Perfluoroalkyl substance pollutants disrupt microglia function and trigger transcriptional and epigenomic changes.

Per- and polyfluoroalkyl substances (PFAS), commonly referred to as "forever chemicals", are widely utilized in various industries and consumer products worldwide. Their exposure has been associated with numerous diseases and malignancies, including neurodevelopmental and neurodegenerative disorders. However, the molecular mechanisms underlying PFAS-induced adverse effects on the central nervous system (CNS) remain poorly understood. In this study, we investigated the transcriptomic and epigenetic changes in microglia exposed to perfluorooctane sulfonate (PFOS), a prevalent PFAS compound. Our findings demonstrate that 24-hour PFOS exposure (25 and 50 µM) disrupts the microglial transcriptome and compromises their homeostatic state, marked by increased inflammation and impaired actin cytoskeleton remodeling. Comparative analysis with in vivo transcriptional states revealed that PFOS-exposed microglia exhibit gene expression profiles resembling those of aged microglia. Additionally, profiling of active chromatin regions uncovered significant alterations in the H3K27ac landscape in PFOS-exposed microglia. Notably, these epigenetic disruptions persisted even after PFOS withdrawal, with a subset of H3K27ac-enriched regions remaining altered, suggesting the presence of lasting epigenetic scars. Furthermore, transcription factor analysis implicated the AP-1 and TEAD families as potential upstream regulators connecting the altered chromatin landscape to transcriptomic changes. Collectively, these findings provide mechanistic insights into how PFOS exposure disrupts microglial function and highlight its potential role in exacerbating neurodegenerative processes.