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: 10241311
• 负责人: Jason R Cannon
• 金额: $ 18.52万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241311
• 关键词: Address; Affect; Amphibia; Animal Model; Animals; Big Data; Biological; Biological Models; Biology; Brain; Cell physiology; Cessation of life; Clinical Trials; Comparative Biology; Comparative Study; Coupled; Data; Detection; Developmental Toxicant; Dose; Environmental Pollution; Exposure to; Goals; Health; Hypothalamic structure; Link; Measures; Modeling; Movement Disorders; Nematoda; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; Neurologic; Neurotransmitters; Outcome; Parkinson Disease; Pathogenesis; Pathogenicity; Pathway interactions; Phase; Phenotype; Phylogenetic Analysis; Plasma; Rana; Research; Research Project Grants; Risk; Risk Factors; Rodent; Rodent Model; Role; System; Testing; Therapeutic; Tissues; Translations; Ursidae Family; bioaccumulation; comparative; disorder risk; dopaminergic neuron; dosage; high reward; high risk; innovation; nervous system disorder; neurobehavioral; neuropathology; neurotoxicity; neurotransmission; novel; oxidative damage; perfluorooctane sulfonate; pituitary thyroid axis; protein aggregation; resilience; response; species difference; success

Parkinson's disease (PD) is a debilitating movement disorder (affecting ~5 million world‐wide) resulting from selective death of dopamine (DA) neurons. To date, numerous rarely encountered exposures have been investigated as risk factors, but none have been clearly linked to PD. Further, the translation of therapeutics that are promising in animal studies to successful clinical trials has been very poor. These gaps in the field suggest serious weaknesses in the utilization of animal models in PD research. Most PD studies test hypotheses in single model systems. However, there are clear advantages with respect to increasing the strength of the findings and advancing the field through understanding species differences. This R21 aims to be highly responsive to PAR‐ 17‐039 (Comparative Biology of Neurodegeneration) by testing PD‐relevant neurodegeneration across three phylogenetically diverse animal model systems. In the spirit of an R21, the proposal utilizes high risk/high reward approaches, where novel risk factors will be tested to advance the understanding of the biology of PD. 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 mechanistic and neuropathology data in nematode and amphibian models suggest that exposure to PFAS, especially perfluorooctane sulfonate (PFOS) induces selective PD‐relevant, DAergic neurotoxicity. This project will address an important gap on how PFAS exposure leads to long‐term neurological disease risk. We will test the hypothesis: that species‐specific responses to PFOS‐induced dopaminergic neurodegeneration will advance understanding of the biology of PD. Importantly, the hypothesis will be 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. We will test our hypothesis through 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 selective dopaminergic neurotoxicity induced by PFOS exposure. We will conduct comparative biology studies that are both phenotypic and mechanistic. Resultant data will be critical in determining: 1) Which species is best suited to PFOS neurodegeneration studies; 2) Identifying which pathogenic pathways directly correlate with neurodegeneration across species. These studies will mechanistically advance the field far beyond data from typical single‐species studies.

帕金森病 (PD) 是一种使人衰弱的运动障碍（影响全球约 500 万人），其原因是 多巴胺（DA）神经元的选择性死亡。迄今为止，许多罕见的暴露已被 作为危险因素进行了调查，但没有一个与 PD 明确相关。此外，治疗学的翻译 在动物研究中很有希望，但临床试验的成功率却很差。该领域的这些空白表明 PD 研究中动物模型的利用存在严重缺陷。大多数 PD 研究都是在单一样本中检验假设 模型系统。然而，在增强研究结果的强度和 通过了解物种差异来推进该领域的发展。该 R21 的目标是对 PAR 高度响应 17-039（神经退行性变的比较生物学）通过测试三个方面的 PD 相关神经退行性变 系统发育多样化的动物模型系统。本着 R21 的精神，该提案利用了高风险/高风险 奖励方法，将测试新的风险因素，以增进对帕金森病生物学的理解。 全氟烷基物质和多氟烷基物质 (PFAS) 是广泛存在的环境污染物，已被 作为发育毒物进行研究，有关长期神经毒性的信息很少。我们的初步 线虫和两栖动物模型的机制和神经病理学数据表明，接触 PFAS、 特别是全氟辛烷磺酸 (PFOS) 会诱导选择性 PD 相关的 DAergic 神经毒性。这个项目 将解决 PFAS 暴露如何导致长期神经系统疾病风险的重要差距。我们将测试 假设：对 PFOS 引起的多巴胺能神经变性的物种特异性反应将会进展 了解 PD 的生物学。重要的是，该假设将在 3 个动物模型系统中进行测试， 一致性将加强发现，不一致将识别物种特异性的生物学方面 对环境引起的神经变性的敏感性。我们将通过两个目标来检验我们的假设： 1. 确定诱导 DAergic 神经变性的物种特异性全氟辛烷磺酸剂量。 PFOS 剂量将是 跨系统协调一致，以达到与环境相关的大脑水平。内部协调 为每个模型系统设置外部应用剂量的剂量水平将使我们能够询问机制 类似侮辱下的假设；目标 2. 确定跨物种的神经生物学基础 有助于对 PFOS 引起的多巴胺能神经变性的不同敏感性。在这里，我们将识别 神经变性的物种特异性差异可能是选择性多巴胺能关键方面的基础 PFOS 暴露引起的神经毒性。我们将进行表型的比较生物学研究 和机械性的。结果数据对于确定：1) 哪种物种最适合 PFOS 至关重要 神经变性研究； 2) 确定哪些致病途径与 跨物种的神经变性。这些研究将机械地推进该领域远远超出来自数据的范围 典型的单物种研究。