This Article Full Text Full Text (PDF) Supplemental Data Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Google Scholar Articles by Heimeier, R. A. Articles by Shi, Y.-B. PubMed PubMed Citation Articles by Heimeier, R. A. Articles by Shi, Y.-B.

The Xenoestrogen Bisphenol A Inhibits Postembryonic Vertebrate Development by Antagonizing Gene Regulation by Thyroid Hormone

Section on Molecular Morphogenesis (R.A.H., B.D., Y.-B.S.), Program on Cell Regulation and Metabolism, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; and Department of Biological Sciences (D.R.B.), University of Cincinnati, Cincinnati, Ohio 45221-0006

Address all correspondence and requests for reprints to: Yun-Bo Shi, Building 18 T, Room 106, Program on Cell Regulation and Metabolism, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892. E-mail: shi{at}helix.nih.gov.

Bisphenol A (BPA), a chemical widely used to manufacture plastics, is estrogenic and capable of disrupting sex differentiation. However, recent in vitro studies have shown that BPA can also antagonize T₃ activation of the T₃ receptor. The difficulty in studying uterus-enclosed mammalian embryos has hampered the analysis on the direct effects of BPA during vertebrate development. This study proposed to identify critical T₃ pathways that may be disrupted by BPA based on molecular analysis in vivo. Because amphibian metamorphosis requires T₃ and encompasses the postembryonic period in mammals when T₃ action is most critical, we used this unique model for studying the effect of BPA on T₃-dependent vertebrate development at both the morphological and molecular levels. After 4 d of exposure, BPA inhibited T₃-induced intestinal remodeling in premetamorphic Xenopus laevis tadpoles. Importantly, microarray analysis revealed that BPA antagonized the regulation of most T₃-response genes, thereby explaining the inhibitory effect of BPA on metamorphosis. Surprisingly, most of the genes affected by BPA in the presence of T₃ were T₃-response genes, suggesting that BPA predominantly affected T₃-signaling pathways during metamorphosis. Our finding that this endocrine disruptor, well known for its estrogenic activity in vitro, functions to inhibit T₃ pathways to affect vertebrate development in vivo and thus not only provides a mechanism for the likely deleterious effects of BPA on human development but also demonstrates the importance of studying endocrine disruption in a developmental context in vivo.