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ToxSci Advance Access published online on December 8, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfi049
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Toxicological Sciences © Society of Toxicology 2004; all rights reserved.
Received August 27, 2004
Accepted November 19, 2004

Endocrine Toxicology

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

Yumiko Kudo 1 and Kiyoshi Yamauchi 1*

1 Department of Biology, Faculty of Science, Shizuoka University, Shizuoka 422-8529, Japan

* To whom correspondence should be addressed.
Kiyoshi Yamauchi, E-mail: sbkyama{at}ipc.shizuoka.ac.jp


  Abstract

We investigated the effects of phenolic and phenol compounds on 3,3',5-[125I]triiodothyronine ([125I]T3) binding to purified Xenopus laevis transthyretin (xTTR) and to the ligand-binding domain of X. laevis thyroid hormone receptor {beta} (xTR LBD), on T3-induced metamorphosis in X. laevis tadpoles and on the induction of T3-dependent reporter gene in a X. laevis cell line. Of the halogenated phenolic and phenol compounds tested, 3,3',5-trichlorobisphenol A and 2,4,6-triiodophenol, respectively, were the most potent competitors of [125I]T3 binding to both xTTR and xTR LBD. Most of the halogenated compounds had stronger interactions with xTTR than with xTR LBD. Generally, chlorinated derivatives with a greater degree of chlorination were more efficient competitors of T3 binding to xTTR and xTR LBD. Structures with a halogen in either ortho positions or in both ortho positions, with respect to the hydroxy group, were more efficient competitors. 3,3',5-Trichlorobisphenol A and 2,4,6-triiodophenol acted as T3 antagonists in the X. laevis tadpole metamorphosis assay. Interestingly, o-t-butylphenol and 2-isopropylphenol, for which xTTR and xTR LBD had weak or no significant affinity, showed T3 antagonist activity in the metamorphosis assay. T3 antagonist activities of all these chemicals except for o-t-butylphenol were verified by T3-dependent reporter gene assay. Our results suggest that some phenolic and phenol compounds target the process of T3 binding to xTTR and xTR and/or an unknown process, and that they interfere with the intracellular T3 signalling pathway.

Keywords: thyroid hormone; transthyretin; thyroid hormone receptor; halogenated phenolic compounds; thyroid disrupting chemicals; metamorphosis; Xenopus laevis.
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