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 thyr...

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Bibliographic Details
Published in:The journal of clinical endocrinology and metabolism 2002-11, Vol.87 (11), p.5185-5190
Main Authors: Moriyama, Kenji, Tagami, Tetsuya, Akamizu, Takashi, Usui, Takeshi, Saijo, Misa, Kanamoto, Naotetsu, Hataya, Yuji, Shimatsu, Akira, Kuzuya, Hideshi, Nakao, Kazuwa
Format: Article
Language:English
Subjects:
Animals
Benzhydryl Compounds
Cell Nucleus - metabolism
DNA-Binding Proteins
Gene Expression - drug effects
Glycoprotein Hormones, alpha Subunit - genetics
Hepatoblastoma
Humans
Iodine Radioisotopes
Ligands
Liver - ultrastructure
Liver Neoplasms
Nuclear Proteins - physiology
Nuclear Receptor Co-Repressor 1
Phenols - metabolism
Phenols - pharmacology
Rats
Rats, Sprague-Dawley
Receptors, Thyroid Hormone - drug effects
Receptors, Thyroid Hormone - metabolism
Recombinant Fusion Proteins
Repressor Proteins - physiology
Saccharomyces cerevisiae Proteins - genetics
Thyroid Hormone Receptors alpha - genetics
Thyroid Hormone Receptors alpha - physiology
Thyroid Hormone Receptors beta - genetics
Thyroid Hormone Receptors beta - physiology
Transcription Factors - genetics
Transcription, Genetic - drug effects
Transfection
Triiodothyronine - administration & dosage
Triiodothyronine - antagonists & inhibitors
Triiodothyronine - metabolism
Tumor Cells, Cultured
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Summary: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 TSHα 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.
ISSN:0021-972X
1945-7197
DOI:10.1210/jc.2002-020209