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Quantitative analysis and toxicological mechanisms of various male infertility inducers: A network meta-analysis and
Muhammad Arif Asghar1, Ao Zhang1, Shixin Tang2
1College of Pharmacy, Chongqing Medical University, Chongqing, PR China.
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.
Insights
Male infertility is a global concern. This study found that environmental toxicants, drugs, and stressors significantly impair male reproductive health, with oxidative stress being a key mechanism. Findings guide risk assessment and potential therapies.
Area of Science:
- Reproductive Toxicology
- Environmental Health
- Molecular Mechanisms of Infertility
Background:
- Male infertility affects nearly half of all infertility cases globally.
- This research investigates the toxicological impacts of common infertility inducers in rodent models.
- Understanding the molecular pathways is crucial for addressing male reproductive health issues.
Purpose of the Study:
- To evaluate the toxicological effects of nine key male infertility inducers.
- To explore the underlying molecular mechanisms of reproductive toxicity.
- To assess the clinical relevance of rodent infertility models for human health.
Main Methods:
- A systematic review and network meta-analysis (NMA) of 201 rodent studies (3,412 animals).
- Comparison of environmental toxicants, pharmacological agents, and metabolic/physical stressors.
- Network pharmacology and enrichment analyses to identify molecular pathways, focusing on oxidative stress.
Main Results:
- Cyclophosphamide, Streptozotocin (STZ), and microplastics demonstrated the most severe reproductive toxicity.
- Significant reductions observed in sperm count, motility, and testosterone levels across various inducers.
- Oxidative stress-related genes (e.g., NFE2L2, SOD1, HMOX1) were identified as common molecular targets.
Conclusions:
- This integrated analysis clarifies how diverse inducers impair male reproductive health.
- Oxidative stress is a central mechanism contributing to male infertility induced by various agents.
- Findings support the use of rodent models for risk assessment and developing therapeutic strategies for male infertility.
