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Identification of the Functional Domain of Thyroid Hormone Receptor Responsible for Polychlorinated Biphenyl–Mediated Suppression of Its Action in Vitro

BACKGROUND: Polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins, and poly-chlorinated dibenzofurans adversely affect the health of humans and various animals. Such effects might be partially exerted through the thyroid hormone (TH) system. We previously reported that one of the hydro...

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Autores principales: Miyazaki, Wataru, Iwasaki, Toshiharu, Takeshita, Akira, Tohyama, Chiharu, Koibuchi, Noriyuki
Formato: Texto
Lenguaje:English
Publicado: National Institute of Environmental Health Sciences 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2535627/
https://www.ncbi.nlm.nih.gov/pubmed/18795168
http://dx.doi.org/10.1289/ehp.11176
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author Miyazaki, Wataru
Iwasaki, Toshiharu
Takeshita, Akira
Tohyama, Chiharu
Koibuchi, Noriyuki
author_facet Miyazaki, Wataru
Iwasaki, Toshiharu
Takeshita, Akira
Tohyama, Chiharu
Koibuchi, Noriyuki
author_sort Miyazaki, Wataru
collection PubMed
description BACKGROUND: Polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins, and poly-chlorinated dibenzofurans adversely affect the health of humans and various animals. Such effects might be partially exerted through the thyroid hormone (TH) system. We previously reported that one of the hydroxylated PCB congeners suppresses TH receptor (TR)-mediated transcription by dissociating TR from the TH response element (TRE). However, the binding site of PCB within TR has not yet been identified. OBJECTIVES: We aimed to identify the functional TR domain responsible for the PCB-mediated suppression of TR action by comparing the magnitude of suppression using several representative PCB/dioxin congeners. MATERIALS AND METHODS: We generated chimeric receptors by combining TR and glucocorticoid receptor (GR) and determined receptor-mediated transcription using transient transfection-based reporter gene assays, and TR-TRE binding using electrophoretic mobility shift assays. RESULTS: Although several PCB congeners, including the hydroxylated forms, suppressed TR-mediated transcription to various degrees, 2,3,7,8-tetrachlorodibenzo-p-dioxin did not alter TR action, but 2,3,4,7,8-pentachlorodibenzofuran weakly suppressed it. The magnitude of suppression correlated with that of TR–TRE dissociation. The suppression by PCB congeners was evident from experiments using chimeric receptors containing a TR DNA-binding domain (DBD) but not a GR-DBD. CONCLUSIONS: Several nondioxin-like PCB congeners and hydroxylated PCB compounds suppress TR action by dissociating TR from TRE through interaction with TR-DBD.
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spelling pubmed-25356272008-09-15 Identification of the Functional Domain of Thyroid Hormone Receptor Responsible for Polychlorinated Biphenyl–Mediated Suppression of Its Action in Vitro Miyazaki, Wataru Iwasaki, Toshiharu Takeshita, Akira Tohyama, Chiharu Koibuchi, Noriyuki Environ Health Perspect Research BACKGROUND: Polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins, and poly-chlorinated dibenzofurans adversely affect the health of humans and various animals. Such effects might be partially exerted through the thyroid hormone (TH) system. We previously reported that one of the hydroxylated PCB congeners suppresses TH receptor (TR)-mediated transcription by dissociating TR from the TH response element (TRE). However, the binding site of PCB within TR has not yet been identified. OBJECTIVES: We aimed to identify the functional TR domain responsible for the PCB-mediated suppression of TR action by comparing the magnitude of suppression using several representative PCB/dioxin congeners. MATERIALS AND METHODS: We generated chimeric receptors by combining TR and glucocorticoid receptor (GR) and determined receptor-mediated transcription using transient transfection-based reporter gene assays, and TR-TRE binding using electrophoretic mobility shift assays. RESULTS: Although several PCB congeners, including the hydroxylated forms, suppressed TR-mediated transcription to various degrees, 2,3,7,8-tetrachlorodibenzo-p-dioxin did not alter TR action, but 2,3,4,7,8-pentachlorodibenzofuran weakly suppressed it. The magnitude of suppression correlated with that of TR–TRE dissociation. The suppression by PCB congeners was evident from experiments using chimeric receptors containing a TR DNA-binding domain (DBD) but not a GR-DBD. CONCLUSIONS: Several nondioxin-like PCB congeners and hydroxylated PCB compounds suppress TR action by dissociating TR from TRE through interaction with TR-DBD. National Institute of Environmental Health Sciences 2008-09 2008-05-14 /pmc/articles/PMC2535627/ /pubmed/18795168 http://dx.doi.org/10.1289/ehp.11176 Text en http://creativecommons.org/publicdomain/mark/1.0/ Publication of EHP lies in the public domain and is therefore without copyright. All text from EHP may be reprinted freely. Use of materials published in EHP should be acknowledged (for example, ?Reproduced with permission from Environmental Health Perspectives?); pertinent reference information should be provided for the article from which the material was reproduced. Articles from EHP, especially the News section, may contain photographs or illustrations copyrighted by other commercial organizations or individuals that may not be used without obtaining prior approval from the holder of the copyright.
spellingShingle Research
Miyazaki, Wataru
Iwasaki, Toshiharu
Takeshita, Akira
Tohyama, Chiharu
Koibuchi, Noriyuki
Identification of the Functional Domain of Thyroid Hormone Receptor Responsible for Polychlorinated Biphenyl–Mediated Suppression of Its Action in Vitro
title Identification of the Functional Domain of Thyroid Hormone Receptor Responsible for Polychlorinated Biphenyl–Mediated Suppression of Its Action in Vitro
title_full Identification of the Functional Domain of Thyroid Hormone Receptor Responsible for Polychlorinated Biphenyl–Mediated Suppression of Its Action in Vitro
title_fullStr Identification of the Functional Domain of Thyroid Hormone Receptor Responsible for Polychlorinated Biphenyl–Mediated Suppression of Its Action in Vitro
title_full_unstemmed Identification of the Functional Domain of Thyroid Hormone Receptor Responsible for Polychlorinated Biphenyl–Mediated Suppression of Its Action in Vitro
title_short Identification of the Functional Domain of Thyroid Hormone Receptor Responsible for Polychlorinated Biphenyl–Mediated Suppression of Its Action in Vitro
title_sort identification of the functional domain of thyroid hormone receptor responsible for polychlorinated biphenyl–mediated suppression of its action in vitro
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2535627/
https://www.ncbi.nlm.nih.gov/pubmed/18795168
http://dx.doi.org/10.1289/ehp.11176
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