AHR can oppose tumor aggression. Resolving this apparent contradiction is critical to the design of AHR-targeted cancer therapeutics. Molecular (siRNA, shRNA, AHR repressor, CRISPR-Cas9) and pharmacological (AHR inhibitors) approaches were used to confirm the hypothesis that AHR inhibition reduces human cancer cell invasion (irregular colony growth in 3D Matrigel cultures and Boyden chambers), migration (scratch wound assay) and metastasis (human cancer cell xenografts in zebrafish). Furthermore, these assays were used for a head-to-head comparison between AHR antagonists and agonists. AHR inhibition or knockdown/knockout consistently reduced human ER⁻/PR⁻/Her2⁻ and inflammatory breast cancer cell invasion, migration, and metastasis. This was associated with a decrease in invasion-associated genes (e.g., Fibronectin, VCAM1, Thrombospondin, MMP1) and an increase in CDH1/E-cadherin, previously associated with decreased tumor aggression. Paradoxically, AHR agonists (2,3,7,8-tetrachlorodibenzo-p-dioxin and/or 3,3′-diindolylmethane) similarly inhibited irregular colony formation in Matrigel and blocked metastasis in vivo but accelerated migration. These data demonstrate the complexity of modulating AHR activity in cancer while suggesting that AHR inhibitors, and, under some circumstances, AHR agonists, may be useful as cancer therapeutics. Full article

(This article belongs to the Special Issue Aryl Hydrocarbon Receptor in Biology and Toxicology)

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10 pages, 3934 KiB

Open AccessArticle

Glyteer, Soybean Tar, Impairs IL-4/Stat6 Signaling in Murine Bone Marrow-Derived Dendritic Cells: The Basis of Its Therapeutic Effect on Atopic Dermatitis

by Masaki Takemura, Takeshi Nakahara, Akiko Hashimoto-Hachiya, Masutaka Furue and Gaku Tsuji

Int. J. Mol. Sci. 2018, 19(4), 1169; https://doi.org/10.3390/ijms19041169 - 12 Apr 2018

Cited by 30 | Viewed by 5087

Abstract

Atopic dermatitis (AD) is a common inflammatory skin disease. Recent studies have revealed the involvement of T helper (Th)2 cytokines including Interleukin 4 (IL-4) in the pathogenesis of AD. Since epidermal Langerhans cells (LCs) and dermal myeloid dendritic cells (DCs) produce CCL17 and [...] Read more.

Atopic dermatitis (AD) is a common inflammatory skin disease. Recent studies have revealed the involvement of T helper (Th)2 cytokines including Interleukin 4 (IL-4) in the pathogenesis of AD. Since epidermal Langerhans cells (LCs) and dermal myeloid dendritic cells (DCs) produce CCL17 and CCL22 that chemoattract Th2 cells, interfering with CCL17 and CCL22 production from LCs and dermal myeloid DCs may be beneficial in the treatment of AD. To investigate this, we stimulated murine bone marrow-derived DCs (BMDCs) with IL-4. IL-4 stimulation produced Ccl17 and Ccl22, which was attenuated by soybean tar Glyteer, a known aryl hydrocarbon receptor (Ahr) activator. Notably, Glyteer treatment blocked the nuclear translocation of Stat6 induced by IL-4 stimulation, suggesting that this treatment impairs the IL-4/Stat6 signaling pathway in BMDCs. Unexpectedly, Glyteer treatment did not potently upregulate the expression of Cyp1a1, a specific Ahr-responsive gene, suggesting that its inhibitory machinery for Ccl17 and Ccl22 expression is likely to operate in an Ahr-independent manner. These findings indicate that Glyteer may exhibit therapeutic potential for AD by downregulating the CCL17 and CCL22 production from DCs in a Th2-deviated microenvironment. Full article

(This article belongs to the Special Issue Aryl Hydrocarbon Receptor in Biology and Toxicology)

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16 pages, 2405 KiB

Open AccessArticle

Aryl Hydrocarbon Receptor Antagonists Mitigate the Effects of Dioxin on Critical Cellular Functions in Differentiating Human Osteoblast-Like Cells

by Chawon Yun, Karina M. Katchko, Michael S. Schallmo, Soyeon Jeong, Jonghwa Yun, Charlotte H. Chen, Joseph A. Weiner, Christian Park, Andrew George, Samuel I. Stupp, Wellington K. Hsu and Erin L. Hsu

Int. J. Mol. Sci. 2018, 19(1), 225; https://doi.org/10.3390/ijms19010225 - 11 Jan 2018

Cited by 14 | Viewed by 7022

Abstract

The inhibition of bone healing in humans is a well-established effect associated with cigarette smoking, but the underlying mechanisms are still unclear. Recent work using animal cell lines have implicated the aryl hydrocarbon receptor (AhR) as a mediator of the anti-osteogenic effects of [...] Read more.

