Early-life PFOS exposure causes lasting impairment of neural stem cell fate, white matter maturation, and olfactory...

Per- and polyfluoroalkyl substances (PFAS) are widespread and persistent environmental pollutants that bioaccumulate and are transferred from mother to offspring during gestation and lactation. Increasing evidence suggests that early-life PFAS exposure may affect neurodevelopment, yet its long-term consequences on neural stem cell dynamics and white matter maturation remain poorly understood. Here, we investigated the long-term neurodevelopmental and functional consequences of early-life exposure to either perfluorooctane sulfonate (PFOS) or perfluorooctanoic acid (PFOA) in the adult mouse. Pregnant mice were exposed to PFOS or PFOA (20 mg/L in drinking water) from embryonic day 15 (E15) to postnatal day 21 (P21). Neuroglial development was assessed in the subventricular zone (SVZ) and corpus callosum at weaning (P21) and adulthood (P90), and olfactory behaviors were evaluated in adult offspring. PFOS, but not PFOA, significantly reduced SVZ neurogenesis at P21 by decreasing neural progenitor proliferation and promoting oligodendroglial lineage commitment. Although SVZ neurogenesis recovered in adulthood, PFOS exposure led to a sustained impairment of oligodendrocyte maturation within the corpus callosum at P90. PFOS also induced early astroglial activation in the SVZ and reduced dopaminergic interneuron density in the olfactory bulb, leading to olfactory memory deficits detectable in adulthood. Together, these findings demonstrate that perinatal PFOS exposure disrupts neural stem cell fate and leads to alterations in white matter development and olfactory function extending well beyond the transient exposure window. Our results identify PFOS as a developmental neurotoxicant affecting both cellular and olfactory-related functional outcomes, supporting the need to carefully evaluate the long-term consequences of early-life PFAS exposure.