Sertoli cell oxidative stress as a convergent hazard endpoint for environmental toxicants: A systematic review,...

Environmental chemical exposures are primary drivers of declining male reproductive health. Sertoli cells (SCs), indispensable for spermatogenesis and blood-testis barrier (BTB) integrity, are preferential targets for toxicant-induced oxidative injury across chemically diverse classes. We conducted a systematic review and meta-analysis organised around an a priori Adverse Outcome Pathway (AOP): toxicant interaction with SC mitochondria or NADPH oxidases (Molecular Initiating Event) → ROS elevation (Key Event 1, KE1) → SC cellular dysfunction including apoptosis, ferroptosis, and BTB disruption (Key Event 2, KE2) → impaired spermatogenesis (Adverse Outcome). Searching PubMed, Embase, Web of Science, and Scopus from inception to January 2026, we identified 1458 records, of which 96 met inclusion criteria for qualitative synthesis and 29 provided extractable data for meta-analysis. All six chemical classes examined - air pollutants (PM₂.₅), endocrine-disrupting chemicals, pesticides, heavy metals, mycotoxins, and emerging contaminants - significantly elevated SC oxidative stress relative to controls. Metals produced the largest pooled standardised mean difference (SMD > 2.0) and air pollutants the second largest (SMD ∼1.8). The direction of effect was uniformly positive across all 29 studies. Cross-study ecological regression supported the AOP linkage between ROS elevation (KE1) and SC apoptosis (KE2; R² = 0.77, p < 0.001). One Health subgroup analysis showed directionally consistent effect sizes across rodent, livestock, and in vitro evidence streams. These findings position SC oxidative stress as a convergent, chemically non-specific, and phylogenetically conserved hazard endpoint warranting formalisation within tiered reproductive toxicity test strategies.