AHR1B, a new functional aryl hydrocarbon receptor in zebrafish: tandem arrangement of ahr1b and ahr2 genes

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that regulates gene expression following activation by TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) or a variety of other synthetic and natural compounds. Previous studies have identified two AHR genes, AHR1 and AHR2, in zebrafish (Danio rerio), a widely used model species for studying vertebrate development and an emerging model in developmental toxicology. Zebrafish AHR2 binds TCDD with high affinity, is transcriptionally active and has a major role in mediating the developmental toxicity of TCDD. Zebrafish AHR1 lacks the ability to bind TCDD and activate transcription, and has no known function. In the present study, we report a new zebrafish AHR, designated AHR1B, which shares 34% amino acid sequence identity with AHR1 (AHR1A). The ahr1b gene resides on chromosome 22, adjacent to ahr2, whereas the ahr1a gene is located on chromosome 16. AHR1B is expressed in embryos as early as 24 hours post-fertilization and increases through the next 2 days, but expression is not inducible by TCDD. In contrast with the previously identified AHR1A, in vitro-expressed AHR1B protein exhibits specific, high-affinity binding of [3H]TCDD. Furthermore, AHR1B is able to activate the transcription of a reporter gene under the control of AHR response elements with an efficacy comparable with that of AHR2, but with a higher EC50. We speculate that AHR1B may have a physiological role, such as in embryonic development, whereas AHR2 mediates the response to xenobiotics.

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In vitro prenatal developmental toxicity induced by some petroleum substances is mediated by their 3- to 7-ring PAH constituent with a potential role for the aryl hydrocarbon receptor (AhR)

Toxicology Letters ◽

10.1016/j.toxlet.2019.08.001 ◽

2019 ◽

Vol 315 ◽

pp. 64-76 ◽

Cited By ~ 9

Author(s):

Lenny Kamelia ◽

Laura de Haan ◽

Hans B. Ketelslegers ◽

Ivonne. M.C.M. Rietjens ◽

Peter J. Boogaard

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Potential Role ◽

Developmental Toxicity ◽

Aryl Hydrocarbon

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

International Journal of Molecular Sciences ◽

10.3390/ijms19123762 ◽

2018 ◽

Vol 19 (12) ◽

pp. 3762 ◽

Cited By ~ 8

Author(s):

Anaïs Wakx ◽

Margaux Nedder ◽

Céline Tomkiewicz-Raulet ◽

Jessica Dalmasso ◽

Audrey Chissey ◽

...

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Human Placenta ◽

Target Genes ◽

Environmental Pollutants ◽

Cell Fractionation ◽

Protein Levels ◽

Aryl Hydrocarbon ◽

Epithelial Barriers ◽

Expression And Activity

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.

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Immunotoxicity of Xenobiotics in Fish: A Role for the Aryl Hydrocarbon Receptor (AhR)?

International Journal of Molecular Sciences ◽

10.3390/ijms22179460 ◽

2021 ◽

Vol 22 (17) ◽

pp. 9460

Author(s):

Helmut Segner ◽

Christyn Bailey ◽

Carolina Tafalla ◽

Jun Bo

Keyword(s):

