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Trialkyltin Compounds Enhance Human CG Secretion and Aromatase Activity in Human Placental Choriocarcinoma Cells

Department of Toxicology (T.N., J.K., S.S., I.J., Y.H., S.T., N.I., K.T.), Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan; and Department of Pharmaceutics (Y.W., N.U.), Showa Pharmaceutical University, Tokyo 194-8543, Japan

Address all correspondence and requests for reprints to: Tsuyoshi Nakanishi, Ph.D., Department of Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6, Yamadaoka Suita, Osaka 565-0871, Japan. E-mail: . nakanishi{at}phs.osaka-u.ac.jp

Abstract

Human choriocarcinoma cell lines have been used as placental models for the study of endocrine function, including aromatase (CYP19) activity and the secretion of human CG (hCG). In the present study, we investigated the effects of trialkyltin compounds, which are suspected endocrine disrupters, on aromatase activity and hCG secretion in human choriocarcinoma JAR, JEG-3, and BeWo cells. Protein synthesis as measured by ³⁵S-methionine incorporation in all cell lines was markedly decreased by treatment with both tributyltin (TBT) and triphenyltin (TPT) at concentrations above 3 x 10^-7 M, due to cytotoxicity. In JAR cells, ³⁵S-methionine uptake was decreased by 50% at 3 x 10^-7 M of TBT. At a TPT concentration of 1 x 10^-7 M, protein synthesis in JAR cells was not affected, whereas JEG-3 and BeWo cells demonstrated slightly decreases. In all cell lines, both TBT and TPT increased levels of hCG secretion and aromatase activity in a dose- and time-dependent fashion following exposure to nontoxic concentration ranges. In addition, these trialkyltin compounds enhanced 8-bromo-cAMP-induced hCG secretion and aromatase activity in JAR cells. TBT caused dose-related increases in steady-state mRNA levels of both hCGß and CYP19 in JAR cells following 24- or 48-h exposure to nontoxic concentrations of TBT. However, these mRNA changes in JAR cells were not comparable to the changes in both hCG secretion and aromatase activity. These results indicate that the observed trialkyltin-induced alterations in human choriocarcinoma cells are due to other mechanism in addition to a regulation of hCG and CYP19 mRNA levels. Our studies suggest that trialkyltin compounds are potent stimulators of human placental hCG production and aromatase activity in vitro; and the placenta represents a potential target organ for trialkyltin compounds, whose endocrine-disrupting effects might be the result of local changes in hCG and estrogen concentrations in pregnant women.

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