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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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| Published in: | The journal of clinical endocrinology and metabolism 2002-11, Vol.87 (11), p.5185-5190 |
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| container_end_page | 5190 |
| container_issue | 11 |
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| container_title | The journal of clinical endocrinology and metabolism |
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| creator | Moriyama, Kenji Tagami, Tetsuya Akamizu, Takashi Usui, Takeshi Saijo, Misa Kanamoto, Naotetsu Hataya, Yuji Shimatsu, Akira Kuzuya, Hideshi Nakao, Kazuwa |
| description | 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. |
| doi_str_mv | 10.1210/jc.2002-020209 |
| format | article |
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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.</description><identifier>ISSN: 0021-972X</identifier><identifier>EISSN: 1945-7197</identifier><identifier>DOI: 10.1210/jc.2002-020209</identifier><identifier>PMID: 12414890</identifier><language>eng</language><publisher>United States: Endocrine Society</publisher><subject>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</subject><ispartof>The journal of clinical endocrinology and metabolism, 2002-11, Vol.87 (11), p.5185-5190</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c443t-e96e1a3fefcb3c0bf7d27ac644b82576ce016440e0ec116421f5a60e861ae9ca3</citedby><cites>FETCH-LOGICAL-c443t-e96e1a3fefcb3c0bf7d27ac644b82576ce016440e0ec116421f5a60e861ae9ca3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12414890$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Moriyama, Kenji</creatorcontrib><creatorcontrib>Tagami, Tetsuya</creatorcontrib><creatorcontrib>Akamizu, Takashi</creatorcontrib><creatorcontrib>Usui, Takeshi</creatorcontrib><creatorcontrib>Saijo, Misa</creatorcontrib><creatorcontrib>Kanamoto, Naotetsu</creatorcontrib><creatorcontrib>Hataya, Yuji</creatorcontrib><creatorcontrib>Shimatsu, Akira</creatorcontrib><creatorcontrib>Kuzuya, Hideshi</creatorcontrib><creatorcontrib>Nakao, Kazuwa</creatorcontrib><title>Thyroid Hormone Action Is Disrupted by Bisphenol A as an Antagonist</title><title>The journal of clinical endocrinology and metabolism</title><addtitle>J Clin Endocrinol Metab</addtitle><description>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.</description><subject>Animals</subject><subject>Benzhydryl Compounds</subject><subject>Cell Nucleus - metabolism</subject><subject>DNA-Binding Proteins</subject><subject>Gene Expression - drug effects</subject><subject>Glycoprotein Hormones, alpha Subunit - genetics</subject><subject>Hepatoblastoma</subject><subject>Humans</subject><subject>Iodine Radioisotopes</subject><subject>Ligands</subject><subject>Liver - ultrastructure</subject><subject>Liver Neoplasms</subject><subject>Nuclear Proteins - physiology</subject><subject>Nuclear Receptor Co-Repressor 1</subject><subject>Phenols - metabolism</subject><subject>Phenols - pharmacology</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors, Thyroid Hormone - drug effects</subject><subject>Receptors, Thyroid Hormone - metabolism</subject><subject>Recombinant Fusion Proteins</subject><subject>Repressor Proteins - physiology</subject><subject>Saccharomyces cerevisiae Proteins - genetics</subject><subject>Thyroid Hormone Receptors alpha - genetics</subject><subject>Thyroid Hormone Receptors alpha - physiology</subject><subject>Thyroid Hormone Receptors beta - genetics</subject><subject>Thyroid Hormone Receptors beta - physiology</subject><subject>Transcription Factors - genetics</subject><subject>Transcription, Genetic - drug effects</subject><subject>Transfection</subject><subject>Triiodothyronine - administration & dosage</subject><subject>Triiodothyronine - antagonists & inhibitors</subject><subject>Triiodothyronine - metabolism</subject><subject>Tumor