title: Identification of the functional domain of thyroid hormone receptor responsible for polychlorinated biphenyl-mediated suppression of its action in vitro.
abstract: 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.
  
  
  OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Department of Integrative Physiology, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Miyazaki
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Iwasaki
authors.forename: Akira
authors.initials: A
authors.lastname: Takeshita
authors.forename: Chiharu
authors.initials: C
authors.lastname: Tohyama
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Koibuchi
mesh_terms: D001572:Benzofurans / Q000378:metabolism / Q000633:toxicity*; D002460:Cell Line; D066298:In Vitro Techniques; D000072317:Polychlorinated Dibenzodioxins / Q000378:metabolism / Q000633:toxicity*; D011988:Receptors, Thyroid Hormone / Q000187:drug effects* / Q000378:metabolism
chemical_list: D001572:Benzofurans; D000072317:Polychlorinated Dibenzodioxins; D011988:Receptors, Thyroid Hormone; C038890:2,3,4,7,8-pentachlorodibenzofuran
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