Cu-induced spermatogenesis disease is related to oxidative stress-mediated germ cell apoptosis and DNA damage

Abstract

Copper is considered as an indispensable trace element for living organisms. However, over-exposure to Cu can lead to adverse health effects on human. In this study, CuSO₄ decreased sperm concentration and motility, increased sperm malformation rate. Concurrently, testicular damage including testicular histopathological aberrations and reduction of testis relative weight were observed. Then, the mechanism underlying Cu-induced testicular toxicity was explored. According to the results, CuSO₄ elevated ROS production while reducing antioxidant function. Additionally, CuSO₄ induced apoptosis which was featured by MMP depolarization and up-regulated levels of cleaved-caspase-3, cleaved-caspase-8, cleaved-caspase-9, caspase-12, cleaved-PARP and Bax, whereas down-regulated Bcl-2 expression. Meanwhile, CuSO₄ caused testis DNA damage (up-regulation of γ-H2AX protein expression) and suppressed DNA repair pathways including BER, NER, HR, MMR, together with the NHEJ repair pathways, yet did not affect MGMT. To investigate the role of oxidative stress in CuSO₄-induced apoptosis and DNA damage, the antioxidant NAC was co-treated with CuSO₄. NAC attenuated CuSO₄-induced ROS production, inhibited apoptosis and DNA damage. Furthermore, the spermatogenesis disorder was also abolished in the co-treatment with CuSO₄ and NAC group. Altogether, abovementioned results indicated that CuSO₄-induced spermatogenesis disorder is related to oxidative stress-mediated DNA damage and germ cell apoptosis, impairing male reproductive function.

Keywords: Apoptosis; CuSO(4); DNA damage; DNA damage repair; Testis.