Cells, Cultured</subject><issn>0021-972X</issn><issn>1945-7197</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><recordid>eNp1kD1PwzAQhi0EoqWwMiJPbCm24yTNGMpHK1ViKRKb5TgX6iixg50M_fe4SiUm5OF8uude6R6E7ilZUkbJU6OWjBAWERZefoHmNOdJlNE8u0TzMKBRnrGvGbrxviGEcp7E12hGGad8lZM5Wu8PR2d1hTfWddYALtSgrcFbj1-0d2M_QIXLI37Wvj-AsS0usPRYGlyYQX5bo_1wi65q2Xq4O9cF-nx73a830e7jfbsudpHiPB4iyFOgMq6hVmWsSFlnFcukSjkvVyzJUgWEhoYAAUXDj9E6kSmBVUol5ErGC_Q45fbO_ozgB9Fpr6BtpQE7epGxNIkTlgRwOYHKWe8d1KJ3upPuKCgRJ22iUeKkTUzawsLDOXksO6j-8LOnACQTAKayymkDvQPvRWNHZ8LN_wX_Aj_heN0</recordid><startdate>200211</startdate><enddate>200211</enddate><creator>Moriyama, Kenji</creator><creator>Tagami, Tetsuya</creator><creator>Akamizu, Takashi</creator><creator>Usui, Takeshi</creator><creator>Saijo, Misa</creator><creator>Kanamoto, Naotetsu</creator><creator>Hataya, Yuji</creator><creator>Shimatsu, Akira</creator><creator>Kuzuya, Hideshi</creator><creator>Nakao, Kazuwa</creator><general>Endocrine Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>200211</creationdate><title>Thyroid Hormone Action Is Disrupted by Bisphenol A as an Antagonist</title><author>Moriyama, Kenji ; Tagami, Tetsuya ; Akamizu, Takashi ; Usui, Takeshi ; Saijo, Misa ; Kanamoto, Naotetsu ; Hataya, Yuji ; Shimatsu, Akira ; Kuzuya, Hideshi ; Nakao, Kazuwa</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c443t-e96e1a3fefcb3c0bf7d27ac644b82576ce016440e0ec116421f5a60e861ae9ca3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Animals</topic><topic>Benzhydryl Compounds</topic><topic>Cell Nucleus - metabolism</topic><topic>DNA-Binding Proteins</topic><topic>Gene Expression - drug effects</topic><topic>Glycoprotein Hormones, alpha Subunit - genetics</topic><topic>Hepatoblastoma</topic><topic>Humans</topic><topic>Iodine Radioisotopes</topic><topic>Ligands</topic><topic>Liver - ultrastructure</topic><topic>Liver Neoplasms</topic><topic>Nuclear Proteins - physiology</topic><topic>Nuclear Receptor Co-Repressor 1</topic><topic>Phenols - metabolism</topic><topic>Phenols - pharmacology</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptors, Thyroid Hormone - drug effects</topic><topic>Receptors, Thyroid Hormone - metabolism</topic><topic>Recombinant Fusion Proteins</topic><topic>Repressor Proteins - physiology</topic><topic>Saccharomyces cerevisiae Proteins - genetics</topic><topic>Thyroid Hormone Receptors alpha - genetics</topic><topic>Thyroid Hormone Receptors alpha - physiology</topic><topic>Thyroid Hormone Receptors beta - genetics</topic><topic>Thyroid Hormone Receptors beta - physiology</topic><topic>Transcription Factors - genetics</topic><topic>Transcription, Genetic - drug effects</topic><topic>Transfection</topic><topic>Triiodothyronine - administration & dosage</topic><topic>Triiodothyronine - antagonists & inhibitors</topic><topic>Triiodothyronine - metabolism</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Moriyama, Kenji</creatorcontrib><creatorcontrib>Tagami, Tetsuya</creatorcontrib><creatorcontrib>Akamizu, Takashi</creatorcontrib><creatorcontrib>Usui, Takeshi</creatorcontrib><creatorcontrib>Saijo, Misa</creatorcontrib><creatorcontrib>Kanamoto, Naotetsu</creatorcontrib><creatorcontrib>Hataya, Yuji</creatorcontrib><creatorcontrib>Shimatsu, Akira</creatorcontrib><creatorcontrib>Kuzuya, Hideshi</creatorcontrib><creatorcontrib>Nakao, Kazuwa</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>The journal of clinical endocrinology and metabolism</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Moriyama, Kenji</au><au>Tagami, Tetsuya</au><au>Akamizu, Takashi</au><au>Usui, Takeshi</au><au>Saijo, Misa</au><au>Kanamoto, Naotetsu</au><au>Hataya, Yuji</au><au>Shimatsu, Akira</au><au>Kuzuya, Hideshi</au><au>Nakao, Kazuwa</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Thyroid Hormone Action Is Disrupted by Bisphenol A as an Antagonist</atitle><jtitle>The journal of clinical endocrinology and metabolism</jtitle><addtitle>J Clin Endocrinol Metab</addtitle><date>2002-11</date><risdate>2002</risdate><volume>87</volume><issue>11</issue><spage>5185</spage><epage>5190</epage><pages>5185-5190</pages><issn>0021-972X</issn><eissn>1945-7197</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><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 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.</abstract><cop>United States</cop><pub>Endocrine Society</pub><pmid>12414890</pmid><doi>10.1210/jc.2002-020209</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| 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 |
| title | Thyroid Hormone Action Is Disrupted by Bisphenol A as an Antagonist |
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