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Thyroid Hormone Action Is Disrupted by Bisphenol A as an Antagonist

Department of Medicine and Clinical Science, Graduate School of Medicine, Kyoto University (K.M., T.A., M.S., N.K., Y.H., K.N.), Kyoto 606-8507, Japan; and Clinical Research Institute, Center for Endocrine and Metabolic Diseases, Kyoto National Hospital (K.M., T.T., T.U., A.S., H.K.), Kyoto 612-8555, Japan

Address all correspondence and requests for reprints to: Tetsuya Tagami, M.D., Ph.D., Clinical Research Institute, Center for Endocrine and Metabolic Diseases, Kyoto National Hospital, 1-1 Mukaihata-cho, Fukakusa, Fushimi-ku, Kyoto 612-8555, Japan. E-mail: ttagami{at}kyotolan.hosp.go.jp.

Abstract

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 (T₃) in a dose-dependent manner. The inhibitory effects were observed in the presence of physiological concentrations of T₃. In contrast, in the case of negatively regulated TSH promoter, BPA activated the gene transcription that is suppressed by T₃. To elucidate possible mechanisms of the antagonistic action of BPA, the effects on T₃ binding and cofactor interaction with TR were examined. The K_i value for BPA was 200 µM when assessed by inhibition of [¹²⁵I]T₃ 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 T₃ from the TR and recruit a transcriptional repressor, resulting in gene suppression. This is the first report that BPA can antagonize T₃ 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.

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