Thyroid hormone action is disrupted by bisphenol A as an antagonist.
Bisphenol A (BPA), a monomer of polycarbonate plastics, has been shown to possess estrogenic properties and act as an agonist for the estrogen receptors. Although an epidemiologically based investigation has suggested that some chemicals could disrupt thyroid function in animals, the effects on thyroid hormone receptors (TRs) are unknown. We show here that BPA inhibits TR-mediated transcription by acting as an antagonist. In the transient gene expression experiments, BPA suppressed transcriptional activity that is stimulated by thyroid hormone (T(3)) in a dose-dependent manner. The inhibitory effects were observed in the presence of physiological concentrations of T(3). In contrast, in the case of negatively regulated TSHalpha promoter, BPA activated the gene transcription that is suppressed by T(3). To elucidate possible mechanisms of the antagonistic action of BPA, the effects on T(3) binding and cofactor interaction with TR were examined. The K(i) value for BPA was 200 micro M when assessed by inhibition of [(125)I]T(3) binding to rat hepatic nuclear TRs. In a mammalian two-hybrid assay, BPA recruited the nuclear corepressor to the TR. These results suggest that BPA could displace T(3) from the TR and recruit a transcriptional repressor, resulting in gene suppression. This is the first report that BPA can antagonize T(3) action at the transcriptional level. BPA may disrupt the function of various types of nuclear hormone receptors and their cofactors to disturb our internal hormonal environment.
Moriyama
Kenji
K
Department of Medicine and Clinical Science, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
Tagami
Tetsuya
T
Akamizu
Takashi
T
Usui
Takeshi
T
Saijo
Misa
M
Kanamoto
Naotetsu
N
Hataya
Yuji
Y
Shimatsu
Akira
A
Kuzuya
Hideshi
H
Nakao
Kazuwa
K
D000818:Animals; D001559:Benzhydryl Compounds; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins; D015870:Gene Expression / Q000187:drug effects; D015292:Glycoprotein Hormones, alpha Subunit / Q000235:genetics; D018197:Hepatoblastoma; D006801:Humans; D007457:Iodine Radioisotopes; D008024:Ligands; D008099:Liver / Q000648:ultrastructure; D008113:Liver Neoplasms; D009687:Nuclear Proteins / Q000502:physiology; D056971:Nuclear Receptor Co-Repressor 1; D010636:Phenols / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011988:Receptors, Thyroid Hormone / Q000187:drug effects / Q000378:metabolism; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins / Q000502:physiology; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics / Q000502:physiology; D037042:Thyroid Hormone Receptors beta / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014284:Triiodothyronine / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D004268:DNA-Binding Proteins; D015292:Glycoprotein Hormones, alpha Subunit; D007457:Iodine Radioisotopes; D008024:Ligands; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D010636:Phenols; D011988:Receptors, Thyroid Hormone; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; D014157:Transcription Factors; D014284:Triiodothyronine; C052130:GAL4 protein, S cerevisiae; C539127:NCOR1 protein, human; C539129:Ncor1 protein, rat; C006780:bisphenol A; D000098826:Bisphenol A Compounds