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

R21AG068787的标题是“全氟辛烷磺酸诱导的跨线虫、两栖动物和 啮齿动物模型“。作为NIA比较的一部分，主要关注帕金森病(PD)终点 神经变性生物学(按PAR-17-039)计划。全氟烷基和多氟烷基物质(PFA)是 作为发育毒物被调查的广泛的环境污染物，几乎没有 关于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 暴露于全氟辛烷磺酸，尤其是全氟辛烷磺酸(PFOS)会导致神经毒性。主要项目 通过测试解决关于全氟辛烷磺酸暴露如何导致长期神经疾病风险的重要差距 以下假设：对全氟辛烷磺酸诱导的多巴胺能神经变性的物种特异性反应将 促进对帕金森病生物学的了解。这一假设正在3个动物模型系统中进行验证， 其中，一致性将加强研究结果，而不一致性将识别特定物种的生物学方面 对环境引起的神经变性的敏感性。受资助的项目有两个目标：目标1.确定 物种特定--全氟辛烷磺酸导致多巴胺能神经变性的剂量。全氟辛烷磺酸的剂量将在 达到与环境相关的大脑水平的系统。协调内部剂量水平以设定 每个模型系统的外部应用剂量将允许我们在以下条件下询问机械假说 类似的侮辱；目标2.确定导致差异的跨物种神经生物学基础 对全氟辛烷磺酸诱导的多巴胺能神经变性的敏感性。在这里，我们将识别特定物种 神经变性的差异可能是全氟辛烷磺酸暴露所致神经毒性的关键方面的基础。 通过我们对PFAS文献的检查，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)相关的扩展得到了强烈支持。 全氟辛烷磺酸(特别是全氟辛烷磺酸)在多种模型中对几种关键AD蛋白产生调节作用 系统。因此，在努力对NOT-AG-20-034(标题为《聚焦阿尔茨海默氏症》)做出高度响应的努力中 NIH不关注阿尔茨海默氏症的行政补助“)，我们将利用 R21AG068787以测试以下旨在探索AD和PD之间重叠的假设：全氟辛烷磺酸 暴露将产生与AD相关的表型，并且特定物种的反应将提前 对阿尔茨海默病生物学的理解。本补充内容利用了原始范围，添加了与AD相关的内容 终末点，其中淀粉样β聚集、tau聚集/过度磷酸化和其他关键AD 将对生化事件进行评估。此外，还增加了与AD相关的神经行为分析 副刊。鉴于PFAS暴露广泛(在99%的人血液中可检测到)，至关重要的是 确定这样的暴露是否代表神经风险。我们的增刊将决定全氟辛烷磺酸 产生与AD相关的神经病理学，并确定AD和PD表型之间的神经毒性重叠。

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.