Enantioselective endocrine-disrupting effects of bifenthrin on hormone synthesis in rat ovarian cells.

Bifenthrin (BF), a broad-spectrum and widely used synthetic pyrethroid, is a typical chiral pesticide. More attention is being paid to the health risk assessment of the enantioselective toxicity of BF isomers. In this study, we used rat ovarian granulosa cells as in vitro model to investigate effects of BF enantiomers on the biosynthesis of two hormones, progesterone and prostaglandin E2 (PGE2), which are critical for mammalian reproduction. We showed that 1S-cis-BF, but not 1R-cis-BF significantly decreased the secretion of progesterone and PGE2 in granulosa cells. 1S-isomer of BF reduced the expression of genes P450scc, StAR, PBR and DBI, as well as COX-2, which are involved in regulating the rate-limiting steps of progesterone or PGE2 biosynthesis. The transcriptional activation of StAR and COX-2 promoter were disrupted by 1S-cis-BF. Furthermore, activity of protein kinase C (PKC), an important signaling mediator of progesterone and PGE2 synthesis, was differentially inhibited by 1S-cis-BF. The data of molecular docking revealed that one hydrogen bond was formed between 1S-cis-BF and PKC protein. In conclusion, we firstly reported in this study the enantioselective disrupting effects of BF isomers on progesterone and PGE2 synthesis via PKC pathway in rat ovarian cells. Our findings suggest that the enantioselective toxicity of chiral pesticides should be considered for evaluating mammalian reproductive health, a toxicologic endpoint of great concern in health risk assessment. Crown