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Mechanisms of Ligand-Induced Aryl Hydrocarbon Receptor-Mediated Biochemical and Toxic Responses

Mechanisms of Ligand-Induced Aryl Hydrocarbon Receptor-Mediated Biochemical and Toxic Responses The ubiquitous environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) is a member of a broad group of halogenated aromatic hydrocarbons (HAHs) that is known to induce a wide range of toxic and biochemical responses in laboratory animals and humans. The effects of HAH exposure are mediated by binding to the cytosolic aryl hydrocarbon receptor (AhR), which is expressed in a tissue- and cell type-specific manner. The AhR is a ligand-activated transcription factor belonging to the basic helix-loop-helix/Per-AhR-Arnt-Sim (bHLH/PAS) superfamily of proteins. The mechanism of induction of gene transcription by TCDD involves Iigand recognition and binding by the AhR, nuclear translocation, and dimerization with the AhR cofactor, AhR nuclear translocator (Arnt). The nuclear heterodimer interacts with cognate xenobiotic responsive elements (XREs) in promoter/enhancer regions of multiple Ah-responsive genes. Subsequent changes in chromatin structure and/or interaction of the AhR complex with the basal transcriptional machinery play a significant role in AhR-mediated gene expression. Although Arnt is a necessary component of a functional nuclear AhR complex, this protein also forms transcriptionally active heterodimers with other bHLH/PAS factors, including those involved in the transcriptional response to hypoxia. Arnt is ubiquitously expressed in mammalian systems, and results from transgenic mouse studies suggest that this protein plays a vital role in early mammalian embryonic development. Similar experiments suggest that the AhR may be involved in development of various organ systems. Thus, molecular mechanistic studies of TCDD action have contributed significantly to an improved understanding of the role of at least 2 bHLH/PAS proteins, as well as organ- and tissue-specific biochemical and toxic responses to this class of environmental toxins. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Toxicologic Pathology SAGE

Mechanisms of Ligand-Induced Aryl Hydrocarbon Receptor-Mediated Biochemical and Toxic Responses

Wilson, Cody L.; Safe, Stephen
Toxicologic Pathology , Volume 26 (5): 15 – Sep 1, 1998
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References (202)

Publisher
SAGE
Copyright
Copyright © by SAGE Publications
ISSN
0192-6233
eISSN
1533-1601
DOI
10.1177/019262339802600510
pmid
9789953
Publisher site
See Article on Publisher Site

Abstract

The ubiquitous environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) is a member of a broad group of halogenated aromatic hydrocarbons (HAHs) that is known to induce a wide range of toxic and biochemical responses in laboratory animals and humans. The effects of HAH exposure are mediated by binding to the cytosolic aryl hydrocarbon receptor (AhR), which is expressed in a tissue- and cell type-specific manner. The AhR is a ligand-activated transcription factor belonging to the basic helix-loop-helix/Per-AhR-Arnt-Sim (bHLH/PAS) superfamily of proteins. The mechanism of induction of gene transcription by TCDD involves Iigand recognition and binding by the AhR, nuclear translocation, and dimerization with the AhR cofactor, AhR nuclear translocator (Arnt). The nuclear heterodimer interacts with cognate xenobiotic responsive elements (XREs) in promoter/enhancer regions of multiple Ah-responsive genes. Subsequent changes in chromatin structure and/or interaction of the AhR complex with the basal transcriptional machinery play a significant role in AhR-mediated gene expression. Although Arnt is a necessary component of a functional nuclear AhR complex, this protein also forms transcriptionally active heterodimers with other bHLH/PAS factors, including those involved in the transcriptional response to hypoxia. Arnt is ubiquitously expressed in mammalian systems, and results from transgenic mouse studies suggest that this protein plays a vital role in early mammalian embryonic development. Similar experiments suggest that the AhR may be involved in development of various organ systems. Thus, molecular mechanistic studies of TCDD action have contributed significantly to an improved understanding of the role of at least 2 bHLH/PAS proteins, as well as organ- and tissue-specific biochemical and toxic responses to this class of environmental toxins.

Journal

Toxicologic Pathology – SAGE

Published: Sep 1, 1998

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