Prenatal exposure to perfluorooctane sulfonate and the risk of neurodevelopmental disorders: Perturbation of placenta-brain axis through DNA methylation.

Per- and poly-fluoroalkyl substances (PFAS) have been increasingly associated with adverse neurodevelopmental outcomes. The placenta serves as a critical interface between the maternal environment and fetal brain development; however, the epigenetic mechanisms underlying the association between prenatal PFAS exposure and neurodevelopmental outcomes remain poorly understood. In this study, we investigated whether maternal exposure to perfluorooctane sulfonate (PFOS) was associated with placental DNA methylation alterations and early-life neurodevelopmental outcomes through a potential placenta-brain axis. Using mother-infant pairs selected from the Shanghai Birth Cohort (SBC), we performed whole-genome DNA methylation profiling on placental samples and found that maternal PFOS levels were inversely associated with cognitive scores at 24 months. PFOS exposure was associated with widespread alterations in the placental methylome, with differentially methylated regions (DMRs) enriched in genes involved in neurodevelopmental processes. Among these, MDGA1, AR, DCC, NFASC, ATP9A, and ADAMTS19 were prioritized as candidate genes based on differential methylation patterns and network-based analyses, and their methylation alterations showed associations with both maternal PFOS exposure and offspring cognitive performance. These candidate epigenetic alterations were further examined in a prenatal PFOS-exposed rat model, in which changes in placental DNA methylation were accompanied by impairments in offspring spatial learning and memory. Collectively, our findings suggest that placental epigenetic dysregulation may represent a potential molecular link between prenatal PFOS exposure and early-life neurodevelopmental outcomes, highlighting the placenta-brain axis as a sensitive target of environmental exposure and providing candidate biomarkers for future investigation.