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Quantitative analysis and toxicological mechanisms of various male infertility inducers: A network meta-analysis and pharmacological approach.
Summary
This network meta-analysis of 201 rodent studies compared nine common male infertility inducers, finding that microplastics caused among the most severe impairments to sperm count and motility — on par with the chemotherapy drug cyclophosphamide. Oxidative stress emerged as a shared mechanistic pathway across all inducers, pointing to it as a key target for understanding and potentially mitigating reproductive harm from environmental exposures.
BACKGROUND: Male infertility is a global health concern, accounting for nearly half of all infertility cases. This study evaluates the toxicological effects of key infertility inducers in rodent models and explores underlying molecular mechanisms. METHODS: A systematic review and network meta-analysis (NMA) compared nine widely studied inducers: environmental toxicants (Bisphenol-A, Lead acetate, microplastics), pharmacological agents (Cyclophosphamide, Streptozotocin, Valproic acid, Tripterygium glycosides), and metabolic/physical stressors (High-Fat Diet, heat stress). Key endpoints included sperm count, motility, morphology, testis weight, and hormone levels. Network pharmacology and enrichment analyses identified molecular pathways, focusing on oxidative stress. Clinical relevance was assessed based on mechanistic alignment with human infertility. RESULTS: A total of 201 studies involving 3412 rodents were analyzed. NMA revealed significant differences in reproductive toxicity among inducers. Cyclophosphamide, STZ, and microplastics caused the most severe impairments, reducing sperm counts to 30.08 ± 19.1, 38.13 ± 8.2, and 18.97 ± 11.1 × 10⁶/mL, and motility to 31.73 ± 6.1 %, 30.74 ± 4.1 %, and 31.32 ± 10.2 %, respectively. Overall, sperm count, motility, and testosterone decreased by 1.46-, 1.21-, and 1.16-fold. Network pharmacology identified oxidative stress-related genes (NFE2L2, SOD1, HMOX1) as common targets, with oxidative stress emerging as shared mechanistic pathways. Trend analysis (2009-2024) revealed rising research on microplastics, HFD, and Lead acetate. CONCLUSIONS: This first integrated toxicological and mechanistic analysis elucidates how diverse inducers impair male reproductive health. Oxidative stress contributes to toxicity, highlighting potential molecular targets for therapy. Findings support the translational relevance of rodent infertility models and guide risk assessment and mitigation strategies for stressors.