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

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，临床表现为运动功能障碍，病理表现为黑质纹状体DA （NSD）系统中产生多巴胺（DA）的神经元消耗。通过流行病学、临床和动物研究，PD的环境危险因素得到了一致的报道。虽然帕金森病通常出现在生命的后期，但神经发育时期的环境作为一个易感性因素正在引起人们的关注。例如，在小鼠中，产前暴露于杀菌剂maneb （MB）大大增加了成年期对农药百草枯（PQ）的易感，导致PD的特征。与NIEHS的使命一致，目前的建议旨在揭示MB改变神经发育的机制，从而使PD中出现的进行性神经退行性变易损性。为了了解多重环境影响的作用，将采用队列设计，其中小鼠在产前暴露于MB，并在整个生命周期中间歇性暴露于PQ。将在多个时间点评估多巴胺能完整性，以作为进行性神经退行性变的证据，并将进行MB和PQ的毒性动力学和毒性动力学研究。据推测，产前MB暴露诱导了一种改变电位（SAP）状态，这种SAP描述了一种临床前的能功能障碍阶段。该SAP将通过基因表达谱和几个生化系统（包括DA稳态、氧化应激反应、营养因子和屏障）的分析来表征；风险因素（如衰老、PQ）可能通过这些系统起作用，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PD中起主要作用，因此假设性腺类固醇激素调节风险；这将通过描述发情周期对正常小鼠NSD系统、PQ毒性动力学和毒性动力学的作用，以及在发育的不同阶段操纵性腺类固醇暴露来评估。

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.