Disrupting Effects Of Bifenthrin And DDT On Ovarian Function In Rat

Synthetic pyrethroids(SPs) are synthetic esters derived from the naturally occurring toxin pyrethrins. SPs is a new insecticides with high-effective and low-toxicity, following organochlorine, organophosphate and carbamate, widely used in agricultural and residential pest control. Organochlorine pesticide DDT has been baned in most countries for three decades, while it is often detected in environment due to its degradation, migration, bioconcentration properties. Since SPs have been used widespread and high-frequency, and DDT had high detection rate, the potential possibility that humans and other mammals long-term exposure to SPs and DDT become very high. In recent years, although SPs and DDT is associated with reproductive toxicity in mammals and has aroused great concern, limited information is available regarding the effects of SPs and DDT on female ovulatory function. In this study, we chose bifenthrin and o,p’-DDT and used rat ovarian granulosa cells as in vitro model to investigate effects on ovarian function in rats, providing a scientific basis for female reproductive health risks assessment.BF is one of the typical type Ⅰ SPs. Previous studies showed that BF has the effect of enantioselectivity, cytotoxicity, immunotoxicity and endocrine disrupting. In this study, we explore the mechanisms of effects of bifenthrin on rat ovarian function from the racemic and enantiomeric level. At the racemic level, we showed the in vitro and in vivo inhibitory effects of BF on luteinizing hormone (LH)-inducible ovulatory gene expression in rat ovarian granulosa cells. Because prostaglandins and their key synthetic enzyme PTGS2play pivotal roles in ovulatory process, we further investigated the molecular mechanism of disruption of PTGS2by BF. we found that BF blocked LH-inducible prostaglandin E2(PGE2) accumulation in cultured medium of granulosa cells. Forskolin stimulated PTGS2expression and the transcriptional activity of forskolin-stimulated PTGS2promoter was decreased by treatment with BF, indicating that BF blocks the expression of PTGS2gene at the transcriptional level. At the enantiomeric level, We showed that1S-cis-BF, but not1R-cis-BF significantly reduced the LH-inducible ovulatory gene expression and the secretion of progesterone and PGE2in granulosa cells. We further investigate the enantioselectivity molecular mechanism of BF on the biosynthesis of two hormones and we showed that BF may enantioselectively disrupt the transcriptional activation of StAR and COX-2promoter, and decrease activity of protein kinase C (PKC) to blok the biosynthesis of two hormones, the interference effect of lS-cis-BF is stronger than1R-cis-BF. In conclusion, we firstly reported in this study the effects of BF on ovarian gene expression networks as well as the synthesis of hormones, and the disrupting effects has enantioselective. Taken together, exposure to SPs may increase the risk of ovulatory dysfunction in females, and it is necessary to integrally assess the potential health impact of SPs enantiomers.DDT in many countries has been disabled, but there are still a high detection rate. The impact that exposure to low concentrations of DDT in the environment on female reproductive health has aroused great concern. In the present study, in vitro exposure to o,p’-DDT (10-11～-10-9M) inhibited LH-inducible ovulatory gene expression in rat ovarian granulosa cells. Using IC1182,780blocked ER-classical pathway, we found that IC1182,780didn’t rescue the inhibition of gene expression by o,p’-DDT. These data indicated that o,p’-DDT may inhibit these genes expression by ER-independent signaling pathway. The results of PKA activity analysis further indicated that o,p’-DDT may inhibit the expression of these genes through the PKA signaling pathway. This study focused on the effects and mechanisms of exposure to low concentrations of o,p’-DDT on ovulation-related gene expression, and it has a great practical significance for accurate evaluation such environmental endocrine disruptors’ health risks. The effect of o,p’-DDT on hCG-inducible genes expression may through multiple mechanisms, thus the other molecular mechanisms have yet to be further studied.