Pesticide-Mediated Generation of a Toxic Neurotransmitter Metabolite

农药介导的有毒神经递质代谢物的产生

基本信息

批准号：
10246376
负责人：
JONATHAN A DOORN
金额：
$ 30.95万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10246376
关键词：
Address Affect Agriculture Aldehydes Animal Model Area Astrocytes Basal Ganglia Cells Chemicals Chlorinated Hydrocarbons Chronic Complex Data Development Dieldrin Disease Disease Progression Dopamine Dopaminergic Cell Dose Environmental Risk Factor Enzymes Epidemiology Etiology Exposure to Functional disorder Generations Genetic Genetic Variation Goals Impairment In Vitro Individual Inflammation Mediators Injury Knock-out Link Literature Mass Spectrum Analysis Measures Mediating Mediator of activation protein Metabolism Molecular Molecular Target Monoamine Oxidase Monoamine Oxidase B Mus Nerve Degeneration Neurodegenerative Disorders Neuroglia Neuronal Injury Neurons Neurotransmitters Nitrogen Oxidative Stress Oxygen Parkinson Disease Pathogenicity Pathologic Pathway interactions Pesticides Production Proteins Quinones Reaction Research Risk Role Testing Toxic effect Transgenic Mice Work aldehyde dehydrogenases basal ganglia injury base cell type cellular targeting disease diagnosis dopamine system dopaminergic neuron early detection biomarkers environmental agent exposed human population gene environment interaction genetic approach glial activation in vivo innovation nervous system disorder neuroinflammation neuron loss neurotoxic neurotoxicity neurotransmitter metabolism new therapeutic target overexpression pesticide exposure pesticide interaction potential biomarker release factor response stem synergism trafficking

项目摘要

PROJECT SUMMARY Exposure to the organochlorine dieldrin predisposes individuals to Parkinson's Disease (PD); however, the mechanisms linking exposure to disease and selective loss of dopaminergic cells are unknown. In addition, dieldrin alone may be insufficient for loss of dopamine (DA) neurons, and neurodegeneration may require an additional “hit”, such as from genetics. Several animal models have demonstrated that altering DA metabolism and/or trafficking yields progressive loss of DA neurons; therefore, a genetic variation modifying DA metabolism may be an additional “hit” that has toxic synergy with pesticide exposure. Cell types other than DA neurons are thought to be involved in PD, such as glia, and toxic factors released via glial activation are realized as a critical contributors to disease progression. Both DA neurons and glial cells (e.g., astrocytes) metabolize DA and other neurotransmitters and generate toxic intermediates such as ROS and aldehydes (3,4-dihydroxyphenylacetaldehyde, DOPAL), via monoamine oxidase. Based on literature precedent and preliminary data, we propose DA metabolism and trafficking as a mechanistic target for the pesticide dieldrin that can produce a build-up of reactive and toxic intermediates such as DOPAL and neuroinflammation. While the role of DA and its quinone have been explored as a mechanism for neurotoxicity, very little is known about DOPAL and the role of aldehyde metabolism. DOPAL generation is proposed as a mechanism unifying pesticide exposure, neuroinflammation and loss of catecholaminergic cells. The goal of this work is to elucidate mechanisms underlying environmental risk factors for neurodegenerative disease, specifically focusing on the interaction of the pesticide dieldrin with DArgic and glia and resulting injury to dopaminergic neurons via reactive intermediates such as DOPAL. In addition, the gene-environment interaction will be explored as dieldrin alone may be insufficient to cause loss of DA neurons. The central hypothesis is that pesticides such as dieldrin target DA metabolism and/or trafficking in neurons and glia, yielding reactive aldehyde metabolites that damage DA neurons and promote neuroinflammatory activation of glial cells. Three Aims will be completed: 1) Determine the effects of pesticide exposure on the nigro-striatal DA system in transgenic mice with altered DA metabolism. 2) Determine the contribution of glial-derived reactive DA intermediates to pesticide-mediated neuronal injury. 3) Identify cellular and molecular targets of reactive intermediates. An innovative and encompassing approach in vivo and in vitro will be used with a robust genetic strategy of mice that are deficient or have overexpression of enzymes key to DA metabolism. These Specific Aims will build upon previous work to address key mechanistic questions regarding critical cellular interactions between astrocytes and neurons that potentiate dysfunction caused by exposure to pesticides.

项目概要然而，接触有机氯狄氏剂会使人易患帕金森病 (PD)；此外，暴露于疾病和多巴胺能细胞选择性丧失之间的机制尚不清楚。单独使用狄氏剂可能不足以消除多巴胺 (DA) 神经元的损失，并且神经退行性疾病可能需要额外的“打击”，例如来自遗传学的影响，一些动物模型已经证明，改变 DA 代谢。和/或贩运导致 DA 神经元逐渐丧失；因此，遗传变异修饰了 DA；新陈代谢可能是一个额外的“打击”，与除 DA 之外的细胞类型具有毒性协同作用。神经元被认为与帕金森病有关，例如神经胶质细胞，通过神经胶质细胞激活释放的毒性因子是 DA 神经元和神经胶质细胞（例如星形胶质细胞）被认为是疾病进展的关键因素。代谢DA和其他神经递质并产生有毒中间体，例如ROS和醛类（3,4-二羟基苯乙醛，DOPAL），通过单胺氧化酶基于文献先例和。初步数据显示，我们建议将 DA 代谢和运输作为农药狄氏剂的机械目标会产生反应性和毒性中间体的积聚，例如 DOPAL 和神经炎症。 DA 及其醌的作用已作为神经毒性机制进行了探索，但人们对此知之甚少 DOPAL 和醛代谢的作用被认为是一种统一的机制。农药接触、神经炎症和儿茶酚胺能细胞的损失这项工作的目标是阐明。神经退行性疾病环境危险因素的潜在机制，特别关注农药狄氏剂与 DArgic 和神经胶质细胞相互作用，并通过以下方式对多巴胺能神经元造成损伤：此外，还将探索基因-环境相互作用。单独使用狄氏剂可能不足以导致 DA 神经元丧失，中心假设是杀虫剂如此类药物。因为狄氏剂靶向神经元和神经胶质细胞中的 DA 代谢和/或运输，产生反应性醛代谢物损害 DA 神经元并促进神经胶质细胞的神经炎症激活将是三个目标。已完成：1）确定农药暴露对转基因小鼠黑质纹状体DA系统的影响 2) 确定神经胶质衍生的反应性 DA 中间体对 DA 代谢的贡献。农药介导的神经元损伤。 3) 识别反应中间体的细胞和分子靶标。体内和体外的创新和包容性方法将与小鼠的强大遗传策略一起使用 DA 代谢关键酶的缺乏或过度表达将建立这些特定目标。基于之前的工作来解决有关关键细胞相互作用的关键机制问题星形胶质细胞和神经元会加剧因接触农药而引起的功能障碍。