PD35-12 KDM5A, A HISTONE H3K4 DEMETHYLASE, REGULATES SPERMATOGENESIS VIA ITS ACTION ON GERM CELL

Abstract

INTRODUCTION AND OBJECTIVES: Cisplatin is a widely used chemotherapeutic agent for the treatment of various genitourinary tumors. Although it is a very effective, its use is limited by its renal and testicular toxicity. Mesenchymal stem cells (MSCs) are pluripotent undifferentiated cells that have the ability to differentiate and divide into another cell types and can self renew. Our aim was to investigate the possible protective role of MSCs against Cisplatin induced testicular apoptosis and damaged oxidant/antioxidant balance in rats. Furthermore, we explored the involvement of apoptotic markers in the pathogenesis of testicular toxicity and their role in monitoring treatment. METHODS: A total of 30 male Sprague Dawley rats were used for the experiment. They were divided into 3 groups: Group 1 served as control group received intraperitoneal (IP) saline, Group 2 (Cisplatin group) received a single IP dose of Cisplatin 7mg/kg and Group 3 (Stem Cells group) received the same IP single dose of Cisplatin and was administered BM-MSCs (2x10 cells) by penile vein injection 24h after the Cisplatin injection. Testicular weight and plasma testosterone level were determined along with testicular malondialdehyde (MDA) and reduced glutathione (GSH) levels as oxidative stress markers. Testicular gene expressions of Caspase-3 and mitogen activated protein kinase (MAPK) were estimated by real time-PCR. Histopathological examination for testicular tissues was also done. RESULTS: Cisplatin induced a significant reduction in testicular weights, plasma testosterone and testicular GSH levels in addition to significant elevation of testicular MDA levels and gene expressions of Caspase-3 and MAPK when compared with control group (p<0.05). Histopathology showed lower tubular diameters and depletion of germ cells, irregular small seminiferous tubules with Sertoli cells only were observed in Cisplatin group. MSCs injection significantly corrected these changes in both biochemical and histopathological parameters. CONCLUSIONS: There is a significant role of oxidative and apoptotic markers in the pathogenesis of Cisplatin induced oxidative injury in rat testis. Cisplatin treatment markedly impaired testicular function in rats through mechanisms that could be significantly salvaged with co-administration of MSCs. To our knowledge, this is the first report in the literature that address the protective role of MSCs in Cisplatin induced testicular toxicity; however, further studies are needed to validate our findings.