In Vitro and In Vivo Analysis of the Thyroid System–Disrupting Activities of Brominated Phenolic and Phenol Compounds in Xenopus laevis

• Published in: Toxicological sciences 2006-07, Vol.92 (1), p.87-95
• Main Authors: Kudo, Yumiko, Yamauchi, Kiyoshi, Fukazawa, Hitoshi, Terao, Yoshiyasu
• Format: Article
• Language: English
• Subjects: Animals; Base Sequence; Blood Proteins - metabolism; brominated phenolic compounds; Bromine - chemistry; DNA Primers; Endocrine Disruptors - metabolism; Endocrine Disruptors - toxicity; In Vitro Techniques; Phenols - chemistry; Phenols - metabolism; Phenols - toxicity; Rana catesbeiana; Thyroid Gland - drug effects; Thyroid Gland - metabolism; thyroid hormone; thyroid hormone receptor; thyroid system–disrupting chemicals; transthyretin; Triiodothyronine - metabolism; Xenopus laevis
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kfj204

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 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.