title: In vitro and in vivo analysis of the thyroid disrupting activities of phenolic and phenol compounds in Xenopus laevis.
abstract: We investigated the effects of phenolic and phenol compounds on 3,3',5-L-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 position 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 signaling pathway.
authors.affiliation: Department of Biology, Faculty of Science, Shizuoka University, Shizuoka 422-8529, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Kudo
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yamauchi
mesh_terms: D000818:Animals; D004347:Drug Interactions; D017930:Genes, Reporter; D066298:In Vitro Techniques; D007814:Larva; D008156:Luciferases / Q000378:metabolism; D008675:Metamorphosis, Biological / Q000187:drug effects; D010636:Phenols / Q000633:toxicity*; D011228:Prealbumin / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013959:Thyroid Diseases / Q000139:chemically induced*; D037042:Thyroid Hormone Receptors beta / Q000187:drug effects / Q000378:metabolism; D013963:Thyroid Hormones / Q000235:genetics; D014284:Triiodothyronine / Q000037:antagonists & inhibitors / Q000235:genetics; D014982:Xenopus laevis
chemical_list: D010636:Phenols; D011228:Prealbumin; D037042:Thyroid Hormone Receptors beta; D013963:Thyroid Hormones; D014284:Triiodothyronine; D008156:Luciferases