Neurotoxicity of Maneb and Roundup

描述(由申请人提供)：根据NIEHS设定的目标，本项目旨在研究杀虫剂在帕克西农病(PD)病因中的作用。许多报告表明，现场PD与包括农药使用在内的农业环境之间存在联系。众所周知，帕金森病患者也有线粒体功能障碍。有趣的是，许多化学物质也是已知的线粒体抑制剂。该项目的长期目标是了解两种毒物--杀菌剂甘露糖和含有草甘膦的除草剂农达--与神经元毒性的关系。以线虫秀丽线虫(C.elegans)为模式生物，我们将检验暴露于多种农用化学品，特别是甘露威和农达，会导致神经元退化的假说。此外，我们假设连续接触这些杀虫剂会导致氧化应激增加。这一假说将通过两个特定的目标进行验证：(1)确定暴露于maneb或Roundup是否会影响已知易受PD或Mn2神经毒性影响的神经元群体；以及(2)确定暴露于maneb或Roundup是否会诱导与氧化应激产生相关的蛋白质上调。为了完成这项研究，我们将使用带有不同神经元种群的转基因线虫或带有绿色荧光蛋白(GFP)标记的抗氧化蛋白。蠕虫将分别暴露于不同浓度的甘露糖或农达，以确定它们是否会诱导神经元退化或通过荧光显微镜评估氧化应激。随后的研究将检查这两种杀虫剂的顺序治疗是否会导致毒性增加。这些新的研究结果将进一步加深我们对多种农药暴露的神经毒性效应的理解。此外，他们还将为这些化学物质在体内诱导线粒体抑制的这种能力提供证据。预计从这些研究中收集的数据将不仅加深我们对农药神经毒性的理解，而且还将加深我们对环境毒物促进特发性帕金森病病因的机制的了解。这些研究对公众健康特别重要，因为普通公众和农业社区越来越多地使用农达和类似的除草剂。虽然Roungup的主要成分相对无毒，但最近的数据显示，当该化学品混合用于商业用途时，最终产品可能毒性更大。此外，这项工作将研究接触多种杀虫剂的影响，这种影响更有可能发生在人类接触中。

DESCRIPTION (provided by applicant): In accordance with the goals set forth by NIEHS, this project seeks to examine the role of pesticides in the etiology of Parksinon's disease (PD). Numerous reports have suggested a link between the on-set of PD and an agricultural environment, which includes pesticide usage. Patients with PD are also known to have mitochondrial dysfunction. Interestingly, many argochemicals are also known mitochondrial inhibitors. The long-term goal of this project is to understand the relationship of two toxicants, the fungicide maneb and the glyphosate-containing herbicide Roundup, to neuronal toxicity. Using the nematode Caenorhabditis elegans (C. elegans) as a model organism, we will test the hypothesis that exposure to multiple agrochemicals, specifically maneb and Roundup, leads to neuronal degeneration. Additionally, we hypothesize that sequential exposure to these pesticides leads to increased oxidative stress. The hypothesis will be tested through two specific aims: (1) to determine whether exposure to maneb or Roundup affects neuronal populations known to be vulnerable in either PD or manganese neurotoxicity; and (2) to determine whether exposure to maneb or Roundup induces the up-regulation of proteins associated with the production of oxidative stress. In order to complete this study, we will use genetically modified C. elegans with various neuronal populations or antioxidant proteins tagged with green fluorescent protein (GFP). Worms will be exposed to varying concentrations of maneb or Roundup, separately, to determine whether they induce neuronal degeneration or oxidative stress as assessed by fluorescent microscopy. Subsequent studies will examine whether sequential treatment of these two pesticides results in increased toxicity. Results from these novel studies will further our understanding of the neurotoxic effects of multiple pesticide exposures. Additioanlly, they will provide evidence about this ability of these chemicals to induce mitochondrial inhibition in vivo. It is anticipated that data gleaned from these studies will further our understanding not only of pesticide neurotoxicity, but also of the mechanism through which environmental toxicants may facilitate the etiology of idiopathic Parkinson's disease. These studies are particularly important to public health because of the increased use of Roundup, and similar herbicides, by the general public and the agricultural community. Although the main ingredient in Roungup is relatively non-toxic, recent data shows that when the chemical is mixed for commercial usage, the final product may be more toxic. Additionally, this work will examine the effects of exposure to multiple pesticides, which is more likely to occur in human exposures.