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, hasbeen shown to possess estrogenic properties and act as an agonistfor the estrogen receptors. Although an epidemiologically basedinvestigation has suggested that some chemicals could disruptthyroid function in animals, the effects on thyroid hormonereceptors (TRs) are unknown. We show here that BPA inhibitsTR-mediated transcription by acting as an antagonist. In thetransient gene expression experiments, BPA suppressed transcriptionalactivity that is stimulated by thyroid hormone (T3) in a dose-dependentmanner. The inhibitory effects were observed in the presenceof physiological concentrations of T3. In contrast, in the caseof negatively regulated TSH promoter, BPA activated the genetranscription that is suppressed by T3. To elucidate possiblemechanisms of the antagonistic action of BPA, the effects onT3 binding and cofactor interaction with TR were examined. TheKi value for BPA was 200 µM when assessed by inhibitionof [125I]T3 binding to rat hepatic nuclear TRs. In a mammaliantwo-hybrid assay, BPA recruited the nuclear corepressor to theTR. These results suggest that BPA could displace T3 from theTR and recruit a transcriptional repressor, resulting in genesuppression. This is the first report that BPA can antagonizeT3 action at the transcriptional level. BPA may disrupt thefunction of various types of nuclear hormone receptors and theircofactors to disturb our internal hormonal environment.
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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 Ki 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. 
