Disrupting effects of bifenthrin on ovulatory gene expression and prostaglandin synthesis in rat ovarian granulosa cells

Synthetic pyrethroids (SPs) are one of the most frequently and widely used classes of pesticides. Although exposure to SPs is associated with reproductive toxicity in mammals, limited information is available regarding the effects of SPs on female ovulatory function. Bifenthrin (BF), a broad-spectrum type I SP, has been widely used for pest control for two decades. Previous studies showed that BF had estrogen-like activity as an endocrine-disrupting chemical. In this work, we showed the in vitro inhibitory effects of BF on luteinizing hormone (LH)-inducible ovulatory gene expression in rat ovarian granulosa cells, including genes P450scc, StAR, PR, AREG, EREG, TGF-β1, C/EBP β, RUNX1, p21, cyclin E1, CYP19a1, SULT1E1 and PTGS2. Our in vivo studies demonstrated that short-term administration of BF to gonadotropin-primed rats disrupted the expression of LH-responsible ovulatory genes, suggesting that BF has similar disrupting effects on in vitro and in vivo LH signaling. Because prostaglandins and their key synthetic enzyme PTGS2 play pivotal roles in ovulatory process, we further investigated the molecular mechanism of disruption of PTGS2 by BF. Importantly, we found that BF blocked LH-inducible prostaglandin E2 (PGE2) accumulation in cultured medium of granulosa cells. Forskolin stimulated PTGS2 expression was decreased by treatment with BF, indicating that BF may inhibit LH-induced PTGS2 expression through the protein kinase A (PKA)-mediated signaling pathway. In addition, the reduction in transcriptional activity of forskolin-stimulated PTGS2 promoter by BF, indicates that BF blocks the expression of PTGS2 gene at the transcriptional level. Taken together, our present study firstly shows the systemic disrupting effects of BF on the network of ovulatory gene expression patterns as well as prostaglandin synthesis, and suggest that exposure to BF may increase the risk of ovulatory dysfunction in females.