School of Health Sciences.
Purdue Institute for Integrative Neurosciences.
Toxicol Sci. 2019 Dec 1;172(2):417-434. doi: 10.1093/toxsci/kfz191.
Perfluorooctane sulfonate (PFOS) has been widely utilized in numerous industries. Due to long environmental and biological half-lives, PFOS is a major public health concern. Although the literature suggests that PFOS may induce neurotoxicity, neurotoxic mechanisms, and neuropathology are poorly understood. Thus, the primary goal of this study was to determine if PFOS is selectively neurotoxic and potentially relevant to specific neurological diseases. Nematodes (Caenorhabditis elegans) were exposed to PFOS or related per- and polyfluoroalkyl substances (PFAS) for 72 h and tested for evidence of neuropathology through examination of cholinergic, dopaminergic, gamma-amino butyric acid (GABA)ergic, and serotoninergic neuronal morphologies. Dopaminergic and cholinergic functional analyses were assessed through 1-nonanol and Aldicarb assay. Mechanistic studies assessed total reactive oxygen species, superoxide ions, and mitochondrial content. Finally, therapeutic approaches were utilized to further examine pathogenic mechanisms. Dopaminergic neuropathology occurred at lower exposure levels (25 ppm, approximately 50 µM) than required to produce neuropathology in GABAergic, serotonergic, and cholinergic neurons (100 ppm, approximately 200 µM). Further, PFOS exposure led to dopamine-dependent functional deficits, without altering acetylcholine-dependent paralysis. Mitochondrial content was affected by PFOS at far lower exposure level than required to induce pathology (≥1 ppm, approximately 2 µM). Perfluorooctane sulfonate exposure also enhanced oxidative stress. Further, mutation in mitochondrial superoxide dismutase rendered animals more vulnerable. Neuroprotective approaches such as antioxidants, PFAS-protein dissociation, and targeted (mitochondrial) radical and electron scavenging were neuroprotective, suggesting specific mechanisms of action. In general, other tested PFAS were less neurotoxic. The primary impact is to prompt research into potential adverse outcomes related to PFAS-induced dopaminergic neurotoxicity in humans.
全氟辛烷磺酸（PFOS）已广泛应用于众多行业。由于其在环境中和生物体内的半衰期较长，PFOS 成为主要的公共卫生关注点。尽管文献表明 PFOS 可能具有神经毒性，但神经毒性机制和神经病理学仍知之甚少。因此，本研究的主要目的是确定 PFOS 是否具有神经选择性毒性，以及其是否与特定的神经疾病相关。研究人员用 PFOS 或相关的全氟和多氟烷基物质（PFAS）处理秀丽隐杆线虫 72 小时，并通过检查胆碱能、多巴胺能、γ-氨基丁酸（GABA）能和 5-羟色胺能神经元形态来检测神经病理学的证据。通过 1-壬醇和 Aldicarb 测定评估多巴胺能和胆碱能功能分析。通过总活性氧、超氧阴离子和线粒体含量评估机制研究。最后，采用治疗方法进一步研究致病机制。与 GABA 能、5-羟色胺能和胆碱能神经元相比，较低的 PFOS 暴露水平（25ppm，约 50µM）就可引起多巴胺能神经病变。此外，PFOS 暴露导致多巴胺依赖性功能缺陷，而不改变乙酰胆碱依赖性瘫痪。PFOS 在远低于引起病理所需的暴露水平（≥1ppm，约 2µM）就会影响线粒体含量。PFOS 暴露还会增强氧化应激。此外，线粒体超氧化物歧化酶的突变使动物更容易受到影响。抗氧化剂、PFAS-蛋白解离和靶向（线粒体）自由基和电子清除等神经保护方法具有神经保护作用，表明其具有特定的作用机制。总的来说，其他测试的 PFAS 的神经毒性较低。本研究主要旨在促使人们研究 PFAS 诱导的多巴胺能神经毒性对人类可能产生的不良后果。
