Toxicol Sci 2006 Jul 01;921:87-95. doi: 10.1093/toxsci/kfj204.

In vitro and in vivo analysis of the thyroid system-disrupting activities of brominated phenolic and phenol compounds in Xenopus laevis.

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We investigated the effects of the brominated phenolic and phenol compounds, some of which are brominated flame retardants, on the binding of (125)I-3,3',5-L-triiodothyronine ((125)I-T(3)) to purified Xenopus laevis transthyretin (xTTR) and to the ligand-binding domain of X. laevis thyroid hormone receptor beta (xTR LBD), on the induction of a T(3)-responsive reporter gene in a recombinant X. laevis cell line (XL58-TRE-Luc) and on T(3)-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 (125)I-T(3) 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 T(3) binding to xTTR and the xTR LBD. 3,3',5-Tribromobisphenol A and 3,3',5,5'-tetrabromobisphenol A, at 0.1-1.0 microM, exerted both T(3) agonist and antagonist activities in the T(3)-responsive reporter gene assay. Sera obtained from fetal bovine and bullfrog tadpoles weakened the T(3) agonist and antagonist activities of 3,3',5-tribromobisphenol A, but not the T(3) antagonist activity of o-t-butylphenol, for which xTTR has no significant affinity. The T(3) agonist and antagonist activities of 0.5 microM 3,3',5-tribromobisphenol A were confirmed in the in vivo, short-term gene expression assay in premetamorphic X. laevis tadpoles using endogenous, T(3)-responsive genes as molecular markers. Our results suggest that 3,3',5-tribromobisphenol A affects T(3) binding to xTTR and xTR and that it interferes with the intracellular T(3) signaling pathway.

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Species referenced: Xenopus laevis
Genes referenced: tdrd6 ttr