A meta-analysis-based adverse outcome pathway for the reproductive toxicity induced by per- and poly-fluoroalkyl...

Per- and poly-fluoroalkyl substances (PFAS) were highly toxic to reproductive systems due to the widespread environmental distribution and persistence. However, the underlying mechanisms were not well understood. This study systematically evaluated the association between existing adverse outcome pathways (AOPs) and PFAS-induced reproductive toxicity using the AOP conceptual framework. A meta-analysis of 28 studies quantified the effect sizes, providing a comprehensive assessment of PFAS-induced reproductive toxicity in animals. Within the AOP framework, the molecular initiating event (MIE) was increased reactive oxygen species (ROS), which triggered several key events (KEs) at different levels. At the cellular level, the KEs included oxidative stress, mitochondrial dysfunction, DNA damage, endoplasmic reticulum stress, reduced steroidogenic protein expression, decreased thyroid hormone synthesis, epigenetic modification process, lipid metabolism disorders, decreased androgen and estrogen receptors. These KEs led to decreased testosterone and elevated estrogen levels, alongside disruptions in spermatogenesis, oocyte maturation, and ovulation. Consequently, this resulted in lower sperm count, impaired sperm quality, and decline in oocyte quantity. Meta-analysis results showed that PFAS exposure significantly decreased juvenile survival rates (Standardized Mean Difference (SMD): -3.10, 95 % Confidence Interval (CI): -4.01, -2.18), reduced male testosterone (SMD: -4.17, 95 % CI: -6.00, -2.33) and female estradiol levels (SMD: -1.98, 95 % CI: -3.15, -0.81) in animals. Our findings systematically summarized the reproductive toxicity mechanisms of PFAS and alternatives, providing scientific basis for assessing the environmental impact.