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

• Published in: Environmental pollution (1987) 2024-12, Vol.363 (Pt 1), p.125098, Article 125098
• Main Authors: Lu, Shiya, Zhu, Xizhi, Zeng, Pinli, Hu, Linxia, Huang, Yan, Guo, Xinhua, Chen, Qiqi, Wang, Yantang, Lai, Li, Xue, Aiqin, Wang, Yanli, Wang, Zhiqiu, Song, Wenbo, Liu, Qian, Bian, Guohui, Li, Jiayuan, Bu, Qian, Cen, Xiaobo
• Format: Article
• Language: English
• Subjects: Alkanesulfonic Acids - toxicity; Alzheimer Disease; Alzheimer's disease pathology; Caprylates - toxicity; Cerebral organoid; class; cognition; Environmental Pollutants - toxicity; Fluorocarbons - toxicity; Humans; Lipid disturbance; lipidomics; metabolism; Neurons - drug effects; neuropathology; neurotoxicity; organoids; Organoids - drug effects; perfluorohexane sulfonic acid; PFAS mixture; phosphorylation; pollution; RNA; scRNA-seq; sphingolipids
• ISSN: 0269-7491; 1873-6424; 1873-6424
• DOI: 10.1016/j.envpol.2024.125098

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. [Display omitted] •Establish a correlation between PFAS and cognitive disorder through scRNA-seq.•PFAS exposure induces Alzheimer's disease-like neurotoxicity in cerebral organoids.•Lipidomic analysis reveales PFAS mixture induced sphingolipid metabolism disruption.