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J.Health Sci., 54(3), 273-280, 2008


Effects of Endocrine Disrupting Chemicals on Amphibian Metamorphosis and Mitochondrial Membrane Permeability Transition

Akihiko Kashiwagi,*, a Kozo Utsumi,b Keiko Kashiwagi,a Shigeru Ohta,c Kazumi Sugihara,c Hideki Hanada,a and Shigeyuki Kitamurad

aInstitute for Amphibian Biology, Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama, Higashihiroshima 739-8526, Japan, bDepartment of Cytology and Histology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikatacho, Okayama 700-8558, Japan, cGraduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan, and dNihon Pharmaceutical University, 10281 Komura, Ina-machi, Kitaadachi-gun, Saitama 362-0806, Japan

The estrogenic chemical bisphenol A (BPA) has multiple hormonal activities, but its effects on thyroid hormone (TH) action are not fully understood. TH is required for the metamorphosis of tadpoles into frogs, and thus tadpole tail regression, one of the most spectacular events in metamorphosis, can be used for studying the effect of BPA and related compounds (BPAs) on TH action. We found that 3,3',5-triiodothyronine (T3)-induced tadpole tail regression in the wrinkled frog Rana rugosa (R. rugosa) is suppressed by BPA, tetrabromobisphenol A (TBBPA), tetrachlorobisphenol A (TCBPA), and tetramethylbisphenol A (TMBPA). BPAs also inhibited spontaneous metamorphosis in the tropical clawed frog Silurana tropicalis (S. tropicalis) controlled by endogenous circulating TH. These results indicate that BPAs are TH antagonists. For the African clawed frog Xenopus laevis (X. laevis), transgenic tadpoles carrying plasmid DNA containing TH response element (TRE) and 5'-upstream promoter region of the TH receptor (TR) βA1 gene linked to an enhanced green fluorescent protein (EGFP) gene, T3 induced a strong EGFP expression in the hind limbs. This expression was suppressed by BPA, TBBPA, TCBPA and TMBPA, suggesting BPAs all act as antagonists to prevent the binding of T3 to TR, resulting in inhibition of TR-mediated gene expression. Much work has been done in examining the apoptotic and other detrimental effects of polychlorinated biphenyls (PCBs), but the role of mitochondrial damage in such toxic action remains obscure. There is evidence however that mitochondrial membrane permeability transition (MPT) plays a crucial role in apoptosis. We investigated the effect of 4-hydroxy-3,3',4',5-tetrachlorobiphenyl (4-OH-TCB) on isolated rat liver mitochondria. In order to help clarify this, biochemical analysis revealed that 4-OH-TCB induced calcium release, reactive oxygen species (ROS) generation, depolarization, swelling and cytochrome c (Cyt. c) release in a time- and concentration-dependent manner. These 4-OH-TCB-induced changes in mitochondrial function were found to be inhibited by the presence of cyclosporin A (CsA), a specific inhibitor of MPT, suggesting a classic type of MPT. It is concluded that 4-OH-TCB induces MPT together with ROS generation, causing apoptosis in certain cells.