Insights into the Neurotoxicology of Traditional and Emerging Per- and Polyfluoroalkyl Substances: Mechanisms and Research Frontiers

Per- and polyfluoroalkyl substances (PFASs), colloquially termed “forever chemicals” due to their environmental persistence, are characterized by the inherent chemical stability that facilitates global dissemination and bioaccumulation, leading to their ubiquitous detection in environmental and biological matrices. Substantial concerns regarding the adverse health implications of traditional PFASs, notably perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA), which encompass multiple biological negative effects, have precipitated regulatory restrictions and phase-out. This regulatory shift has spurred the introduction of substitutes, yet emerging evidence indicates that these replacements have themselves become pervasive contaminants, such as chlorinated polyfluoroalkyl ether sulfonate (Cl-PFAES, F-53B) and hexafluoropropylene oxide dimer acid (HFPO–DA, Genx), which have been shown to possess toxicological profiles comparable to or exceeding those of their predecessors. The present review aims to comprehensively synthesize the current state of knowledge concerning the neurotoxicity of traditional and emerging PFASs, integrating insights from epidemiological studies, elucidation of central nervous system (CNS) penetration mechanisms, in vitro and in vivo neurotoxicological evidence, and proposed molecular pathways underlying neuronal damage. This review identifies critical, persistent knowledge gaps and proposes prioritized directions for future research endeavors aimed at elucidating and mitigating the neurological health risks presented by this ubiquitous class of contaminants.