Fenvalerate inhibits progesterone production through cAMP-dependent signal pathway.
Fenvalerate is a widely used synthetic pyrethroid insecticide and is known to impede the male reproductive function. However, the mechanisms remain to be elucidated. In this study, mouse Leydig tumor cells (MLTC-1) were used to investigate the effects of fenvalerate on progesterone production. Fenvalerate treatment inhibited progesterone secretion induced by human chorionic gonadotropin (hCG), cholera toxin (CT) or forskolin and decreased cAMP levels induced by hCG, but not by CT or forskolin, which suggested a repaired site on the upstream components of G protein or G protein per se by fenvalerate in the cAMP-mediated signal pathway. Furthermore, the addition of cAMP analog, 8-Br-cAMP, could not reverse fenvalerate-suppressed progesterone synthesis, indicating that fenvalerate interfered with the downstream molecules of cAMP. In addition, fenvalerate decreased steroidogenic acute regulatory protein (StAR) mRNA and protein levels, and also profoundly inhibited the activity of P450 side chain cleavage enzyme (P450scc) which was consistent with the decreased expression of P450scc mRNA and protein in MLTC-1 cells. These results suggested that fenvalerate might inhibit progesterone production by attenuating cAMP generation and inhibiting StAR expression and P450scc activity.
Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, PR China.
Jian-Hua
JH
Qu
Xia
X
Hong
Jian-Feng
JF
Chen
Yu-Bang
YB
Wang
Hong
H
Sun
Xiao-Lin
XL
Xu
Ling
L
Song
Shou-Lin
SL
Wang
Xin-Ru
XR
Wang
D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002772:Cholera Toxin / Q000494:pharmacology; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006063:Chorionic Gonadotropin / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000633:toxicity*; D006888:Hydroxycholesterols / Q000378:metabolism; D007306:Insecticides / Q000633:toxicity*; D007984:Leydig Cell Tumor / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D009570:Nitriles / Q000633:toxicity*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011284:Pregnenolone / Q000378:metabolism; D011374:Progesterone / Q000378:metabolism*; D011722:Pyrethrins / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000098682:Steroidogenic Acute Regulatory Protein
D006063:Chorionic Gonadotropin; D004791:Enzyme Inhibitors; D006888:Hydroxycholesterols; D007306:Insecticides; D009570:Nitriles; D010750:Phosphoproteins; D011722:Pyrethrins; D012333:RNA, Messenger; D000098682:Steroidogenic Acute Regulatory Protein; C003585:22-hydroxycholesterol; D005576:Colforsin; C016276:8-bromocyclic GMP; D011374:Progesterone; D011284:Pregnenolone; D002772:Cholera Toxin; D000242:Cyclic AMP; D002786:Cholesterol Side-Chain Cleavage Enzyme; D006152:Cyclic GMP; C017690:fenvalerate