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

基本信息

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
项目类别：
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&apos 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

项目摘要

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 的标题是“全氟辛烷磺酸诱导的线虫、两栖类和两栖类多巴胺能神经变性” 啮齿动物模型”，主要关注帕金森病 (PD) 终点，作为 NIA 比较的一部分。神经变性生物学（至 PAR-17-039）计划是全氟烷基物质和多氟烷基物质 (PFAS)。广泛存在的环境污染物已被研究为发育毒物，但很少有我们在线虫和两栖动物模型中的初步数据表明，长期神经毒性的信息。接触PFAS，尤其是全氟辛烷磺酸（PFOS）会引起神经毒性。通过测试解决了 PFAS 暴露如何导致长期神经系统疾病风险的重要差距以下假设：对 PFOS 引起的多巴胺能神经变性的物种特异性反应将促进对 PD 生物学的理解，该假设正在 3 个动物模型系统中进行测试，一致性将加强研究结果，不一致将确定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该资助项目有两个目标：目标 1. 确定诱导 DAergic 神经变性的物种特异性 PFOS 剂量将在各个国家进行协调。系统实现与环境相关的大脑水平协调内部剂量水平。每个模型系统的外部应用剂量将使我们能够在以下条件下询问机械假设目标 2：确定导致差异的跨物种神经生物学基础对 PFOS 引起的多巴胺能神经变性的敏感性在这里，我们将识别物种特异性。神经变性的差异可能是 PFOS 暴露引起的神经毒性的关键方面的基础。在我们对 PFAS 文献的审查过程中，以及我们自己新收集的初步数据 R21AG068787，很明显，阿尔茨海默病（AD）相关的扩张得到了强烈支持。 PFAS（特别是 PFOS）暴露会对多种模型中的几种关键 AD 蛋白产生调节作用因此，为了对 NOT-AG-20-034（标题为“以阿尔茨海默氏症为中心”）做出高度响应。 NIH 拨款的行政补充，不针对阿尔茨海默病”），我们将利用 R21AG068787 检验以下旨在探索 AD 和 PD 之间重叠的假设：PFOS 暴露会产生与 AD 相关的表型，并且物种特异性反应将促进本补充材料利用了原有的范围，添加了与 AD 相关的内容。终点，其中淀粉样蛋白聚集、tau 聚集/过度磷酸化和其他关键 AD 此外，还将评估与 AD 相关的神经行为分析。鉴于 PFAS 暴露非常普遍（在 > 99% 的人类血液中可检测到），因此补充 PFAS 至关重要。确定此类暴露是否构成神经系统风险。我们的补充剂将确定 PFOS 是否存在。产生与 AD 相关的神经病理学，并识别 AD 和 PD 表型之间的神经毒性重叠。