Pesticides And Parkinson s Disease In The Agricultural H

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，帕金森病不是一种单基因疾病。涉及多个基因的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代谢。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可能涉及几个相互作用的机制，包括线粒体功能障碍、氧化应激、蛋白质聚集和泛素-蛋白酶体系统功能障碍，环境神经毒物通过这些途径发挥作用。 我们正在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。父母AHS是一项队列研究，在1993-97年间招募了约90,000名有执照的农药施用者及其配偶，旨在研究与农业相关暴露有关的癌症和其他健康后果。帕金森病嵌套病例对照研究的具体目的是研究帕金森病与下列因素的关系：(I)与农药接触；(Ii)与其他神经毒物，尤其是金属；(Iii)与星状诺卡氏菌；(Iv)与饮食、吸烟和咖啡因等生活方式因素；(V)与皮肤黑色素，以检查种族/民族差异；以及(Vi)与异种代谢、多巴胺能神经传递或异种生物特异性膜运输有关的基因的多态性。 病例对照研究的现场工作已接近完成；我们已纳入114例病例和379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。 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。 作为试点数据分析，我们评估了在AHS中收集的横断面和前瞻性数据，使用自我报告的PD作为结果。我们使用了来自农业健康研究(AHS)中登记的约84,000名有执照的私人农药施用者及其配偶的数据，以评估自我报告的帕金森病与农药暴露的关系。队列成员提供了登记时终生使用杀虫剂的详细信息，并在登记时(流行病例，n=83)和五年后(事件病例，n=78)报告了医生诊断的帕金森病；将自我报告的帕金森病病例与其余队列进行比较。流行病例更有可能报告包括手震在内的帕金森症状；事件病例也报告在登记时手震增加，在报告PD之前五年。在事件病例中，累计使用杀虫剂的天数与施用者及其配偶的帕金森病风险有关(OR2.3，95%CI1.2-4.5，与最低的使用四分位数相比；p为趋势0.009)。接受与农药相关的医疗护理与增加风险相关，使用个人防护装备减少潜在暴露与降低风险相关。风险与氯乙酰苯胺、苯氧乙酸酯和硫代氨基甲酸酯除草剂以及几种有机磷杀虫剂和一些杀菌剂有关(ORS&GT；1.5)。在流行病例中，帕金森病与农药暴露呈明显的负相关(OR 0.5，95%CI 0.2-1.1)，可能是因为对农药使用的偏见报告或暴露于帕金森病患者的个人未能登记在最初的AHS队列中。这项研究进一步支持了暴露于某些杀虫剂会增加帕金森病风险的假设。对特定化学品的调查结果必须谨慎解释，但可能会为进一步调查提供富有成效的线索。这一分析受到使用帕金森病自我报告诊断的限制，这一问题将在我们的病例对照研究中解决，该研究将有神经科医生确认的病例。

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 PD was not a mongenic disorder. Genetic susceptibility to environmental exposures involving multiple genes may still play a role: PD has been linked to polymorphisms in several genes, typically involving dopamine neurochemistry or metabolism 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, protein aggregation, and dysfunction of the ubiquitin-proteasome system, and that environmental neurotoxicants work through these pathways. We are conducting a case-control study of PD nested in the Agricultural Health Study (AHS). The parent AHS is a cohort study of ~90,000 licensed pesticide applicators and their spouses, recruited in 1993-97, designed to study cancer and other health outcomes in relation to farming associated exposures. The specific aims of the nested case-control study of PD 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. Field work for the case-control study is nearly finished; we have enrolled 114 cases and 379 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. 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. As a pilot data analysis, we have evaluated cross-sectional and prospective data collected in the AHS, using self-reported PD as an outcome. We used data from ~84,000 licensed private pesticide applicators and their spouses enrolled in the Agricultural Health Study (AHS) to evaluate the relationship of self-reported PD to pesticide exposure. Cohort members provided detailed information on lifetime pesticide use at enrollment and reported physician-diagnosed PD both at enrollment (prevalent cases, n=83) and five years later (incident cases, n=78); self-reported PD cases were compared to the remaining cohort. Prevalent cases were more likely to report parkinsonian symptoms including hand tremor; incident cases also reported increased hand tremor at enrollment, five years before reporting PD. Among incident cases, cumulative days of pesticide use was associated with PD risk for both applicators and their spouses (OR 2.3, 95% CI 1.2-4.5 for the highest quartile of use, compared to the lowest; p for trend 0.009). Receiving pesticide-related medical care was associated with increased risk, and using personal protective equipment to reduce potential exposure was associated with decreased risk. Risk was associated with chloroacetanilide, phenoxyacetate, and thiocarbamate herbicides as well as several organophosphate insecticides and some fungicides (ORs > 1.5). There was an apparent inverse association of PD with pesticide exposure among prevalent cases (OR 0.5, 95% CI 0.2-1.1), possibly because of biased reporting of pesticide use or failure of exposed individuals with PD to enroll in the original AHS cohort. This study provides further support for the hypothesis that exposure to certain pesticides increases PD risk. Findings for specific chemicals must be interpreted cautiously but may provide fruitful leads for further investigation. This analysis is limited by its use of self-reported diagnoses of PD, a problem that will be addressed in our case-control study, which will have neurologist-confirmed cases.