Organochlorine-Mediated Generation of a Dopamine Derived Neurotoxin

有机氯介导的多巴胺衍生神经毒素的产生

基本信息

批准号：
7539937
负责人：
JONATHAN A DOORN
金额：
$ 29.97万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-01-01 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7539937
关键词：
3,4-Dihydroxyphenylacetic Acid 4 hydroxynonenal Accounting Acetic Acids Address Affect Agriculture Aldehydes Antibodies Brain Brain region Cells Cellular Stress Chlorinated Hydrocarbons Chronic Complex Corpus striatum structure Data Dieldrin Disease Dopamine Dopaminergic Cell Dose Environmental Exposure Exposure to Foundations Future Generations Goals Health Human Impairment In Vitro Incidence Individual Link Lipid Peroxidation Mediating Metabolic Biotransformation Metabolism Mitochondria Modeling Mus Nerve Degeneration Neurotoxins Outcomes Research Oxidative Stress Parkinson Disease Pathogenesis Pathway interactions Pesticides Post-Translational Protein Processing Proteins Rattus Research Risk Factors Role Simulate Testing Therapeutic Intervention Toxic effect Toxin Translating Work aldehyde dehydrogenases base cofactor environmental agent environmental chemical exposed human population in vivo inhibitor/antagonist innovation mouse model neurotoxic neurotoxicity novel novel strategies pesticide exposure treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Exposure to environmental chemicals is a risk factor for Parkinson's Disease (PD). Specifically, pesticides used in agriculture, such as the organochlorine dieldrin, are associated with PD incidence; however, the link between exposure and disease is not known, and the underlying mechanisms remain to be determined. A potential pathway involves oxidative stress. Dieldrin, which is associated with PD incidence, has been shown to induce this injurious condition. However, it is not known how general oxidative stress, resulting from environmental exposure, can translate into specific dopaminergic toxicity. A proposed mechanism to account for this involves 3,4-dihydroxyphenylacetaldehyde (DOPAL), a dopamine (DA) derived neurotoxin. DA is metabolized to the toxic intermediate, DOPAL, which is oxidized via mitochondrial aldehyde dehydrogenase (mALDH) to 3,4-dihydroxyphenyl acetic acid (DOPAC) using the cofactor NAD. Aldehydes generated via oxidative stress, e.g., 4-hydroxynonenal (4HNE), are potent inhibitors of mALDH; therefore, cellular stress resulting from environmental agents may inhibit DOPAL metabolism yielding high levels of the DA-derived aldehyde. Furthermore, impairment of complex I, responsible for generation of mitochondrial NAD, has been observed for pesticides, and such an insult would also decrease the ability of mALDH to metabolize DOPAL. Preliminary data presented in this application demonstrate that both the oxidative stress product 4HNE and dieldrin yield inhibition of mitochondrial metabolism of DOPAL; furthermore, the DA-derived aldehyde is highly reactive toward proteins. Based on previous studies and preliminary data presented in this application, it is hypothesized that the organochlorine dieldrin inhibits cellular metabolism of DOPAL, yielding aberrant levels of this endogenous aldehyde neurotoxin and subsequent protein modification. To test the hypothesis, three specific aims will be completed. Specific Aim 1 will examine the ability of dieldrin to impair DOPAL metabolism in dopaminergic cells and elucidate the mechanism of inhibition. Specific Aim 2 will demonstrate protein adduction by the DA-derived aldehyde in cells treated with dieldrin. Specific Aim 3 will determine the extent of protein modification by DOPAL in vivo in a mouse model of chronic dieldrin dosing. The work proposed in this application is significant and innovative and will serve as a foundation for future research aimed at determining the role of environmetal exposure in PD pathogenesis.

描述（由申请人提供）：接触环境化学物质是帕金森氏病（PD）的危险因素。具体而言，在农业中使用的农药，例如有机氯丁香蛋白，与PD发病率有关。但是，尚不清楚暴露与疾病之间的联系，并且潜在的机制仍有待确定。潜在的途径涉及氧化应激。与PD发病率相关的Dieldrin已被证明会诱导这种有害状况。但是，尚不清楚环境暴露引起的一般氧化应激如何转化为特定的多巴胺能毒性。解决此问题的一种提议的机制涉及3,4-二羟基苯基甲醛（多巴胺），一种多巴胺（DA）衍生的神经毒素。 DA被代谢为有毒的中间体多巴尔，该do通过线粒体醛脱氢酶（MALDH）氧化，使用辅因子NAD氧化为3,4-二羟基苯基乙酸（DOPAC）。通过氧化应激产生的醛，例如4-羟基诺纳尔（4hne）是MALDH的有效抑制剂；因此，由环境药物引起的细胞应激可能抑制产生高水平的DA衍生醛的代谢。此外，已经观察到农药的损害，负责线粒体NAD产生的损伤，这种侮辱也将降低MALDH代谢多巴尔的能力。本申请中提供的初步数据表明，氧化应激产物4HNE和狄氏蛋白均可抑制多帕尔的线粒体代谢。此外，DA衍生的醛对蛋白质高反应。根据本应用程序中提出的先前的研究和初步数据，假设有机氯二甲蛋白抑制了多帕尔的细胞代谢，从而产生这种内源性醛神经毒素的异常水平和随后的蛋白质修饰。为了检验假设，将完成三个具体目标。具体的目标1将检查二甲蛋白在多巴胺能细胞中损害多巴多州代谢的能力并阐明抑制机制。具体的目标2将证明在用二旋蛋白处理的细胞中，DA衍生的醛在蛋白质中添加了蛋白质。特定的目标3将确定慢性dieldrin剂量小鼠模型中多巴尔体内蛋白质修饰的程度。本应用中提出的工作具有重要意义，具有创新性，并将成为未来研究的基础，旨在确定环境暴露在PD发病机理中的作用。