Neurotoxicity of per- and polyfluoroalkyl substances: Evidence and future directions

Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals widely used in various products, including food packaging, textiles, and firefighting foam, owing to their unique properties such as amphiphilicity and strong CF bonds. Despite their widespread use, concerns have arisen due to their resistance to degradation and propensity for bioaccumulation in both environmental and human systems. Emerging evidence suggests a potential link between PFAS exposure and neurotoxic effects, spanning cognitive deficits, neurodevelopmental disorders, and neurodegenerative diseases. This review comprehensively synthesizes current knowledge on PFAS neurotoxicity, drawing insights from epidemiological studies, animal experiments, and mechanistic investigations. PFAS, known for their lipophilic nature, tend to accumulate in lipid-rich tissues, including the brain, breaching biological barriers such as the blood-brain barrier (BBB). The accumulation of PFAS within the central nervous system (CNS) has been implicated in a spectrum of neurological maladies. Neurotoxicity induced by PFAS manifests through a multitude of direct and indirect mechanisms. A growing body of research associated PFAS exposure with BBB disruption, calcium dysregulation, neurotransmitter alterations, neuroinflammation, oxidative stress, and mitochondrial dysfunction, all contributing to neuronal impairment. Despite notable strides in research, significant lacunae persist, necessitating further exploration to elucidate the full spectrum of PFAS-mediated neurotoxicity. Prospective research endeavors should prioritize developing biomarkers, delineating sensitive exposure windows, and exploring mitigation strategies aimed at safeguarding neurological integrity within populations vulnerable to PFAS exposure.