Are PFAS alternatives safer? A network toxicology analysis suggests comparable or novel risks for hypertensive disorders of pregnancy.

Per- and polyfluoroalkyl substances (PFAS), including legacy compounds (PFOA, PFOS) and their alternatives (HFPO-DA, OBS), pose potential risks for hypertensive disorders of pregnancy (HDP). This study systematically evaluated their mechanisms using network toxicology and molecular docking. Toxicity predictions indicated that alternatives exhibit significant multi-organ toxicity risks comparable to legacy PFAS. Network analysis revealed that alternatives not only share core HDP-related targets (STAT3, CASP3) with legacy PFAS but also engage unique targets (e.g., MTOR, AKT1), indicating broader pathogenic networks. Molecular docking demonstrated strong binding affinities, with OBS showing higher affinity for STAT3 and CASP3 than PFOS. Pathway enrichment analysis further implicated disruptions in placental development, immune inflammation, and vascular function. These findings suggest that PFAS alternatives do not present a superior safety profile and may introduce novel risks via distinct molecular pathways, underscoring the need for rigorous health risk assessments of these emerging contaminants.