| Identification of the Functional Domain of Thyroid Hormone Receptor Responsible for Polychlorinated Biphenyl–Mediated Suppression of Its Action In Vitro Wataru Miyazaki,1 Toshiharu Iwasaki,1 Akira Takeshita,2 Chiharu Tohyama,3 and Noriyuki Koibuchi1 1Department of Integrative Physiology, Gunma University Graduate School of Medicine, Maebashi, Japan; 2Endocrine Center, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, Tokyo, Japan; 3Laboratory of Environmental Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan Abstract
Background: Polychlorinated biphenyls (PCBs) , polychlorinated dibenzo-p-dioxins, and polychlorinated 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. Key words: dioxin, DNA-binding domain, polychlorinated biphenyl, thyroid hormone receptor, transcription. Environ Health Perspect 116:1231–1236 (2008) . doi:10.1289/ehp.11176 available via http://dx.doi.org/ [Online 14 May 2008]
Address correspondence to T. Iwasaki, Department of Integrative Physiology, Division of Biological Regulation, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan. Telephone: 81-27-220-7923. Fax: 81-27-220-7926. E-mail: tiwasaki@med.gunma-u.ac.jp Supplemental Material is available online at http://www.ehponline.org/members/2008/11176/suppl.pdf This study was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (17510039 to T.I. ; 17390060 to N.K. ; 187859 to W.M.) and a grant for Long-Range Research Initiation from the Japan Chemical Industry Association (T.I. and N.K.) . T.I. was previously employed by Eli Lilly and Company. The other authors declare they have no competing financial interests. Received 15 December 2007 ; accepted 13 May 2008.
The full version of this article is available for free in HTML or PDF formats. |
