Molecular Toxicology Key Laboratory of Sichuan Provincial Education office, West China School of Public Health and West China Fourth Hospital, and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, 610041, China.
School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
Environ Pollut. 2024 Dec 15;363(Pt 1):125098. doi: 10.1016/j.envpol.2024.125098. Epub 2024 Oct 9.
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.
全氟和多氟烷基物质（PFASs）是一类普遍存在的合成有机化学品，广泛应用于各种工业应用中。然而，人类暴露于 PFAS 混合物中的长期神经健康影响仍知之甚少。为了解决这一差距，我们设计了一项综合研究，使用单细胞 RNA 测序（scRNA-seq）和大脑类器官来预测和验证 PFAS 的细胞类型特异性神经毒性。大脑类器官在浓度为 1×（10ng/ml PFOS 和 PFOA，以及 1ng/ml PFHxS）、30×和 900×的 PFAS 混合物中暴露 35 天，并在第 70 天进行后续分析。分析病理性改变和脂质组学谱，以确定受干扰的分子途径和机制。scRNA-seq 数据显示 PFAS 对神经元有重大影响，这表明其在阿尔茨海默病（AD）病理学以及智力和认知障碍中可能发挥作用。PFAS 处理的大脑类器官表现出 Aβ 积累和 tau 磷酸化。脂质组学分析进一步揭示了脂质对 PFAS 混合物暴露的反应紊乱，将 PFAS 诱导的 AD 样神经病理学与鞘脂代谢紊乱联系起来。总之，我们的研究结果提供了对 PFAS 诱导的神经毒性的新见解，强调了鞘脂代谢在 AD 样神经病理学发展中的重要性。大脑类器官和 scRNA-seq 的使用为评估与环境污染物相关的健康风险提供了一种强大的方法，特别是那些具有神经毒性潜力的污染物。
