Cisplatin-induced Testicular Damage and the Autophagy-modulating Effects of Melatonin

Background: Cisplatin (Cis) is a chemotherapeutic agent in the treatment of solid tumors; however, it has serious side effects such as testicular toxicity and long-term reproductive dysfunction. Cisplatin-induced testicular damage is associated with oxidative stress, apoptosis, and impaired spermatogenesis. Melatonin (Mel), which has strong antioxidant properties, has been shown to exert cytoprotective effects and modulate apoptosis and autophagy pathways. Aim: This study aimed to investigate the protective role of melatonin against cisplatin-induced testicular damage, with particular emphasis on its effects on apoptosis and autophagy-related pathways. Methods: Forty adult male Wistar albino rats were randomly divided into four groups (n = 10): Control, Cis, Mel, and Mel + Cis. Cis (7 mg/kg) was administered intraperitoneally as a single dose, while Mel (10 mg/kg/day) was administered intraperitoneally for seven consecutive days. Testicular tissues were evaluated using hematoxylin-eosin staining and Johnson Testicular Biopsy Score (JTBS). Immunohistochemical analysis of Caspase-3, Light Chain3 (LC3), and SIRT-1 (Sirtuin-1) were performed. Serum testosterone, LH and FSH levels were measured by ELISA. Apoptosis was assessed using the TUNEL assay and DNA damage by Comet assay. Results: Cisplatin administration resulted in significant histological deterioration, a decrease in JTBS scores (p < 0.05), increased apoptosis (p < 0.05), reduced expression of autophagy-related markers (p < 0.05), impaired hormonal profiles (p < 0.05), and elevated DNA damage (p < 0.05). Melatonin administration significantly increased LC3 and SIRT-1 expression while decreasing Caspase-3 expression (p < 0.05). Improvement in hormonal levels was also observed, and the number of apoptotic cells was significantly reduced (p < 0.05). Conclusion: Melatonin exerts a protective effect against cisplatin-induced testicular damage by suppressing apoptosis and modulating autophagy-related markers. These findings suggest that melatonin may be a promising supportive therapy to protect testicular function against cisplatin damage.