Pesticides And Parkinson's Disease

摘要 帕金森氏病(PD)是一种进行性运动障碍，影响着50多万美国居民。帕金森病的病因尚不清楚。最近的一项双胞胎研究表明，没有高渗透性基因参与其中。对环境暴露的遗传易感性仍可能发挥作用：帕金森病与几个基因的多态有关，通常涉及多巴胺神经化学或外源物质的解毒。帕金森病的病因可能与环境因素有关。流行病学研究表明，帕金森病的风险与农村生活、井水饮用、农业、杀虫剂和金属有关。特别是，一些尽管不是所有的研究都表明，接触杀虫剂与帕金森病风险增加有关。帕金森病的风险也与接触金属以及年龄、饮食和生活方式因素有关，包括吸烟，这是有保护作用的。一个有趣的潜在危险因素是土壤病原体星状诺卡氏菌。这种分枝杆菌会导致小鼠和猴子的黑质退化和L-多巴反应性运动障碍。接触诺卡氏菌可能为与农村生活和农业相关的风险提供了一种解释，但对帕金森病和诺卡氏菌暴露的人类研究一直没有定论。流行病学和实验证据表明，帕金森病的病理生理机制可能涉及多个相互作用的机制，包括线粒体功能障碍、氧化应激和蛋白质聚集，环境神经毒物通过这些途径发挥作用。 我们正在与帕金森研究所的卡罗琳·坦纳博士合作，进行一项嵌套在农业健康研究(AHS)中的帕金森病病例对照研究。(有关队列研究的说明，请参阅AHS年度报告。)具体目的是研究PD(I)与农药暴露的关系；(Ii)与其他神经毒物，特别是金属的关系；(Iii)与星状诺卡氏菌的关系；(Iv)与包括饮食、吸烟和咖啡因在内的生活方式因素的关系；(V)与皮肤黑色素的关系，以检查种族/民族差异；以及(Vi)与异物代谢、多巴胺能神经传递或异物特异性膜运输有关的基因的多态性。这项研究首次使用前瞻性收集的暴露信息来评估农药暴露与帕金森病风险相关的假设。它利用AHS提供的独特机会，将严格的病例发现方法与几种相辅相成的暴露评估方法结合起来，在由农药使用界定的职业群体中解决这一问题。 进度： 病例对照研究的实地工作正在进行中。目前我们已经登记了46例病例和181名对照；最终我们将登记大约160例PD病例和大约480名对照。使用来自AHS的信息来识别可疑病例，并使用家庭神经学检查和医疗记录来验证PD的存在。对照是从其余队列中随机抽取的样本，按年龄、性别和州与病例匹配。使用来自三个互补来源的数据来评估接触情况。我们利用AHS已经收集的关于杀虫剂使用、其他暴露和生活方式的访谈信息。此外，我们还收集血液样本来测量有机氯、金属和诺卡氏菌的暴露情况，并用于DNA银行。我们收集房屋和农场设备的灰尘样本来测量某些杀虫剂和金属。我们还进行额外的访谈，通过病例报告或动物研究，以及接触其他神经毒物，获得与帕金森病有关的特定杀虫剂的终生使用信息。

Summary Parkinson's disease (PD) is a progressive movement disorder affecting over 500,000 US residents. The etiology of PD is still unclear. A recent twin study suggested that no highly penetrant gene was involved. Genetic susceptibility to environmental exposures may still play a role: PD has been linked to polymorphisms in several genes, typically involving dopamine neurochemistry or detoxification of xenobiotics. The etiology of PD likely has an environmental component. Epidemiologic studies have demonstrated that PD risk is associated with rural living, well water drinking, farming, pesticides, and metals. In particular, several although not all studies have shown that pesticide exposure is associated with increased PD risk. PD risk has also been associated with exposure to metals and with age, diet, and lifestyle factors including cigarette smoking, which is protective. An interesting potential risk factor is the soil pathogen Nocardia asteroides. This mycobacterium causes nigral degeneration and an L-dopa responsive movement disorder in mice and monkeys. Exposure to Nocardia might present an explanation for the risk associated with rural living and farming, but human studies of PD and Nocardia exposure have been inconclusive. Epidemiologic and experimental evidence indicates that the pathophysiology of PD likely involves several interacting mechanisms, including mitochondrial dysfunction, oxidative stress, and protein aggregation, and that environmental neurotoxicants work through these pathways. We are conducting a case-control study of PD nested in the Agricultural Health Study (AHS) in collaboration with Dr Caroline Tanner of the Parkinson's Institute. (Please see the AHS annual report for a description on the cohort study.) Specific aims are to examine the relationship of PD (i) to pesticide exposure; (ii) to other neurotoxicants, particularly metals; (iii) to Nocardia asteroides; (iv) to lifestyle factors including diet, smoking, and caffeine; (v) to skin melanin, to examine racial/ethnic differences; and (vi) to polymorphisms in genes involved in xenobiotic metabolism, dopaminergic neurotransmission, or xenobiotic-specific membrane transport. This study is the first to use prospectively collected exposure information to evaluate the hypothesis that pesticide exposure is related to PD risk. It exploits the unique opportunity provided by the AHS to address this issue in an occupational group defined by pesticide use, combining rigorous methods of case-finding with several complementary methods of exposure assessment. Progress: Field work for the case-control study is in progress. Presently we have enrolled 46 cases and 181 controls; ultimately we will enroll ~160 PD cases and ~480 controls. Suspect cases are identified using information from the AHS, and the presence of PD is verified using an in-home neurologic exam and medical records. Controls are a random sample from the remaining cohort, matched to cases by age, sex, and state. Exposure is evaluated using data from three complementary sources. We utilize interview information on pesticide use, other exposures, and lifestyle already collected in the AHS. In addition, we collect blood samples to measure organochlorines, metals, and Nocardia exposure and for DNA banking. We collect samples of house and farm equipment dust to measure certain pesticides and metals. We also conduct additional interviews to obtain information on lifetime use of specific pesticides implicated in PD by case reports or animal research as well as exposure to other neurotoxicants.