title: In vitro and in vivo analysis of the thyroid system-disrupting activities of brominated phenolic and phenol compounds in Xenopus laevis.
abstract: 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.
authors.affiliation: Department of Biology, Faculty of Science, Shizuoka University, 836 Ohya, Shizuoka 422-8529, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Kudo
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yamauchi
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Fukazawa
authors.forename: Yoshiyasu
authors.initials: Y
authors.lastname: Terao
mesh_terms: D000818:Animals; D001483:Base Sequence; D001798:Blood Proteins / Q000378:metabolism; D001966:Bromine / Q000737:chemistry*; D017931:DNA Primers; D052244:Endocrine Disruptors / Q000378:metabolism / Q000633:toxicity*; D066298:In Vitro Techniques; D010636:Phenols / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D013961:Thyroid Gland / Q000187:drug effects* / Q000378:metabolism; D014284:Triiodothyronine / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D001798:Blood Proteins; D017931:DNA Primers; D052244:Endocrine Disruptors; D010636:Phenols; D014284:Triiodothyronine; D001966:Bromine