Cypermethrin exposure reduces the ovarian reserve by causing mitochondrial dysfunction in granulosa cells

Cypermethrin (CYP) is one of the most highly effective synthetic pyrethroid insecticides and is recommended for insect control because it is considered to be relatively non-toxic to humans in all stages of life. However, recent data have shown that CYP has adverse effects on fertility, immune system, cardiovascular, hepatic metabolism and enzyme activity in vertebrates. Our objective was to investigate the toxicity of CYP to the ovary and to elucidate the underlying molecular mechanisms. Twenty 8-week-old CD-1 female mice were randomly assigned to four groups, that were separately exposed to CYP at doses of 12.5, 25 and 50 mg/kg/day or to corn oil (vehicle) for 28 days by intragastric administration. Moreover, human granulosa KGN cells were treated with CYP for 24 h at concentrations of 100 μM and 200 μM or to anhydrous ethanol (vehicle). This study clearly demonstrated that, compared to vehicle exposure, CYP exposure caused abnormal estrous cyclicity and decreased follicle numbers in all stages of mice with a dose-dependent manner. Interestingly, the apoptosis signals were mainly located in granulosa cells, and the expression levels of Caspase 3, Bax and Bcl-2 were increased in the 25 and 50 mg/kg/d groups. In KGN cells, CYP (100 and 200 μM) clearly induced apoptosis together with mitochondrial membrane potential depolarization and abnormal ROS generation compared to the control group. Altogether, these results suggest that CYP exposure reduced the ovarian reserve in mice by inducing apoptosis in granulosa cells via mitochondrial-related pathways.