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: 7679127
• 负责人: Brian Barlow
• 金额: $ 4.35万
• 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 2011-03-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7679127
• 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; Environment; Environmental Risk Factor; Epidemiology; Estrogens; Estrous Cycle; Etiology; Experimental Models; Exposure to; Functional disorder; Future; Gender; Gender Role; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Gonadal Steroid Hormones; Health; Homeostasis; Hormones; Human; Individual; Industrial fungicide; Life; Link; Longevity; Maneb; Measures; Mediating; Mission; Modeling; Motor; Mus; National Institute of Environmental Health Sciences; Neurodegenerative Disorders; Neurons; Oxidative Stress; Paraquat; Parkinson Disease; Pesticides; Phase; Play; Population; Population Genetics; Predisposition; Pregnancy; 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; emerging adult; fetal; insight; neurodevelopment; neurotoxic; nigrostriatal system; oxidation; pesticide exposure; pre-clinical; prenatal; prenatal exposure; progressive neurodegeneration; public health relevance; 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(申请人提供)：帕金森病(PD)是一种进行性神经退行性疾病，临床特征是运动功能障碍，病理特征是黑质纹状体(NSD)系统中产生多巴胺(DA)的神经元枯竭。通过流行病学、临床和动物研究，帕金森病的环境风险因素一直被报道。虽然帕金森病通常出现在生命的后期，但处于神经发育时期的环境正作为一个易感因素受到关注。例如，在小鼠中，出生前接触杀菌剂maneb(MB)极大地增加了成年后对杀虫剂百草枯(PQ)的易感性，导致了帕金森病的特征。与NIEHS的使命一致，目前的提案试图解开MB改变神经发育的机制，从而使帕金森病的进行性神经退化变得脆弱。为了了解多个环境因素的作用，将采用队列设计，在出生前暴露于甲基溴的小鼠将在整个生命周期内被跟踪，并间歇性地暴露于PQ。将在多个时间点评估多巴胺能完整性，以寻找进行性神经变性的证据，并将进行MB和PQ的毒代动力学和毒理动力学研究。据推测，产前接触MB会导致一种电位改变状态(SAP)，这种SAP描述了DAR能功能障碍的临床前阶段。这种SAP将通过基因表达谱和几个生化系统(包括DA动态平衡、氧化应激反应、营养因子和屏障)的分析来表征；风险因素(如衰老、PQ)可能通过这些系统发挥作用，这些终点也将在这些风险因素的背景下进行研究。最后，由于性别在帕金森病中起主要作用，假设性腺类固醇激素调节风险；这将通过表征发情周期在正常小鼠NSD系统中的作用，对PQ毒代动力学和毒理动力学的作用，以及通过控制不同发育阶段的性腺类固醇暴露来评估。 公共卫生相关性：帕金森氏病(PD)是一个主要的健康问题，尽管症状通常发生在生命的晚期，但早在产前的环境因素可能会对这种疾病的发展产生长期的影响。利用产前接触杀菌剂maneb的动物模型，该建议试图1.了解maneb如何造成长期的易感性，2.定义描述脆弱的症状前状态的生化和基因表达谱，3.澄清性别在调节这些影响中的作用。除了提供对帕金森病病因的洞察和对风险评估范式的贡献外，我们还将确定稳定的目标，这些目标可能适合于操纵以改变帕金森病的风险和/或严重性。