Prenatal PFAS exposure and offspring health: evidence review and implications for intergenerational risk assessment

Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) represents a critical developmental concern because several PFAS cross the placenta and may perturb biological programming during sensitive windows. Although epidemiological and experimental studies have linked prenatal exposure to several measured PFAS, primarily legacy perfluoroalkyl acids such as perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), Perfluorohexane Sulfonic Acid (PFHxS), and Perfluorononanoic Acid (PFNA), to diverse offspring outcomes, the strength of evidence differs substantially across compounds and health domains. Current human evidence is strongest for impaired vaccine antibody responses and altered growth or metabolic trajectories in studies dominated by legacy PFAS, whereas evidence for other congeners, short-chain PFAS, ether-based alternatives, and fluorotelomer compounds remains sparse. Mechanistically, placental transfer, nuclear receptor perturbation, thyroid hormone transport disruption, mitochondrial stress, immune modulation, and epigenetic reprogramming may jointly contribute to developmental susceptibility. We further discuss how emerging PFAS alternatives and real-world mixture exposures challenge single-chemical and adult-centered assessment paradigms. Finally, we outline a conceptual framework for developmental hazard assessment, in which exposure-window characterization, congener-specific toxicokinetics, human-relevant models, multi-omics biomarkers, and PBPK/PBTK modeling are positioned as complementary components rather than as a fully operational assessment system.