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Fetal Pituitary Gonadotropin as an Initial Target of Dioxin in Its Impairment of Cholesterol Transportation and Steroidogenesis in Rats

Graduate School of Pharmaceutical Sciences (J.M., J.T., K.O., T.I., Y.I., H.Y.), Kyushu University, Fukuoka 812-8582, Japan; Department of Cell Fate Modulation (T.K.), Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan; Division of Active Transport (T.K.), National Institute for Physiological Sciences, Aichi 444-8585, Japan

Address all correspondence and requests for reprints to: Hideyuki Yamada, Ph.D., Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail: yamada{at}xenoba.phar.kyushu-u.ac.jp.

Reproductive and developmental disorders are the most sensitive toxic effects caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD is thought to produce many, if not all, of these toxic effects by impairing steroidogenesis and/or steroid action during the prenatal or early postnatal stages. However, the mechanism of the antisex steroid effect of TCDD is not well understood. This study revealed that steroidogenic acute-regulatory protein (StAR), a key transporter of cholesterol for steroidogenesis, in the testes of fetal rats are down-regulated by maternal exposure to TCDD. It was also shown that many mRNAs of steroidogenetic enzymes, including cytochromes P450 11A1, 17, and 11B1 and 3ß-hydroxysteroid dehydrogenase, are reduced in fetuses of TCDD-treated dams in a testis-specific manner. The same was also observed for the expression of estrogen- receptors and androgen receptors. Whereas StAR expression was not affected by TCDD in cultured fetal testis, the fetal serum content of LH, a pituitary regulator of StAR, was significantly reduced by TCDD. In agreement with this, pituitary expression of LHß subunit mRNA in fetuses was reduced by maternal exposure to TCDD, whereas the -subunit remained unchanged. The reduction in LHß is suggested to occur by a mechanism different from the reduction in the GnRH level. Direct supply of exogenous gonadotropin to TCDD-exposed fetuses completely abolished the reduction of StAR expression. Taken together, these results demonstrate that TCDD impairs steroidogenesis in the fetus by targeting pituitary gonadotropins.

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