The inhibition of bone healing in humans is a well-established effect associated with cigarette smoking, but the underlying mechanisms are still unclear. Recent work using animal cell lines have implicated the aryl hydrocarbon receptor (AhR) as a mediator of the anti-osteogenic effects of cigarette smoke, but the complexity of cigarette smoke mixtures makes understanding the mechanisms of action a major challenge. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, dioxin) is a high-affinity AhR ligand that is frequently used to investigate biological processes impacted by AhR activation. Since there are dozens of AhR ligands present in cigarette smoke, we utilized dioxin as a prototype ligand to activate the receptor and explore its effects on pro-osteogenic biomarkers and other factors critical to osteogenesis using a human osteoblast-like cell line. We also explored the capacity for AhR antagonists to protect against dioxin action in this context. We found dioxin to inhibit osteogenic differentiation, whereas co-treatment with various AhR antagonists protected against dioxin action. Dioxin also negatively impacted cell adhesion with a corresponding reduction in the expression of integrin and cadherin proteins, which are known to be involved in this process. Similarly, the dioxin-mediated inhibition of cell migration correlated with reduced expression of the chemokine receptor CXCR4 and its ligand, CXCL12, and co-treatment with antagonists restored migratory capacity. Our results suggest that AhR activation may play a role in the bone regenerative response in humans exposed to AhR activators, such as those present in cigarette smoke. Given the similarity of our results using a human cell line to previous work done in murine cells, animal models may yield data relevant to the human setting. In addition, the AhR may represent a potential therapeutic target for orthopedic patients who smoke cigarettes, or those who are exposed to secondhand smoke or other environmental sources of aryl hydrocarbons. Full article

(This article belongs to the Special Issue Aryl Hydrocarbon Receptor in Biology and Toxicology)

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Review

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19 pages, 885 KiB

Open AccessReview

The Aryl Hydrocarbon Receptor and the Maintenance of Lung Health

by Necola Guerrina, Hussein Traboulsi, David H. Eidelman and Carolyn J. Baglole

Int. J. Mol. Sci. 2018, 19(12), 3882; https://doi.org/10.3390/ijms19123882 - 05 Dec 2018

Cited by 55 | Viewed by 7569

Abstract

Much of what is known about the Aryl Hydrocarbon Receptor (AhR) centers on its ability to mediate the deleterious effects of the environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin). However, the AhR is both ubiquitously-expressed and evolutionarily-conserved, suggesting that it evolved for purposes beyond strictly [...] Read more.

Much of what is known about the Aryl Hydrocarbon Receptor (AhR) centers on its ability to mediate the deleterious effects of the environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin). However, the AhR is both ubiquitously-expressed and evolutionarily-conserved, suggesting that it evolved for purposes beyond strictly mediating responses to man-made environmental toxicants. There is growing evidence that the AhR is required for the maintenance of health, as it is implicated in physiological processes such as xenobiotic metabolism, organ development and immunity. Dysregulation of AhR expression and activity is also associated with a variety of disease states, particularly those at barrier organs such as the skin, gut and lungs. The lungs are particularly vulnerable to inhaled toxicants such as cigarette smoke. However, the role of the AhR in diseases such as chronic obstructive pulmonary disease (COPD)—a respiratory illness caused predominately by cigarette smoking—and lung cancer remains largely unexplored. This review will discuss the growing body of literature that provides evidence that the AhR protects the lungs against the damaging effects of cigarette smoke. Full article

(This article belongs to the Special Issue Aryl Hydrocarbon Receptor in Biology and Toxicology)

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15 pages, 659 KiB

Open AccessReview

The Role of the Aryl Hydrocarbon Receptor (AHR) in Immune and Inflammatory Diseases

by Drew R. Neavin, Duan Liu, Balmiki Ray and Richard M. Weinshilboum

Int. J. Mol. Sci. 2018, 19(12), 3851; https://doi.org/10.3390/ijms19123851 - 03 Dec 2018

Cited by 154 | Viewed by 14252

Abstract

The aryl hydrocarbon receptor (AHR) is a nuclear receptor that modulates the response to environmental stimuli. It was recognized historically for its role in toxicology but, in recent decades, it has been increasingly recognized as an important modulator of disease—especially for its role [...] Read more.

