P,p′-Dichlorodiphenoxydichloroethylene induced apoptosis of Sertoli cells through oxidative stress-mediated p38 MAPK and mitochondrial pathway

Abstract

p,p′-DDE, the major metabolite of dichlorodiphenoxytrichloroethane (DDT), is a known persistent organic pollutant and male reproductive toxicant. However, the mechanism underlying its male reproductive toxicity remains limited. Our previous studies have demonstrated that p,p′-DDE could induce mitochondria-mediated apoptosis of cultured rat Sertoli cells. In the present study, we investigated mitogen-activated protein kinase pathways as well as other mitochondria-related molecules including Bax family members and cytochrome c. Results showed that p,p′-DDE could induce oxidative stress-mediated p38 and JNK phosphorylation. In addition, elevated mRNA levels of cytochrome c and ratios of bax/bcl-w and bak/bcl-w were induced by p,p′-DDE treatment, which could be inhibited by RNA synthesis inhibitor (actinomycin D). p,p′-DDE-induced apoptosis was blocked by NAC (N-acetyl-L-cystein) preincubation and attenuated by pretreatment with p38 inhibitor (SB202190) or actinomycin D, but not with JNK inhibitor (SP600125). All of the findings suggested that oxidative stress-mediated p38 MAPK pathway and the balance between pro- and anti-apoptotic bax-gene family might play critical roles in p,p′-DDE-induced apoptosis.