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: 10805097
• 负责人: Shreesh Raj Sammi
• 金额: $ 24.9万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10805097
• 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; Poly-fluoroalkyl substances; 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; 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 sulfonate; programs; response; skill acquisition; sporadic Parkinson' s Disease; 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.

项目摘要： 该NIH K99/R00提案寻求支持，以制定旨在的独立研究计划 解决与全氟辛烷磺酸（PFO）有关的问题作为潜在危险因素 多巴胺能细胞损失。多氟烷基物质（PFA）在消防设备中具有重要用途， 由于其独特的排斥油和水的功能，不粘炊具，地毯等。这些化学物质构成 由于受保护的半衰期和抵抗环境的能力，立即构成环境健康威胁 由于其牢固的碳氟键，退化。广泛的存在和巨大的知识差距 与神经毒性作用和潜在机制有关 主要的神经退行性疾病迫使可怕的需要研究这种化合物。我们的初步 秀丽隐杆线虫中PFO的研究表明，DA神经毒性，线粒体含量的降低并增加 活性氧（Sammi等，2019）。这些影响是帕金森氏病中的特征表现 （PD），在90％的零星PD病例中，原因在很大程度上未知。鉴于Caenorhabditis的初步数据 秀丽隐杆线，显示出对PFO的DA细胞损失，我将在诱导的多能干细胞中发展专业知识。一个 将进行体内和体外模型的多管置方法，以进一步识别 神经毒性和神经发育缺陷具有更大的重点，以阐明线粒体和GSH如何延伸 它们在神经病理学中的作用。通常，毒性评估在很大程度上取决于基于终点的研究，而 机械方面仍然在很大程度上被理解。化学物质的有害作用出现在 以病理形式的时间，这是机械改变或畸变的集体结果。所以， 一系列生化事件的识别最终在神经毒性中最终对定义不利至关重要 结果途径（AOP）。确定的机制值得设计干预措施，机理 评估相似化合物和安全化合物的合成。我的方法包括体外和体内 阐明PFO的神经毒性作用的系统。与AOP有关的信息将作为机械 在类似的化合物（PFA）之间进行比较评估的终点/标记，支持 结构活性关系的推导。总而言之，我将在PFO的体外绘制体内签名 介导的多巴胺毒性。此外，详细的职业发展计划需要课程， 在科学会议上学习新技术/模型系统，代表和出席 咨询委员会的建设是为了帮助候选人。我的计划包括接受指导的培训 关键的新技术/模型系统，结合我现有的专业知识，这将使开发能够开发 科学重点与精神实验室不同，并促进了独立的研究职业。