The role of poly ADP-ribose polymerase (PARP) pathway in varicocele induced testicular damage

Varicocele has long been implicated as a major cause of male infertility. However, pathogenetic mechanisms by which varicocele induces testicular dysfunction and infertility are not fully understood. Recently, studies evaluating the role of oxidative stress in male infertility have shown that sperm dysfunction in varicocele patients are related to oxidative stress. Poly(ADP-ribosyl)ation is a cellular response to DNA strand breaks that is catalyzed by poly(ADP-ribose) polymerases (PARPs). PARP-1 is the most active and best-characterized member of the PARP family. PARP overactivation occurs in various pathological conditions involving oxidative stress or inflammation. Extensive activation of PARP leads to cell dysfunction and can culminate in cell death, either apoptosis or necrosis. Despite the long history associated with varicoceles, no medical treatment could be successfully used until now. PARP overactivation during high levels of oxidative stress and their interaction suggested us the hypothesis that ?testicular damage and sperm dysfunction in varicocele patients may be in part related with overactivation of PARP pathways?. Adult animals, which were 7-weeks-old, were randomly separated into three groups. First group rats were used as control group (n:10), second group rats underwent a sham operation (n:10) and third group rats were used for experimental groups and underwent partial ligation of renal vein (n:10). Rats in all groups were sacrified after induction of experimental varicocele. Western blot and immunohistochemical analysis of PARP-1, PAR and 4-HNE (oxidative stress marker) in left testicular tissues were done. TUNEL analysis was performed for apoptotic cell evaluation. The tissue weights of varicocele induced testes decreased significantly, whereas, tubule degeneration was significant in these testes. Western blot analyses have confirmed increased oxidative stress in varicocele groups. Both werstern blot an immunohistochemical analysis have confirmed that PARP-1 and PAR expressions increased significantly in all germ cell types. Moreover, the ratio of apoptotic germ cells in varicocele groups were significantly higher when compared to control and sham groups.In conclusion, for the first time in the literature it has been confirmed that increased oxidative stress in varicocele triggered the activation of PARP pathway which in turn induced germ cell apoptosis. By evaluating the role of PARP pathway in varicocele testes, this study contributes very much to molecular mechanisms of varicocele patogenesis when compared to studies those generally evaluate the sperm cells of varicocele patients. Studies regarding the effects of pharmacological PARP inhibition to exprimental varicocele are in progress in our laboratory.