PFOS-induced dopaminergic neurodegeneration across nematode, amphibian, and rodent models

线虫、两栖动物和啮齿动物模型中全氟辛烷磺酸诱导的多巴胺能神经变性

• 批准号: 10289079
• 负责人: Jason R Cannon
• 金额: $ 30.85万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10289079
• 关键词: Address; Administrative Supplement; Alzheimer' s Disease; Amphibia; Animal Model; Biochemical; Biological; Biological Models; Biology; Blood; Brain; Brain region; Cell model; Cells; Comparative Biology; Comparative Study; Data; Dementia; Development; Developmental Toxicant; Dose; Environmental Exposure; Environmental Pollution; Event; Exposure to; Funding; Goals; Grant; Hippocampus (Brain); Histologic; Human; Literature; Measures; Modeling; National Institute on Aging; Nematoda; Nerve Degeneration; Neurobiology; Neurologic; Neurotransmitters; Parkinson Disease; Pathogenicity; Pathology; Pathway interactions; Phenotype; Plasma; Proteins; Rana; Risk; Risk Factors; Rodent; Rodent Model; Stains; System; Testing; Tissues; United States National Institutes of Health; Ursidae Family; Vertebrates; abeta accumulation; disease phenotype; disorder risk; dosage; epidemiology study; experimental study; nervous system disorder; neurobehavioral; neurochemistry; neuropathology; neurotoxic; neurotoxicity; oxidative damage; perfluorooctane sulfonate; programs; protein aggregation; response; species difference; tau Proteins; tau aggregation; virtual; Address; Administrative Supplement; Alzheimer' s Disease; Amphibia; Animal Model; Biochemical; Biological; Biological Models; Biology; Blood; Brain; Brain region; Cell model; Cells; Comparative Biology; Comparative Study; Data; Dementia; Development; Developmental Toxicant; Dose; Environmental Exposure; Environmental Pollution; Event; Exposure to; Funding; Goals; Grant; Hippocampus (Brain); Histologic; Human; Literature; Measures; Modeling; National Institute on Aging; Nematoda; Nerve Degeneration; Neurobiology; Neurologic; Neurotransmitters; Parkinson Disease; Pathogenicity; Pathology; Pathway interactions; Phenotype; Plasma; Proteins; Rana; Risk; Risk Factors; Rodent; Rodent Model; Stains; System; Testing; Tissues; United States National Institutes of Health; Ursidae Family; Vertebrates; abeta accumulation; disease phenotype; disorder risk; dosage; epidemiology study; experimental study; nervous system disorder; neurobehavioral; neurochemistry; neuropathology; neurotoxic; neurotoxicity; oxidative damage; perfluorooctane sulfonate; programs; protein aggregation; response; species difference; tau Proteins; tau aggregation; virtual

