Molecular Mechanisms of PFAS-induced Neurotoxicity: Dysregulation of PPARs and VDR as a New Therapeutic Frontier

Per- and polyfluoroalkyl substances (PFAS), formerly known as PFCs, are manmade compounds that have accumulated in the environment and in the human brain, posing significant risks to human mental health. This study emphasises how Peroxisome Proliferator-Activated Receptors (PPARs) and Vitamin D Receptors (VDRs) affect brain function and metabolism. The exposure to PFAS, particularly through water contamination, may lead to neurological disorders characterised by disturbances in lipid metabolism, inflammatory responses, and calcium homeostasis in neurons. PPAR regulates these processes, including PPARα, PPARγ, and PPARδ, while VDR plays a key role in calcium homeostasis and neuroprotection. Disruption of these processes by PFAS through the molecular interaction with PPARs and VDR is involved in generating neurological complications. This review brings together a new paradigm for PFAS neurotoxicity via PPARs and VDR interaction, which hampers the gene expression of functional neuronal proteins. This work will also explore the role of potential CSF biomarkers like tau protein, beta-amyloids, and oxidative stress biomarkers like superoxide dismutase (SOD) and malondialdehyde (MDA). These biomarkers are utilised to detect the neurotoxicological impact of PFAS on the structural and functional anomalies in nervous tissue at an early stage.