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

• 批准号: 7996622
• 负责人: JONATHAN A DOORN
• 金额: $ 29.38万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 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/7996622
• 关键词: 3,4-Dihydroxyphenylacetic Acid; 4 hydroxynonenal; Accounting; Acetic Acids; Address; Affect; Agriculture; Aldehydes; Animals; Antibodies; Body Burden; Brain; Brain region; Cells; Cellular Stress; Chlorinated Hydrocarbons; Chronic; Complex; Corpus striatum structure; Data; Dieldrin; Disease; Dopamine; Dopaminergic Cell; Dose; Environmental Exposure; Exposure to; Food; Foundations; Generations; Goals; Health; Human; Immunohistochemistry; Impairment; In Vitro; Incidence; Individual; Ingestion; Link; Lipid Peroxidation; Measurement; Mediating; Metabolic Biotransformation; Metabolism; Mitochondria; Modeling; Mus; Nerve Degeneration; Neurotoxins; Oral; Oral Administration; Outcomes Research; Oxidative Stress; Parkinson Disease; Pathogenesis; Pathway interactions; Pesticides; Post-Translational Protein Processing; Principal Investigator; Proteins; Rattus; Research; Risk Factors; Role; Route; Simulate; Testing; Therapeutic Intervention; Time; Toxic effect; Toxin; Translating; Tyrosine 3-Monooxygenase; Work; aldehyde dehydrogenases; base; cofactor; environmental agent; environmental chemical; exposed human population; in vivo; inhibitor/antagonist; innovation; mouse model; neurotoxic; neurotoxicity; novel; novel strategies; programs; research study; statistics; tissue preparation; treatment strategy

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病 (PD) 的危险因素。具体来说，农业中使用的杀虫剂，如有机氯狄氏剂，与帕金森病的发病率有关。然而，暴露与疾病之间的联系尚不清楚，其潜在机制仍有待确定。一个潜在的途径涉及氧化应激。狄氏剂与帕金森病的发生有关，已被证明会诱发这种有害病症。然而，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。解释这一现象的拟议机制涉及 3,4-二羟基苯乙醛 (DOPAL)，一种多巴胺 (DA) 衍生的神经毒素。 DA 代谢为有毒中间体 DOPAL，通过辅因子 NAD 通过线粒体乙醛脱氢酶 (mALDH) 将其氧化为 3,4-二羟基苯乙酸 (DOPAC)。通过氧化应激产生的醛，例如 4-羟基壬烯醛 (4HNE)，是 mALDH 的有效抑制剂；因此，环境因素引起的细胞应激可能会抑制 DOPAL 代谢，从而产生高水平的 DA 衍生醛。此外，已观察到农药对负责生成线粒体 NAD 的复合物 I 造成损害，这种损害也会降低 mALDH 代谢 DOPAL 的能力。本申请中提供的初步数据表明，氧化应激产物 4HNE 和狄氏剂都会抑制 DOPAL 的线粒体代谢；此外，DA 衍生的醛对蛋白质具有高度反应性。基于之前的研究和本申请中提供的初步数据，推测有机氯狄氏剂抑制DOPAL的细胞代谢，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。为了检验该假设，将完成三个具体目标。具体目标 1 将检查狄氏剂损害多巴胺能细胞中 DOPAL 代谢的能力并阐明抑制机制。具体目标 2 将证明在用狄氏剂处理的细胞中 DA 衍生的醛可进行蛋白质加合。具体目标 3 将确定在长期服用狄氏剂的小鼠模型中 DOPAL 体内蛋白质修饰的程度。本申请中提出的工作具有重要意义和创新性，将作为未来研究的基础，旨在确定环境金属暴露在帕金森病发病机制中的作用。