Oxaliplatin-induced testicular toxicity is associated with transglutaminase-4 upregulation, hormonal dysregulation, and inflammatory responses

Oxaliplatin-induced toxicity presents a major challenge in cancer management because of its damaging effects on normal tissues, including the reproductive system. Transglutaminase 4 (TG4), a member of the transglutaminase enzyme family, is known for its role in protein cross-linking and cellular stress responses, but its role in chemotherapy-induced reproductive toxicity remains poorly understood. This study examines the impact of oxaliplatin, a platinum-based chemotherapeutic drug, on TG4 expression, enzymatic activity, and testicular toxicity in a rat model following intraperitoneal administration of oxaliplatin (10 mg/kg body weight weekly for six weeks). Biochemical analysis revealed significant hormonal and inflammatory alterations, including elevated serum interleukin-1β (IL-1β) levels, decreased testosterone concentrations, and increased follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels. These endocrine disturbances were accompanied by significant upregulation of TG4 expression in oxaliplatin-treated testicular tissue (OXP-TT), as demonstrated by quantitative real-time reverse transcription PCR (qRT-PCR) and immunohistochemical (IHC) analyses. Immunofluorescence (IF) further confirmed enhanced TG4 localization within both interstitial and seminiferous tubular regions. In addition, expression of the pro-inflammatory cytokines IL-6 and TNF was significantly increased. A marked elevation in total transglutaminase enzymatic activity was also detected in oxaliplatin-treated tissues. Collectively, these hormonal, inflammatory, and structural alterations occurred concurrently with increased TG4 expression and transglutaminase activity, suggesting that TG4 participates in the testicular response to oxaliplatin-induced stress. These findings indicate that TG4 is associated with chemotherapy-related reproductive toxicity and may represent a stress-responsive indicator of testicular injury. Further studies are required to determine whether TG4 plays a protective or pathogenic role in oxaliplatin-induced testicular damage and to evaluate its potential relevance in preserving fertility during platinum-based chemotherapy.