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

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）， 多巴胺（DA）神经元的选择性死亡。到目前为止，已经有许多罕见的接触， 作为风险因素进行了研究，但没有一个与PD明确相关。此外，治疗方法的翻译， 从动物实验到成功的临床试验的前景一直很差。这些领域的空白表明 PD研究中动物模型的利用存在严重缺陷。大多数PD研究都是在单一的 模型系统然而，在加强调查结果的力度方面有明显的优势， 通过了解物种差异来推进这一领域。该R21旨在高度响应PAR- 17 - 039（神经退行性变的比较生物学），通过测试三个PD相关神经退行性变 遗传多样性动物模型系统。根据R21的精神，该提案利用高风险/高风险 奖励方法，将测试新的风险因素，以促进对PD生物学的理解。 全氟烷基和多氟烷基物质（PFAS）是广泛存在的环境污染物， 作为发育毒物进行研究，关于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， 特别是全氟辛烷磺酸（PFOS）诱导选择性PD相关DA能神经毒性。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提前 了解PD的生物学。重要的是，该假设将在3种动物模型系统中进行检验， 一致性将加强发现，不一致性将确定物种特异性的生物学方面 对环境诱发的神经退化的敏感性我们将通过两个目标来检验我们的假设： 1.确定引起DA能神经变性的物种特异性全氟辛烷磺酸剂量。全氟辛烷磺酸剂量将 协调各系统，以实现与环境相关的大脑水平。协调内部 为每个模型系统设定外部应用剂量的剂量水平将允许我们询问 假设在可比的侮辱;目的2.确定跨物种的神经生物学基础， 导致对全氟辛烷磺酸诱导的多巴胺能神经变性的敏感性不同。在这里，我们将识别 神经变性的种属特异性差异可能是选择性多巴胺能神经递质的关键方面的基础。 接触全氟辛烷磺酸引起的神经毒性。我们将进行比较生物学研究， 机械的。由此产生的数据对于确定以下方面至关重要：1）哪种物种最适合全氟辛烷磺酸 神经变性研究; 2）确定哪些致病途径与神经变性直接相关。 跨物种的神经退化这些研究将从机械上推动该领域的发展， 典型的单物种研究

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.