Elucidation of mitochondrial mechanisms critical to mediating PFAS neurotoxicity

阐明对介导 PFAS 神经毒性至关重要的线粒体机制

• 批准号: 10301852
• 负责人: Shreesh Raj Sammi
• 金额: $ 10.48万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10301852
• 关键词: Address; Advisory Committees; Analytical Chemistry; Animals; Antioxidants; Biochemical; Bioenergetics; Biological; Biological Models; Brain; Caenorhabditis elegans; Carbon; Carpet; Carrier Proteins; Cell Culture Techniques; Cells; Characteristics; Chemicals; Complex; DNA Sequence Alteration; Data; Defect; Dependence; Derivation procedure; Development; Development Plans; Dopaminergic Cell; Dose; Environmental Health; Equipment; Etiology; Evaluation; Event; Feedback; Fluorine; Future; Gene Expression; Genes; Genetic; Genus Hippocampus; Goals; Half-Life; Health; Health Benefit; Health Hazards; Human; Impairment; In Vitro; Individual; Industrialization; Intervention; Knowledge; LRRK2 gene; Laboratories; Learning; Light; Mediating; Mentors; Metals; Methods; Mitochondria; Nematoda; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Oils; Organelles; Outcome; Oxygen Consumption; Parkinson Disease; Pathologic; Pathology; Pathway interactions; Patients; Pesticides; Phase; Program Development; Protein Import; Protons; Public Health; Publishing; Reactive Oxygen Species; Research; Resistance; Respiration; Risk; Risk Factors; Role; Series; Soil; Stains; Structure; Structure-Activity Relationship; Sulfonic Acids; System; Techniques; Teratogenic effects; Testing; Time; Toxic effect; Training; Transgenic Organisms; United States National Institutes of Health; Validation; Water; Water Pollutants; Whole Organism; Work; adverse outcome; alpha synuclein; anthropogenesis; base; career; career development; comparative; dopamine toxicity; dopaminergic neuron; experimental study; exposed human population; gene environment interaction; in vitro Model; in vivo; induced pluripotent stem cell; knock-down; meetings; neurodevelopmental effect; neuropathology; neurotoxic; neurotoxicity; overexpression; perfluorooctane; programs; response; skills; substance use; therapy design; toxicant; toxicant interaction; translational impact; uptake

Project Summary: This NIH K99/R00 proposal seeks support for the development of an independent research program aimed at addressing the questions pertaining to perfluorooctane sulfonic acid (PFOS) as a potential risk factor dopaminergic cell loss. Polyfluoroalkyl substances (PFAS) have important usage in firefighting equipment, nonstick cookware, carpets, etc. due to their unique capabilities to repel oil and water. These chemicals pose an immediate environmental health threat due to their protracted half-life and ability to resist environmental degradation, owing to its strong carbon-fluorine bond. The extensive presence and huge gaps in knowledge pertaining to neurotoxic effects and underlying mechanisms alongside a larger percentage of sporadic cases in major neurodegenerative disorders compel the dire need to investigate such compounds. Our preliminary studies on PFOS in C. elegans have shown DA neurotoxicity, reduction in mitochondrial content, and increased reactive oxygen species (Sammi et al., 2019). These effects are characteristic manifestations in Parkinson’s disease (PD), with cause largely unknown in 90% of sporadic PD cases. In light of the preliminary data in Caenorhabditis elegans, showing DA cell loss in response to PFOS, I will develop expertise in Induced pluripotent stem cells. A multi-pronged approach comprising of in vivo and in vitro models will be conducted to further identify neurotoxic and neurodevelopmental defects with a larger focus to elucidate how mitochondria and GSH extend their role in neuropathology. Conventionally, toxicity evaluation relies heavily on end-point based studies, while mechanistic aspects remain largely understudied. Deleterious effects of the chemicals appear over the span of time in the form of pathologies, which is a collective result of mechanistic alterations or aberrations. Therefore, identification of the series of biochemical events culminating in neurotoxicity is vital to define the Adverse outcome pathway (AOP). The identified mechanisms warrant the ability to design interventions, mechanistic assessment of similar compounds and synthesis of safer compounds. My approach consists of in vitro and in vivo systems to elucidate the neurotoxic effects of PFOS. Information pertaining to AOPs will serve as mechanistic endpoints/markers for comparative evaluation amongst a similar class of compounds (PFAS), facilitating derivation of the structure-activity relationship. In summary, I will draw an in vivo, in vitro signature of PFOS mediated Dopamine toxicity. Additionally, a detailed career development program entailing coursework, learning new techniques/model systems, representation and attendance at scientific meetings and feedback from the advisory committee has been constructed to help the candidate. My plan includes mentored training in critical new techniques/model systems, combined with my existing expertise that will enable the development of a scientific focus distinct from the mentor’s lab and promoting an independent research career.

项目总结： 这项NIH K99/R00提案寻求支持制定一项独立研究计划，旨在 解决与全氟辛烷磺酸(全氟辛烷磺酸)作为潜在风险因素有关的问题 多巴胺能细胞丢失。多氟烷基物质(PFA)在消防设备中有重要用途， 不粘锅、地毯等，因为它们具有独特的拒油和拒水能力。这些化学物质构成了一种 由于其长时间的半衰期和抵抗环境的能力，对环境健康的直接威胁 由于它有很强的碳氟键，所以不能降解。知识的广泛存在和巨大差距 关于神经毒性效应和潜在机制的，伴随着较大比例的散发性病例 主要的神经退行性疾病迫使迫切需要研究这类化合物。我们的预赛 线虫体内全氟辛烷磺酸的研究表明，DA具有神经毒性，线粒体含量减少，而线粒体含量增加 活性氧物种(Sammi等人，2019年)。这些效应是帕金森氏病的特征表现 (PD)，在90%的散发性PD病例中，原因大多不明。根据炎的初步数据 优雅，显示全氟辛烷磺酸导致DA细胞丢失，我将发展诱导多能干细胞的专业知识。一个 包括体内和体外模型在内的多管齐下的方法将进一步确定 神经毒性和神经发育缺陷，以更大的焦点阐明线粒体和GSH如何延伸 它们在神经病理学中的作用。传统上，毒性评估在很大程度上依赖于终点研究，而 机械方面在很大程度上仍未得到充分研究。这些化学物质的有害影响出现在 时间以病理的形式存在，这是机械性改变或偏差的集体结果。因此， 确定最终导致神经毒性的一系列生化事件对于确定不良反应至关重要 结果通路(AOP)。确定的机制保证了设计干预措施的能力，机械性的 类似化合物的评估和更安全化合物的合成。我的方法包括体外和体内 系统，以阐明全氟辛烷磺酸的神经毒性效应。与AOPS有关的信息将作为机械性的 用于同类化合物(PFA)之间的比较评估的终点/标记物，便于 结构-活性关系的推导。总之，我将在体内、体外绘制全氟辛烷磺酸的签名 介导的多巴胺毒性。此外，一个详细的职业发展计划需要完成课程， 学习新技术/模型系统、科学会议的陈述和出席以及来自 咨询委员会的成立是为了帮助这位候选人。我的计划包括在 关键的新技术/模型系统，结合我现有的专业知识，将使开发 不同于导师的实验室的科学重点，并促进独立的研究事业。