In vitro and in vivo analysis of the thyroid system-disrupting activities of brominated phenolic and phenol compounds in Xenopus laevis.
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.
Kudo
Yumiko
Y
Department of Biology, Faculty of Science, Shizuoka University, 836 Ohya, Shizuoka 422-8529, Japan.
Yamauchi
Kiyoshi
K
Fukazawa
Hitoshi
H
Terao
Yoshiyasu
Y
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
D001798:Blood Proteins; D017931:DNA Primers; D052244:Endocrine Disruptors; D010636:Phenols; D014284:Triiodothyronine; D001966:Bromine