Risk Assessment of PFAS-Induced Male Reproductive Toxicity: A Comprehensive Evaluation Using the TRAEC Strategy

Male fertility has declined rapidly in recent decades, a trend coinciding with increased environmental exposure pressures. Among these, perfluorinated and polyfluorinated alkyl substances (PFAS) have been reported to exert male reproductive toxicity, yet comparative risks across individual PFAS remain unclear. In this study, we employed an innovative systematic review strategy, the Targeted Risk Assessment of Environmental Chemicals (TRAEC) strategy, integrating all available evidence from 25 epidemiological studies, 75 in vivo, and 43 in vitro experiments, alongside independent experiments, to assess the effects of multiple PFAS on semen quality and sex hormone levels. The integrated evidence indicated that PFAS exposure posed a moderate risk level to male reproductive health with a comprehensive risk score of 6.47. Among individual PFAS, exposure to perfluorooctanesulfonic acid (PFOS, risk score: 7.43) and perfluorononanoic acid (PFNA, risk score: 6.38) presented the highest risk of sperm abnormalities, followed by perfluorodecanoic acid (PFDoA, risk score: 6.29), perfluorooctanoic acid (PFOA, risk score: 5.83), and perfluorohexyl sulfonic acid (risk score: 4.87), all of which are at moderate risk levels. And the risk of these PFAS compounds causing reproductive hormone abnormalities was at a low to moderate level, with the risk scores ranging from 3.79 (PFOA) to 6.74 (PFDoA). Additionally, PFAS exposure showed a relatively high risk of adversely affecting sperm progressive motility (risk score range: 5.23-5.62), particularly for PFOS (risk score: 5.57) and PFNA (risk score: 5.62). Risk for other sperm parameters was relatively lower (risk score range: 4.01-5.49). Notably, independent in vivo experiments confirmed that PFNA exposure significantly impaired sperm routine parameters and sperm dynamics across multiple mouse strains (including C57BL/6J, CC002, CC037, and CC057 strains). Our study identified PFOS and PFNA as particularly detrimental to male reproductive health across multiple dimensions, underscoring the urgent need for measures to reduce PFAS exposure and mitigate risks to male fertility.