Immune System ◽

Aryl Hydrocarbon Receptor ◽

Disease Susceptibility ◽

Immune Cell ◽

Physiological Role ◽

Immune Gene ◽

Immune Systems ◽

Aryl Hydrocarbon ◽

The Impact

The impact of anthropogenic contaminants on the immune system of fishes is an issue of growing concern. An important xenobiotic receptor that mediates effects of chemicals, such as halogenated aromatic hydrocarbons (HAHs) and polyaromatic hydrocarbons (PAHs), is the aryl hydrocarbon receptor (AhR). Fish toxicological research has focused on the role of this receptor in xenobiotic biotransformation as well as in causing developmental, cardiac, and reproductive toxicity. However, biomedical research has unraveled an important physiological role of the AhR in the immune system, what suggests that this receptor could be involved in immunotoxic effects of environmental contaminants. The aims of the present review are to critically discuss the available knowledge on (i) the expression and possible function of the AhR in the immune systems of teleost fishes; and (ii) the impact of AhR-activating xenobiotics on the immune systems of fish at the levels of immune gene expression, immune cell proliferation and immune cell function, immune pathology, and resistance to infectious disease. The existing information indicates that the AhR is expressed in the fish immune system, but currently, we have little understanding of its physiological role. Exposure to AhR-activating contaminants results in the modulation of numerous immune structural and functional parameters of fish. Despite the diversity of fish species studied and the experimental conditions investigated, the published findings rather uniformly point to immunosuppressive actions of xenobiotic AhR ligands in fish. These effects are often associated with increased disease susceptibility. The fact that fish populations from HAH- and PAH-contaminated environments suffer immune disturbances and elevated disease susceptibility highlights that the immunotoxic effects of AhR-activating xenobiotics bear environmental relevance.

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Hepatitis B Virus X-Associated Protein 2 Is a Subunit of the Unliganded Aryl Hydrocarbon Receptor Core Complex and Exhibits Transcriptional Enhancer Activity

Molecular and Cellular Biology ◽

10.1128/mcb.18.2.978 ◽

1998 ◽

Vol 18 (2) ◽

pp. 978-988 ◽

Cited By ~ 251

Author(s):

Brian K. Meyer ◽

Marilyn G. Pray-Grant ◽

John P. Vanden Heuvel ◽

Gary H. Perdew

Keyword(s):

Amino Acid ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Aryl Hydrocarbon Receptor ◽

In Vitro Translation ◽

Luciferase Reporter ◽

Core Complex ◽

Aryl Hydrocarbon ◽

B Virus

ABSTRACT Prior to ligand activation, the unactivated aryl hydrocarbon receptor (AhR) exists in a heterotetrameric 9S core complex consisting of the AhR ligand-binding subunit, a dimer of hsp90, and an unknown subunit. Here we report the purification of an ∼38-kDa protein (p38) from COS-1 cell cytosol that is a member of this complex by coprecipitation with a FLAG-tagged AhR. Internal amino acid sequence information was obtained, and p38 was identified as the hepatitis B virus X-associated protein 2 (XAP2). The simian ortholog of XAP2 was cloned from a COS-1 cDNA library; it codes for a 330-amino-acid protein containing regions of homology to the immunophilins FKBP12 and FKBP52. A tetratricopeptide repeat (TPR) domain in the carboxy-terminal region of XAP2 was similar to the third and fourth TPR domains of human FKBP52 and the Saccharomyces cerevisiae transcriptional modulator SSN6, respectively. Polyclonal antibodies raised against XAP2 recognized p38 in the unliganded AhR complex in COS-1 and Hepa 1c1c7 cells. It was ubiquitously expressed in murine tissues at the protein and mRNA levels. It was not required for the assembly of an AhR-hsp90 complex in vitro. Additionally, XAP2 did not directly associate with hsp90 upon in vitro translation, but was present in a 9S form when cotranslated in vitro with murine AhR. XAP2 enhanced the ability of endogenous murine and human AhR complexes to activate a dioxin-responsive element–luciferase reporter twofold, following transient expression of XAP2 in Hepa 1c1c7 and HeLa cells.

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Increase Paclitaxel Sensitivity to Better Suppress Serous Epithelial Ovarian Cancer via Ablating Androgen Receptor/Aryl Hydrocarbon Receptor-ABCG2 Axis

Cancers ◽

10.3390/cancers11040463 ◽

2019 ◽

Vol 11 (4) ◽

pp. 463 ◽

Cited By ~ 4

Author(s):

Wei-Min Chung ◽

Yen-Ping Ho ◽

Wei-Chun Chang ◽

Yuan-Chang Dai ◽

Lumin Chen ◽

...

