MOE Key Lab of Environment and Health, Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, Hubei, PRChina.
Toxicol Lett. 2011 Apr 10;202(1):55-60. doi: 10.1016/j.toxlet.2011.01.020. Epub 2011 Jan 28.
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.
p,p'-DDE 是二氯二苯对二氯乙烷（DDT）的主要代谢物，是一种已知的持久性有机污染物和雄性生殖毒物。然而，其雄性生殖毒性的机制仍有限。我们之前的研究表明，p,p'-DDE 可诱导培养的大鼠支持细胞中线粒体介导的细胞凋亡。在本研究中，我们研究了丝裂原活化蛋白激酶途径以及其他与线粒体相关的分子，包括 Bax 家族成员和细胞色素 c。结果表明，p,p'-DDE 可诱导氧化应激介导的 p38 和 JNK 磷酸化。此外，p,p'-DDE 处理可诱导细胞色素 c 的 mRNA 水平升高，以及 bax/bcl-w 和 bak/bcl-w 的比值升高，这种升高可被 RNA 合成抑制剂（放线菌素 D）抑制。NAC（N-乙酰-L-半胱氨酸）预处理可阻断 p,p'-DDE 诱导的细胞凋亡，并可减轻 p38 抑制剂（SB202190）或放线菌素 D 预处理，但不能减轻 JNK 抑制剂（SP600125）的减轻作用。所有这些发现表明，氧化应激介导的 p38 MAPK 途径和促凋亡与抗凋亡 bax 基因家族之间的平衡可能在 p,p'-DDE 诱导的凋亡中起关键作用。
