Adverse outcome pathway for the neurotoxicity of Per- and polyfluoroalkyl substances: A systematic review

Abstract

Per- and polyfluoroalkyl substances (PFAS) are endocrine disruptors with unambiguous neurotoxic effects. However, due to variability in experimental models, population characteristics, and molecular endpoints, the elucidation of mechanisms underlying PFAS-induced neurotoxicity remains incomplete. In this review, we utilized the adverse outcome pathway (AOP) framework, a comprehensive tool for evaluating toxicity across multiple biological levels (molecular, cellular, tissue and organ, individual, and population), to elucidate the mechanisms of neurotoxicity induced by PFAS. Based on 271 studies, the reactive oxygen species (ROS) generation emerged as the molecular initiating event 1 (MIE1). Subsequent key events (KEs) at the cellular level include oxidative stress, neuroinflammation, apoptosis, altered Ca²⁺ signal transduction, glutamate and dopamine signaling dyshomeostasis, and reduction of cholinergic and serotonin. These KEs culminate in synaptic dysfunction at organ and tissue levels. Further insights were offered into MIE2 and upstream KEs associated with altered thyroid hormone levels, contributing to synaptic dysfunction and hypomyelination at the organ and tissue levels. The inhibition of Na⁺/I⁻ symporter (NIS) was identified as the MIE2, initiating a cascade of KEs at the cellular level, including altered thyroid hormone synthesis, thyroid hormone transporters, thyroid hormone metabolism, and binding with thyroid hormone receptors. All KEs ultimately result in adverse outcomes (AOs), including cognition and memory impairment, autism spectrum disorders, attention deficit hyperactivity disorders, and neuromotor development impairment. To our knowledge, this review represents the first comprehensive and systematic AOP analysis delineating the intricate mechanisms responsible for PFAS-induced neurotoxic effects, providing valuable insights for risk assessments and mitigation strategies against PFAS-related health hazards.