Keyword(s):

Ovarian Cancer ◽

Androgen Receptor ◽

Epithelial Ovarian Cancer ◽

Aryl Hydrocarbon Receptor ◽

Proximal Promoter ◽

Luciferase Reporter ◽

Aryl Hydrocarbon ◽

Paclitaxel Treatment

Background: Epithelial ovarian cancer (EOC) is one of the most lethal gynecological malignancies and presents chemoresistance after chemotherapy treatment. Androgen receptor (AR) has been known to participate in proliferation. Yet the mechanisms of the resistance of this drug and its linkage to the AR remains unclear. Methods: To elucidate AR-related paclitaxel sensitivity, co-IP, luciferase reporter assay and ChIP assay were performed to identify that AR direct-regulated ABCG2 expression under paclitaxel treatment. IHC staining by AR antibody presented higher AR expression in serous-type patients than other types. AR degradation enhancer (ASC-J9) was used to examine paclitaxel-associated and paclitaxel-resistant cytotoxicity in vitro and in vivo. Results: We found AR/aryl hydrocarbon receptor (AhR)-mediates ABCG2 expression and leads to a change in paclitaxel cytotoxicity/sensitivity in EOC serous subtype cell lines. Molecular mechanism study showed that paclitaxel activated AR transactivity and bound to alternative ARE in the ABCG2 proximal promoter region. To identify AR as a potential therapeutic target, the ASC-J9 was used to re-sensitize paclitaxel-resistant EOC tumors upon paclitaxel treatment in vitro and in vivo. Conclusion: The results demonstrated that activation of AR transactivity beyond the androgen-associated biological effect. This novel AR mechanism explains that degradation of AR is the most effective therapeutic strategy for treating AR-positive EOC serous subtype.

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A mixture of persistent organic pollutants relevant for human exposure inhibits the transactivation activity of the aryl hydrocarbon receptor in vitro

Environmental Pollution ◽

10.1016/j.envpol.2019.113098 ◽

2019 ◽

Vol 254 ◽

pp. 113098 ◽

Cited By ~ 3

Author(s):

T.Q. Doan ◽

H.F. Berntsen ◽

S. Verhaegen ◽

E. Ropstad ◽

L. Connolly ◽

...

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Organic Pollutants ◽

Persistent Organic Pollutants ◽

Human Exposure ◽

Transactivation Activity ◽

Aryl Hydrocarbon

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Environmental Benzopyrene Attenuates Stemness of Placenta-Derived Mesenchymal Stem Cells via Aryl Hydrocarbon Receptor

Stem Cells International ◽

10.1155/2019/7414015 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 4

Author(s):

June Seok Heo ◽

Ja-Yun Lim ◽

Sangshin Pyo ◽

Dae Wui Yoon ◽

Dongsook Lee ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Aryl Hydrocarbon Receptor ◽

Molecular Mechanisms ◽

Cell Activity ◽

Bone Diseases ◽

Purine Derivative ◽

Aryl Hydrocarbon ◽

Polycyclic Aromatic

The toxic effects of particulate matter have been linked to polycyclic aromatic hydrocarbons (PAHs) such as benzopyrene. PAHs are potent inducers of the aryl hydrocarbon receptor (AhR), which is an expressed nuclear receptor that senses environmental stimuli and modulates gene expression. Even though several studies have shown that the benzopyrene (BP) of chemical pollutants significantly impaired stem cell activity, the exact molecular mechanisms were not clearly elucidated. In the present study, we aimed to investigate the effects of BP on placenta-derived mesenchymal stem cells (PD-MSCs) in vitro. We found that the AhR in PD-MSCs was expressed under the treatment of BP, and its activation markedly disrupted osteogenic differentiation through the alteration of stemness activity of PD-MSCs. Moreover, BP treatment significantly reduced the proliferation activity of PD-MSCs and expression of pluripotent markers through the induction of AhR. Treatment with StemRegenin 1 (SR1), a purine derivative that antagonizes the AhR, effectively prevented BP-induced reduction of the proliferation and differentiation activity of PD-MSCs. In this study, we found that BP treatment in PD-MSCs markedly obstructs PD-MSC stemness through AhR signaling. Noteworthy, SR1-mediated MSC application will contribute to new perspectives on MSC-based therapies for air pollution-related bone diseases.

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