title: 2,2',4,4'-Tetrabromodiphenyl ether (BDE-47) decreases progesterone synthesis through cAMP-PKA pathway and P450scc downregulation in mouse Leydig tumor cells.
abstract: Polybrominated diphenyl ethers (PBDEs) are commonly used as flame retardants in textiles, plastics and electronics and represent a group of persistent environmental contaminants. They have been found to accumulate in human and marine mammals. Previous studies have shown that PBDEs have endocrine-disrupting properties and reproductive toxicity. However, the mechanisms under the reproductive disruptions are still not well understood. In this study, we explored the effects of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) on progesterone biosynthesis and possible mechanisms in mouse Leydig tumor cells (mLTC-1). Our results showed that BDE-47 could reduce progesterone production and decrease the intracellular cAMP level induced by hCG or forskolin. These suggested that BDE-47 decreasing progesterone production in mLTC-1 cells may be associated with the decline of intracellular cAMP level. Moreover, our data also indicated that the site G protein in cAMP-PKA pathway may be involved in this process. Furthermore, the addition of cAMP analog, 8-Br-cAMP, could not reverse the decrease of progesterone biosynthesis, indicating that a post-cAMP site (or sites) might be involved into the BDE-47-decreased progesterone production. In addition, we found BDE-47 reduced the activity of P450 side chain cleavage enzyme (P450scc), which was companied with the decline of P450scc mRNA and protein level in mLTC-1 cells. Put all together, these results suggested that progesterone synthesis decrease induced by BDE-47 may be associated with attenuation of cAMP generation and reduction of P450scc activity.
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Xiumei
authors.initials: X
authors.lastname: Han
authors.forename: Rong
authors.initials: R
authors.lastname: Tang
authors.forename: Xiaojiao
authors.initials: X
authors.lastname: Chen
authors.forename: Bo
authors.initials: B
authors.lastname: Xu
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Qin
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Hu
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.forename: Ling
authors.initials: L
authors.lastname: Song
authors.forename: Yankai
authors.initials: Y
authors.lastname: Xia
authors.forename: Xinru
authors.initials: X
authors.lastname: Wang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics* / Q000378:metabolism; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055768:Halogenated Diphenyl Ethers; D006801:Humans; D007984:Leydig Cell Tumor; D051379:Mice; D011075:Polybrominated Biphenyls / Q000633:toxicity*; D011374:Progesterone / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D006063:Chorionic Gonadotropin; D055768:Halogenated Diphenyl Ethers; D011075:Polybrominated Biphenyls; D012333:RNA, Messenger; C511295:2,2',4,4'-tetrabromodiphenyl ether; D005576:Colforsin; D011374:Progesterone; D000242:Cyclic AMP; D002786:Cholesterol Side-Chain Cleavage Enzyme; D017868:Cyclic AMP-Dependent Protein Kinases