title: Fetal pituitary gonadotropin as an initial target of dioxin in its impairment of cholesterol transportation and steroidogenesis in rats.
abstract: 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 3beta-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-alpha 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 LHbeta subunit mRNA in fetuses was reduced by maternal exposure to TCDD, whereas the alpha-subunit remained unchanged. The reduction in LHbeta 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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Junpei
authors.initials: J
authors.lastname: Mutoh
authors.forename: Junko
authors.initials: J
authors.lastname: Taketoh
authors.forename: Kazuharu
authors.initials: K
authors.lastname: Okamura
authors.forename: Tetsushi
authors.initials: T
authors.lastname: Kagawa
authors.forename: Takumi
authors.initials: T
authors.lastname: Ishida
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishii
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yamada
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D015536:Down-Regulation; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D012739:Gonadal Steroid Hormones / Q000378:metabolism; D037101:Luteinizing Hormone, beta Subunit / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D008297:Male; D018811:Maternal Exposure; D008565:Membrane Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D010902:Pituitary Gland / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D013254:Steroid 17-alpha-Hydroxylase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013737:Testis / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D004785:Environmental Pollutants; D012739:Gonadal Steroid Hormones; D037101:Luteinizing Hormone, beta Subunit; D008565:Membrane Proteins; D010750:Phosphoproteins; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D000098682:Steroidogenic Acute Regulatory Protein; D002784:Cholesterol; D013254:Steroid 17-alpha-Hydroxylase