Neurotoxicity of Maneb and Roundup

描述（由申请人提供）：根据NIEHS提出的目标，本项目旨在研究杀虫剂在Parksinon病（PD）病因学中的作用。许多报告表明PD的发病与农业环境（包括农药使用）之间存在联系。PD患者也已知具有线粒体功能障碍。有趣的是，许多argochemicals也是已知的线粒体抑制剂。该项目的长期目标是了解两种有毒物质，杀真菌剂代森锰和含草甘膦除草剂农达与神经毒性的关系。利用秀丽隐杆线虫（Causophabditis elegans，C.作为模式生物，我们将测试暴露于多种农用化学品，特别是代森锰和农达，导致神经元变性的假设。此外，我们假设连续暴露于这些农药会导致氧化应激增加。该假设将通过两个特定的目标进行测试：（1）确定暴露于maneb或Roundup是否会影响已知在PD或锰神经毒性中脆弱的神经元群体;（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的上调。为了完成这项研究，我们将使用转基因C。具有各种神经元群体或用绿色荧光蛋白（GFP）标记的抗氧化蛋白的线虫。将蠕虫分别暴露于不同浓度的代森锰或农达，以确定它们是否诱导神经元变性或氧化应激，如通过荧光显微镜所评估的。随后的研究将检查这两种杀虫剂的连续处理是否会导致毒性增加。这些新研究的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，它们将提供关于这些化学物质在体内诱导线粒体抑制的能力的证据。预计从这些研究中收集的数据不仅将进一步了解农药的神经毒性，而且还了解环境毒物可能促进特发性帕金森病病因学的机制。这些研究对公众健康特别重要，因为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中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，最终产品可能更具毒性。此外，这项工作将研究接触多种农药的影响，这更有可能发生在人类接触。

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.