Methylsulfonylmethane (MSM) Mitigates Cisplatin-Induced Early Oxidative Testicular Dysfunction Through Modulation of...

Background/Objectives: Cisplatin-induced testicular toxicity is commonly associated with oxidative stress; however, the early biological events preceding overt tissue injury remain incompletely characterized. Identifying interventions capable of preserving redox homeostasis during this subacute phase may improve our understanding of the initial mechanisms underlying testicular dysfunction. This study investigated whether methylsulfonylmethane (MSM), a naturally occurring organosulfur compound with antioxidant properties, modulates early oxidative responses in a subacute rat model of cisplatin-induced testicular toxicity. Methods: Thirty-two adult male Sprague-Dawley rats were randomly assigned to Control, Cisplatin (CIS), MSM, and CIS + MSM groups (n = 8/group). MSM (500 mg/kg/day, intraperitoneally) was administered for 10 consecutive days, while a single dose of cisplatin (7 mg/kg, intraperitoneally) was given on day 7. Oxidative stress biomarkers, antioxidant enzyme activities, intratesticular testosterone concentrations, inflammatory cytokines, GPX4 and HO-1 protein expression, histopathological alterations, and correlation analyses were evaluated. Results: Cisplatin exposure induced a marked oxidative imbalance, evidenced by increased malondialdehyde levels and reduced superoxide dismutase, catalase, glutathione peroxidase, and intratesticular testosterone concentrations (p < 0.05). MSM administration attenuated lipid peroxidation, restored antioxidant enzyme activities, and preserved intratesticular testosterone levels. Western blot analysis demonstrated a significant increase in GPX4 protein expression following cisplatin exposure, whereas MSM normalized GPX4 expression toward control values. In contrast, HO-1 expression and intratesticular IL-6 and TNF-α levels did not differ among the experimental groups. Histopathological evaluation revealed only mild structural alterations without corresponding differences in Johnsen score, indicating that biochemical and molecular disturbances preceded overt tissue degeneration. Correlation analysis further demonstrated close associations between antioxidant defense and preservation of endocrine function. Conclusions: Subacute cisplatin exposure primarily disrupted testicular redox homeostasis before prominent histopathological injury became evident. MSM was associated with attenuation of these early oxidative alterations accompanied by improved endogenous antioxidant enzyme activity, higher intratesticular testosterone concentrations, and normalization of GPX4 expression. These findings suggest that MSM may contribute to the maintenance of testicular redox homeostasis during the early phase of cisplatin-induced toxicity under the present experimental conditions.