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: Xiumei Han, Rong Tang, Xiaojiao Chen, Bo Xu, Yufeng Qin, Wei Wu, Yanhui Hu, Bin Xu, Ling Song, Yankai Xia, Xinru Wang
• Journal: Toxicology (Toxicology) Vol. 302 Issue 1 Pg. 44-50 (Dec 08 2012) ISSN: 1879-3185 [Electronic] Ireland
• PMID: 22867812 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Chorionic Gonadotropin
• Halogenated Diphenyl Ethers
• Polybrominated Biphenyls
• RNA, Messenger
• 2,2',4,4'-tetrabromodiphenyl ether
• Colforsin
• Progesterone
• Cyclic AMP
• Cholesterol Side-Chain Cleavage Enzyme
• Cyclic AMP-Dependent Protein Kinases

Topics

• Animals
• Cell Line, Tumor
• Cholesterol Side-Chain Cleavage Enzyme (genetics, metabolism)
• Chorionic Gonadotropin (pharmacology)
• Colforsin (pharmacology)
• Cyclic AMP (metabolism)
• Cyclic AMP-Dependent Protein Kinases (metabolism)
• Down-Regulation (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Halogenated Diphenyl Ethers
• Humans
• Leydig Cell Tumor
• Mice
• Polybrominated Biphenyls (toxicity)
• Progesterone (biosynthesis)
• RNA, Messenger (metabolism)