ToxSci Advance Access originally published online on April 20, 2006
Toxicological Sciences 2006 92(1):87-95; doi:10.1093/toxsci/kfj204
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In Vitro and In Vivo Analysis of the Thyroid System–Disrupting Activities of Brominated Phenolic and Phenol Compounds in Xenopus laevis
* Department of Biology, Faculty of Science, Shizuoka University, Shizuoka, Japan; Shizuoka Institute of Environment and Hygiene, Shizuoka, Japan; and Institute for Environmental Sciences, University of Shizuoka, Shizuoka, Japan
Received February 17, 2006; accepted April 16, 2006
We investigated the effects of the brominated phenolic and phenol compounds, some of which are brominated flame retardants, on the binding of 125I-3,3',5-L-triiodothyronine (125I-T3) to purified Xenopus laevis transthyretin (xTTR) and to the ligand-binding domain of X. laevis thyroid hormone receptor ß (xTR LBD), on the induction of a T3-responsive reporter gene in a recombinant X. laevis cell line (XL58-TRE-Luc) and on T3-induced or spontaneous metamorphosis in X. laevis tadpoles. Of the brominated phenolic and phenol compounds tested, 3,3',5-tribromobisphenol A and 3,3'-dibromobisphenol A were the most potent competitors of 125I-T3 binding to xTTR and the xTR LBD, respectively. Structures with a bromine in either ortho positions with respect to the hydroxy group competed more efficiently with T3 binding to xTTR and the xTR LBD. 3,3',5-Tribromobisphenol A and 3,3',5,5'-tetrabromobisphenol A, at 0.1–1.0µM, exerted both T3 agonist and antagonist activities in the T3-responsive reporter gene assay. Sera obtained from fetal bovine and bullfrog tadpoles weakened the T3 agonist and antagonist activities of 3,3',5-tribromobisphenol A, but not the T3 antagonist activity of o-t-butylphenol, for which xTTR has no significant affinity. The T3 agonist and antagonist activities of 0.5µM 3,3',5-tribromobisphenol A were confirmed in the in vivo, short-term gene expression assay in premetamorphic X. laevis tadpoles using endogenous, T3-responsive genes as molecular markers. Our results suggest that 3,3',5-tribromobisphenol A affects T3 binding to xTTR and xTR and that it interferes with the intracellular T3 signaling pathway.
Key Words: thyroid hormone; transthyretin; thyroid hormone receptor; brominated phenolic compounds; thyroid system–disrupting chemicals; Xenopus laevis.