Per- and polyfluoroalkyl substances and platelet-related hematotoxicity: An integrated study of in silico,...

The hematological impact of per- and polyfluoroalkyl substances (PFAS) remains poorly characterized, particularly regarding platelet function and its regulatory mechanisms. In this study, 36 legacy and novel PFAS were quantified in serum samples from 2042 participants aged 3-79 years in Zhejiang Province, China, alongside evaluation of four platelet indices. Notably, elderly participants (60-79 years) exhibited the highest cumulative PFAS concentrations (∑₁₄PFAS: 42.62 ng/mL). A broad spectrum of PFAS demonstrated significant negative associations with mean platelet volume (MPV), highlighting MPV as a potential sensitive biomarker for PFAS-induced platelet dysfunction. Consistently, PFAS mixtures were negatively associated with MPV across all age groups, as well as with platelet distribution width (PDW) in adults as estimated using quantile-based g-computation model. To elucidate the mechanistic basis, a conceptual adverse outcome pathway (AOP) was proposed, implicating interactions between PFAS and biomacromolecular targets such as CTNNB1 as molecular initiating events. These disruptions may interfere with megakaryocyte differentiation and downstream platelet activation. Integration of PFAS serum concentrations and molecular docking-derived binding affinities within a toxicological priority index (ToxPi) model enabled the prioritization of PFAS by their platelet-toxic potential, identifying PFOA and PFOS as the most concerning and informing regulatory risk management. Collectively, these findings underscore the need for increased scrutiny of PFAS-related platelet toxicity and support further mechanistic investigations using both in vivo and in vitro studies.