Impact of per- and polyfluoroalkyl substances (PFAS) on brain development and function.

Per- and polyfluoroalkyl substances (PFAS), persistent environmental chemicals known as "forever chemicals," demonstrate significant neurotoxic effects across the human lifespan. This review examines the evidence linking PFAS exposure to neurodevelopmental disorders and neurological dysfunction. Epidemiological studies have shown that prenatal PFAS exposure is associated with reduced intelligence quotient in children, increased attention-deficit/hyperactivity disorder and autism spectrum disorder, and impaired motor and cognitive development, with males exhibiting greater susceptibility. Animal studies have revealed that developmental PFAS exposure disrupts neural progenitor proliferation, neuronal migration, and synaptic formation by targeting key proteins (GAP-43 and BDNF) and genes (PPARγ and UCP3), resulting in behavioral abnormalities resembling neurodevelopmental disorders. In adults, PFAS cross the blood-brain barrier (BBB) and accumulate in brain tissue, disrupting calcium homeostasis via AMPA/NMDA receptors and causing neuronal hyperexcitability. PFAS also compromise synaptic plasticity, alter neurotransmitter systems (dopamine, acetylcholine, GABA, and serotonin), and increase levels of neurodegenerative markers (tau and amyloid precursor protein). PFAS neurotoxicity operates through multiple mechanisms: (1) neuroinflammation via astrocyte activation and pro-inflammatory cytokine release (TNF-α and IL-1β); (2) oxidative stress through mitochondrial dysfunction and reactive oxygen species generation; (3) BBB disruption by reducing tight junction proteins; and (4) endocrine disruption affecting thyroid hormone regulation. PFAS are potent neurotoxicants that interfere with brain development and function through interconnected pathways. Given their environmental persistence and bioaccumulation, minimizing human exposure during critical developmental periods is essential to protect neurological health.