The aryl hydrocarbon receptor (AHR) is a nuclear receptor that modulates the response to environmental stimuli. It was recognized historically for its role in toxicology but, in recent decades, it has been increasingly recognized as an important modulator of disease—especially for its role in modulating immune and inflammatory responses. AHR has been implicated in many diseases that are driven by immune/inflammatory processes, including major depressive disorder, multiple sclerosis, rheumatoid arthritis, asthma, and allergic responses, among others. The mechanisms by which AHR has been suggested to impact immune/inflammatory diseases include targeted gene expression and altered immune differentiation. It has been suggested that single nucleotide polymorphisms (SNPs) that are near AHR-regulated genes may contribute to AHR-dependent disease mechanisms/pathways. Further, we have found that SNPs that are outside of nuclear receptor binding sites (i.e., outside of AHR response elements (AHREs)) may contribute to AHR-dependent gene regulation in a SNP- and ligand-dependent manner. This review will discuss the evidence and mechanisms of AHR contributions to immune/inflammatory diseases and will consider the possibility that SNPs that are outside of AHR binding sites might contribute to AHR ligand-dependent inter-individual variation in disease pathophysiology and response to pharmacotherapeutics. Full article

(This article belongs to the Special Issue Aryl Hydrocarbon Receptor in Biology and Toxicology)

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27 pages, 1422 KiB

Open AccessReview

The Aryl Hydrocarbon Receptor and the Nervous System

by Ludmila Juricek and Xavier Coumoul

Int. J. Mol. Sci. 2018, 19(9), 2504; https://doi.org/10.3390/ijms19092504 - 24 Aug 2018

Cited by 87 | Viewed by 8822

Abstract

The aryl hydrocarbon receptor (or AhR) is a cytoplasmic receptor of pollutants. It translocates into the nucleus upon binding to its ligands, and forms a heterodimer with ARNT (AhR nuclear translocator). The heterodimer is a transcription factor, which regulates the transcription of xenobiotic [...] Read more.

The aryl hydrocarbon receptor (or AhR) is a cytoplasmic receptor of pollutants. It translocates into the nucleus upon binding to its ligands, and forms a heterodimer with ARNT (AhR nuclear translocator). The heterodimer is a transcription factor, which regulates the transcription of xenobiotic metabolizing enzymes. Expressed in many cells in vertebrates, it is mostly present in neuronal cell types in invertebrates, where it regulates dendritic morphology or feeding behavior. Surprisingly, few investigations have been conducted to unravel the function of the AhR in the central or peripheral nervous systems of vertebrates. In this review, we will present how the AhR regulates neural functions in both invertebrates and vertebrates as deduced mainly from the effects of xenobiotics. We will introduce some of the molecular mechanisms triggered by the well-known AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which impact on neuronal proliferation, differentiation, and survival. Finally, we will point out the common features found in mice that are exposed to pollutants, and in AhR knockout mice. Full article

(This article belongs to the Special Issue Aryl Hydrocarbon Receptor in Biology and Toxicology)

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Other

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8 pages, 343 KiB

Open AccessConference Report

Old Receptor, New Tricks—The Ever-Expanding Universe of Aryl Hydrocarbon Receptor Functions. Report from the 4th AHR Meeting, 29–31 August 2018 in Paris, France

by Charlotte Esser, B. Paige Lawrence, David H. Sherr, Gary H. Perdew, Alvaro Puga, Robert Barouki and Xavier Coumoul

Int. J. Mol. Sci. 2018, 19(11), 3603; https://doi.org/10.3390/ijms19113603 - 15 Nov 2018

Cited by 46 | Viewed by 6126

Abstract

In a time where “translational” science has become a mantra in the biomedical field, it is reassuring when years of research into a biological phenomenon suddenly points towards novel prevention or therapeutic approaches to disease, thereby demonstrating once again that basic science and [...] Read more.

In a time where “translational” science has become a mantra in the biomedical field, it is reassuring when years of research into a biological phenomenon suddenly points towards novel prevention or therapeutic approaches to disease, thereby demonstrating once again that basic science and translational science are intimately linked. The studies on the aryl hydrocarbon receptor (AHR) discussed here provide a perfect example of how years of basic toxicological research on a molecule, whose normal physiological function remained a mystery for so long, has now yielded a treasure trove of actionable information on the development of targeted therapeutics. Examples are autoimmunity, metabolic imbalance, inflammatory skin and gastro-intestinal diseases, cancer, development and perhaps ageing. Indeed, the AHR field no longer asks, “What does this receptor do in the absence of xenobiotics?” It now asks, “What doesn’t this receptor do?”. Full article

(This article belongs to the Special Issue Aryl Hydrocarbon Receptor in Biology and Toxicology)

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