Understanding the impact of streptozotocin on diabetic male infertility: perspectives from rodent models and pharmacological networking

Streptozotocin (STZ) is a common agent for inducing diabetes in animal models, including those used to study male infertility. However, the lack of standardized validation for these models poses challenges for research in this area. This study aimed to comprehensively assess the impact of STZ on male fertility parameters in rodent models of diabetic male infertility. Additionally, it sought to investigate into the underlying molecular mechanisms using pharmacological networking tools. A systematic search of PubMed, Scopus, Web of Science, and PsycINFO yielded 92 eligible studies involving 1535 male rodents. Hedges’ g was utilized to compare fertility parameters between STZ-treated and control groups. Meta-regression analysis was conducted to explore the relationship between STZ dosing and fertility damage. Pharmacological networking techniques were employed to identify critical targets and pathways associated with STZ-induced infertility. The analysis revealed significant reductions in sperm count (Hedges’ g = -8.56), motility (Hedges’ g = -8.21), and testis weight (Hedges’ g = -7.95) following STZ administration, accompanied by an increase in abnormal sperm morphology (Hedges’ g = 7.80). However, no clear dose-response relationship was observed between STZ dosing and fertility damage, indicating potential threshold effects. The power analysis revealed adequate statistical power (estimated at 0.82) for detecting the estimated effect size in our meta-analysis of male fertility outcomes. Pharmacological networking identified key targets (GAPDH, PTGS2, MAPK1, CASP3) and pathways potentially implicated in STZ-induced infertility i.e. IL-17 signaling pathway, TNF signaling pathway, Cellular senescence emerged as the primary pathways linked to oxidative stress and inflammation. These findings highlight the substantial impact of STZ on male fertility parameters in rodent models of diabetic male infertility. The absence of a clear dose-response relationship suggests complexities in STZ-induced infertility mechanisms, warranting further investigation. Identified molecular targets and pathways provide promising opportunities for future therapeutic interventions. Standardizing STZ-induced diabetic male infertility models is imperative for advancing research in this field. The study’s insights into potential therapeutic targets based on identified molecular mechanisms offer the way for further investigations and the development of targeted interventions.