R21AG068787 is entitled, “PFOS-induced dopaminergic neurodegeneration across nematode, amphibian, and rodent models”. The primary focus is on Parkinson’s disease (PD) endpoints as part of NIA’s Comparative Biology of Neurodegeneration (to PAR-17-039) program. Per- and polyfluoroalkyl substances (PFAS) are widespread environmental contaminants that have been investigated as developmental toxicants, with little information on long-term neurotoxicity. Our preliminary data in nematode and amphibian models suggest that exposure to PFAS, especially perfluorooctane sulfonate (PFOS) induces neurotoxicity. The main project addresses an important gap on how PFAS exposure leads to long-term neurological disease risk through testing the following hypothesis: that species-specific responses to PFOS-induced dopaminergic neurodegeneration will advance understanding of the biology of PD. This hypothesis is being tested across 3 animal model systems, where concordance will strengthen findings, and discordance will identify biological aspects of species-specific sensitivity to environmentally induced neurodegeneration. The funded project has two aims: Aim 1. To identify species specific-PFOS doses that induce DAergic neurodegeneration. PFOS doses will be harmonized across systems to achieve brain levels that bear environmental relevance. Harmonization of internal dose levels to set external applied dosages for each model system will allow us to interrogate mechanistic hypothesis under comparable insults; Aim 2. Identify neurobiological underpinnings across species that contribute to differential sensitivity to PFOS-induced dopaminergic neurodegeneration. Here, we will identify species-specific differences in neurodegeneration that may underlie critical aspects of neurotoxicity induced by PFOS exposure. Throughout our examination of the PFAS literature, along with our own preliminary data newly collected from R21AG068787, it has become apparent that Alzheimer’s disease (AD)-relevant expansion is strongly supported. PFAS (specifically PFOS) exposure produces modulation of several critical AD proteins in multiple model systems. Thus, in an effort to be highly responsive to NOT-AG-20-034 (entitled, “Alzheimer’s-focused administrative supplements for NIH grants that are not focused on Alzheimer’s disease”), we will leverage R21AG068787 to test the following hypothesis that is aimed at exploring overlap between AD and PD: PFOS exposure will produce an AD-relevant phenotype and that species-specific responses will advance understanding of the biology of AD. This supplement leverages the original scope, adding AD-relevant endpoints, where amyloid beta aggregation, tau aggregation/hyperphosphorylation and other key AD biochemical events will be assessed. Furthermore, AD-relevant neurobehavioral analyses are added in this supplement. Given PFAS exposures are widespread (detectable in >99% of human blood), it is critical to determine if such exposures represent a neurological risk. Our supplement will determine whether PFOS produces neuropathology relevant to AD and identify neurotoxic overlap between AD and PD phenotypes.

R21AG068787名为“ PFOS诱导的多巴胺能神经变性，两栖动物，两栖动物和 啮齿动物模型”。作为NIA比较的一部分，主要重点是帕金森氏病（PD）终点 神经退行性生物学（至PAR-17-039）程序。每种和多氟烷基物质（PFA）是 被研究为发育有毒物质的宽度环境污染物，很少 有关长期神经毒性的信息。我们在线虫和两栖动物模型中的初步数据表明 暴露于PFA，尤其是全氟辛烷磺酸盐（PFO）会诱导神经毒性。主要项目 解决了PFA暴露如何通过测试导致长期神经疾病风险的重要差距 以下假设：针对PFOS诱导的多巴胺能神经变性的规范响应将 对PD生物学的提前理解。该假设正在3个动物模型系统中进行检验， 一致性将加强发现，而不一致将确定物种特异性的生物学方面 对环境诱导的神经变性的敏感性。资助的项目有两个目标：目标1。 规格特定的PFO剂量会影响Daergic神经退行性。 PFO剂量将在 实现具有环境相关性的大脑水平的系统。内部剂量水平的协调 每个模型系统的外部应用剂量将使我们能够审问下 可比的侮辱；目标2。识别跨物种的神经生物学基础，导致差异 对PFOS诱导的多巴胺能神经退行性的敏感性。在这里，我们将确定规格特定的 神经变性的差异可能是PFOS暴露引起的神经毒性关键方面的基础。 在我们对PFA文献的研究中，以及我们自己的初步数据。 R21AG068787，很明显，阿尔茨海默氏病（AD） - 延伸的扩张得到了强有力的支持。 PFA（特别是PFO）暴露会在多种模型中对几种关键AD蛋白进行调制 系统。这是为了高度响应非AG-20-034（标题为“阿尔茨海默氏症的专注” 不专注于阿尔茨海默氏病的NIH赠款的行政补品”，我们将利用 R21AG068787用于测试旨在探索AD和PD之间重叠的以下假设：PFO 暴露会产生与广告相关的表型，并且规格特定的响应将推进 对AD生物学的理解。这种补充利用原始范围，增加了广告含量 终点，淀粉样蛋白β聚集，tau聚集/高磷酸化和其他键AD 将评估生化事件。此外，在此添加了与广告相关的神经行为分析 补充。鉴于PFA的暴露是宽度的（可检测到人类血液的99％），至关重要 确定这种暴露是否代表神经系统风险。我们的补充剂将确定PFO是否 产生与AD相关的神经病理学，并鉴定AD和PD表型之间的神经毒性重叠。