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

Abstract

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 β (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 125 I-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 3 binding to xTTR and xTR and that it interferes with the intracellular T3 signaling pathway. © 2006 Oxford University Press.