Exploring the neurodegenerative potential of per- and polyfluoroalkyl substances through an adverse outcome pathway network

While emerging evidence links per - and polyfluoroalkyl substances (PFAS) to neurotoxicity, their potential role in neurodegeneration remains poorly understood. Moreover, existing neurodegeneration-related adverse outcome pathways (AOPs) available on AOP-Wiki have not yet been integrated into a unified network. To address these gaps, this study aims to develop the first neurodegeneration-related AOP network and utilize it to explore the possible contributions of long-chain legacy PFAS to neurodegeneration, specifically concerning Alzheimer's and Parkinson's diseases. A total of 74 AOPs were screened from AOP-Wiki, of which 13 neurodegeneration-related AOPs met the eligibility criteria and were incorporated into a network. We analyzed the resulting AOP network using topological parameters such as in-degree, out-degree, eccentricity, and betweenness centrality. To elucidate the mechanistic contributions of PFAS exposure to neurodegenerative pathways, we integrated evidence linking PFAS exposure to key events (KEs) within the network. The results highlighted increased intracellular calcium as the network hub with the highest connectivity followed by critical KEs such as neurodegeneration, neuronal apoptosis, oxidative stress, N -methyl- d -aspartate receptor (NMDA-R) overactivation, and mitochondrial dysfunction. Consistent with toxicological evidence, the pathways highlighted by the AOP network indicate that PFAS may adversely affect neurotransmitter systems, particularly through NMDA-R overactivation, leading to excitotoxicity. This may result in calcium dyshomeostasis, mitochondrial dysfunction, inflammatory-oxidative cascades, neuroinflammation, and neuronal cell death. By providing a mechanistic basis for understanding the neurodegenerative potential of PFAS, this study offers a crucial framework for assessing the risks associated with these chemicals which may inform future regulatory measures and public health strategies. Further experimental validation is needed to confirm the mechanistic contributions of PFAS exposure in neurodegeneration, particularly in animal models or human populations. • A neurodegeneration-related adverse outcome pathway (AOP) network was developed • AOP network revealed increased intracellular Ca 2+ as the most significant key event • Long-chain PFAS induce neurotransmitter alterations and excitotoxicity • Long-chain PFAS trigger oxidative stress, mitochondrial dysfunction, inflammation, and apoptosis in neuronal cells • Neurodegenerative pathways induced by long-chain PFAS align with AOP network analysis findings