title: Organotin compounds cause structure-dependent induction of progesterone in human choriocarcinoma Jar cells.
abstract: Organotin compounds, such as tributyltin (TBT) and triphenyltin (TPT), are typical environmental contaminants and suspected endocrine-disrupting chemicals because they cause masculinization in female mollusks. In addition, previous studies have suggested that the endocrine disruption by organotin compounds leads to activation of peroxisome proliferator-activated receptor (PPAR)γ and retinoid X receptor (RXR). However, whether organotin compounds cause crucial toxicities in human development and reproduction is unclear. We here investigated the structure-dependent effect of 12 tin compounds on mRNA transcription of 3β-hydroxysteroid dehydrogenase type I (3β-HSD I) and progesterone production in human choriocarcinoma Jar cells. TBT, TPT, dibutyltin, monophenyltin, tripropyltin, and tricyclohexyltin enhanced progesterone production in a dose-dependent fashion. Although tetraalkyltin compounds such as tetrabutyltin increased progesterone production, the concentrations necessary for activation were 30-100 times greater than those for trialkyltins. All tested active organotins increased 3β-HSD I mRNA transcription. We further investigated the correlation between the agonistic activity of organotin compounds on PPARγ and their ability to promote progesterone production. Except for DBTCl2, the active organotins significantly induced the transactivation function of PPARγ. In addition, PPARγ knockdown significantly suppressed the induction of mRNA transcription of 3β-HSD I by all active organotins except DBTCl2. These results suggest that some organotin compounds promote progesterone biosynthesis in vitro by inducing 3β-HSD I mRNA transcription via the PPARγ signaling pathway. The placenta represents a potential target organ for these compounds, whose endocrine-disrupting effects might cause local changes in progesterone concentration in pregnant women.
authors.affiliation: Laboratory of Hygienic Chemistry and Molecular Toxicology, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, Gifu, 501-1196, Japan; Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University, 2-1723 Omori, Moriyamaku, Nagoya, Aichi, 463-8521, Japan.
authors.forename: Youhei
authors.initials: Y
authors.lastname: Hiromori
authors.affiliation: Laboratory of Hygienic Chemistry and Molecular Toxicology, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, Gifu, 501-1196, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yui
authors.affiliation: Laboratory of Health Sciences, School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University, 11-68 Kyuban-cho, Koshien, Nishinomiya, Hyogo, 663-8179, Japan.
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Nishikawa
authors.affiliation: Laboratory of Hygienic Chemistry and Molecular Toxicology, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, Gifu, 501-1196, Japan.
authors.forename: Hisamitsu
authors.initials: H
authors.lastname: Nagase
authors.affiliation: Laboratory of Hygienic Chemistry and Molecular Toxicology, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, Gifu, 501-1196, Japan. Electronic address: nakanishi@gifu-pu.ac.jp.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Nakanishi
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D052244:Endocrine Disruptors / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D009947:Organotin Compounds / Q000494:pharmacology*; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011247:Pregnancy; D011374:Progesterone / Q000819:agonists* / Q000096:biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic; D014327:Trophoblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: D052244:Endocrine Disruptors; D009947:Organotin Compounds; D047495:PPAR gamma; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011374:Progesterone; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase
keywords: 3β-Hydroxysteroid dehydrogenase type I; PPARγ; Placenta; Tributyltin (TBT); Triphenyltin (TPT)