Exposure to PFOA, PFOS, and PFHxS induces Alzheimer's disease-like neuropathology in cerebral organoids.

Per- and polyfluoroalkyl substances (PFASs), a class of ubiquitous synthetic organic chemicals, are widely utilized across various industrial applications. However, the long-term neurological health effects of PFAS mixture exposure in humans remain poorly understood. To address this gap, we have designed a comprehensive study to predict and validate cell-type-specific neurotoxicity of PFASs using single-cell RNA sequencing (scRNA-seq) and cerebral organoids. Cerebral organoids were exposed to a PFAS mixture at concentrations of 1 × (10 ng/ml PFOS and PFOA, and 1 ng/ml PFHxS), 30 × , and 900 × over 35 days, with a follow-up analysis at day 70. Pathological alterations and lipidomic profiles were analyzed to identify disrupted molecular pathways and mechanisms. The scRNA-seq data revealed a significant impact of PFASs on neurons, suggesting a potential role in Alzheimer's Disease (AD) pathology, as well as intellectual and cognitive impairments. PFAS-treated cerebral organoids exhibited Aβ accumulation and tau phosphorylation. Lipidomic analyses further revealed lipid disturbances in response to PFAS mixture exposure, linking PFAS-induced AD-like neuropathology to sphingolipid metabolism disruption. Collectively, our findings provide novel insights into the PFAS-induced neurotoxicity, highlighting the significance of sphingolipid metabolism in the development of AD-like neuropathology. The use of cerebral organoids and scRNA-seq offers a powerful methodology for evaluating the health risks associated with environmental contaminants, particularly those with neurotoxic potential.