Exposure to Pesticides: A Fetal Environmental Risk Factor for Parkinson's Disease

接触农药：帕金森病的胎儿环境风险因素

• 批准号: 7501329
• 负责人: Brian Barlow
• 金额: $ 3.09万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2011-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7501329
• 关键词: Age; Aging; Animal Model; Animals; Attention; Barker Hypothesis; Biochemical; Brain; Cell physiology; Cells; Clinical; Computer Systems Development; Degenerative Disorder; Development; Disease; Dopamine; End Point; Environment; Environmental Risk Factor; Estrogens; Estrous Cycle; Etiology; Experimental Models; Exposure to; Functional disorder; Future; Gender; Gender Role; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genetic; Gonadal Steroid Hormones; Health; Homeostasis; Hormones; Human; Individual; Industrial fungicide; Life; Link; Longevity; Maneb; Measures; Mediating; Mission; Modeling; Motor; Mus; Neurodegenerative Disorders; Neurons; Oxidative Stress; Paraquat; Parkinson Disease; Pesticides; Phase; Play; Population; Predisposition; Pregnancy; Public Health; Reporting; Research; Risk; Risk Assessment; Risk Factors; Role; Severities; Severity of illness; Staging; Symptoms; System; Toxic Environmental Substances; Toxic effect; Toxicant exposure; Toxicokinetics; aging population; base; biological adaptation to stress; cohort; design; disease phenotype; disorder risk; dopamine system; fetal; insight; neurodevelopment; neurotoxic; nigrostriatal system; oxidation; pesticide exposure; pre-clinical; prenatal; prenatal exposure; progressive neurodegeneration; response

DESCRIPTION (provided by applicant): Parkinson's Disease (PD) is a progressive neurodegenerative disorder characterized clinically by motor dysfunction and pathologically by depletion of dopamine (DA)-producing neurons in the nigrostriatal DA (NSD) system. Environmental risk factors for PD are consistently reported, via epidemiological, clinical, and animal studies. Though PD typically emerges late in life, the environment in periods of neurodevelopment is gaining attention as a susceptibility factor. For example, in mice, prenatal exposure to the fungicide maneb (MB) greatly increased adulthood susceptibility to the pesticide paraquat (PQ), resulting in features of PD. Concordant with the mission of the NIEHS, the current proposal seeks to unravel the mechanism by which MB alters neurodevelopment to confer vulnerability to the progressive neurodegeneration seen in PD. To understand the role of multiple environmental hits, a cohort design will be employed in which mice prenatally exposed to MB will be followed across the lifespan, with intermittent exposure to PQ. Dopaminergic integrity will be assessed at many timepoints for evidence of progressive neurodegeneration, and toxicokinetic and toxicodynamic study of MB and PQ will be undertaken. It is hypothesized that prenatal MB exposure induces a state of altered potential (SAP), and that this SAP describes a pre-clinical phase of DAergic dysfunction. This SAP will be characterized through gene expression profiling and analysis of several biochemical systems (including those for DA homeostasis, oxidative stress response, trophic factors, and barriers); risk factors (e.g. aging, PQ) may act through these systems, and these endpoints will also be studied in the context of these risk factors. Finally, since gender plays a major role in PD, it is hypothesized that gonadal steroid hormones modulate risk; this will be assessed by characterizing the role of the estrous cycle on the normal mouse NSD system, on PQ toxicokinetics and toxicodynamics, and also by manipulating gonadal steroid exposure at various stages of development. PUBLIC HEALTH RELEVANCE: Parkinson's disease (PD) is a major health concern, and though onset of symptoms typically occurs late in the lifespan, environmental factors as early as prenatal life may have long-lasting consequences for development of this disease. Using an animal model of prenatal exposure to the fungicide maneb, this proposal seeks 1. to understand how maneb creates long-lasting susceptibility, 2. to define the biochemical and gene expression profile that describes the pre-symptomatic state of vulnerability, and 3. to clarify the role of gender in mediating these effects. In addition to providing insight into the etiology of PD and contributing to risk assessment paradigms, we will identify stable targets that may be amenable to manipulation to modify risk and/or severity of PD.

描述（由申请人提供）：帕金森病（PD）是一种进行性神经退行性疾病，其临床特征为运动功能障碍，病理特征为黑质纹状体DA（NSD）系统中产生多巴胺（DA）的神经元耗竭。通过流行病学、临床和动物研究，持续报告了PD的环境风险因素。虽然PD通常出现在生命的后期，但神经发育时期的环境作为易感因素越来越受到关注。例如，在小鼠中，产前暴露于杀真菌剂代森锰（MB）大大增加了成年期对杀虫剂百草枯（PQ）的易感性，导致PD的特征。与NIEHS的使命一致，目前的建议旨在阐明MB改变神经发育的机制，从而使PD中出现的进行性神经变性变得脆弱。为了了解多种环境影响的作用，将采用队列设计，其中将在整个寿命期内对产前暴露于MB的小鼠进行随访，间歇性暴露于PQ。将在许多时间点评估多巴胺能完整性，以获得进行性神经变性的证据，并将进行MB和PQ的毒代动力学和毒代动力学研究。假设产前MB暴露诱导了一种电位改变状态（SAP），该SAP描述了DA能功能障碍的临床前阶段。该SAP将通过基因表达谱分析和几种生化系统（包括DA稳态、氧化应激反应、营养因子和屏障）的分析进行表征;风险因素（例如衰老、PQ）可能通过这些系统起作用，也将在这些风险因素的背景下研究这些终点。最后，由于性别在PD中起着重要作用，因此假设性腺类固醇激素调节风险;这将通过表征发情周期对正常小鼠NSD系统、PQ毒代动力学和毒代动力学的作用以及在发育的各个阶段操纵性腺类固醇暴露来评估。 公共卫生关系：帕金森病（PD）是一个主要的健康问题，虽然症状的发作通常发生在生命的后期，早在产前生活的环境因素可能会对这种疾病的发展产生长期的影响。使用产前暴露于杀真菌剂代森锰锌的动物模型，该提案寻求1。要了解maneb如何产生持久的易感性，2.定义描述易感性症状前状态的生物化学和基因表达谱，以及3.阐明性别在调节这些影响中的作用。除了提供对PD病因学的深入了解和有助于风险评估范例之外，我们还将确定可能适合操作以改变PD风险和/或严重程度的稳定靶点。