Pesticides And Parkinson s Disease In The Agricultural H

帕金森病（PD）是一种进行性运动障碍，影响超过50万美国居民。PD的病因尚不清楚。最近的一项双胞胎研究表明，PD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可能仍然起作用：PD与几个基因的多态性有关，通常涉及多巴胺神经化学或外源性物质的代谢。PD的病因可能有环境因素。流行病学研究表明，PD风险与农村生活，饮用井水，农业，农药和金属有关。特别是，有几项（尽管不是所有）研究表明，农药暴露与PD风险增加有关。PD风险还与金属暴露以及年龄、饮食和生活方式因素（包括吸烟）相关，吸烟具有保护作用。一个有趣的潜在风险因素是土壤病原体星状诺卡氏菌。这种分枝杆菌导致小鼠和猴子的黑质变性和左旋多巴反应性运动障碍。暴露于诺卡氏菌可能会解释与农村生活和农业相关的风险，但PD和诺卡氏菌暴露的人类研究尚未得出结论。流行病学和实验证据表明，PD的病理生理学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-蛋白酶体系统的功能障碍，以及环境神经毒物通过这些途径发挥作用。 我们正在进行一项与农业健康研究（AHS）嵌套的PD病例对照研究。母体AHS是一项队列研究，涉及1993-97年招募的约90，000名持牌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结果。PD巢式病例对照研究的具体目的是检查PD与以下因素的关系：（i）农药暴露;（ii）其他神经毒物，特别是金属;（iii）星状诺卡氏菌;（iv）生活方式因素，包括饮食、吸烟和咖啡因;（v）皮肤黑色素，以检查种族/民族差异;和（vi）涉及异生物质代谢、多巴胺能神经传递或异生物质特异性膜转运的基因多态性。 病例对照研究的现场工作已经完成;我们已经招募了115例病例和381例对照。使用AHS的信息识别可疑病例，并使用家庭神经系统检查和医疗记录验证PD的存在。对照组是从剩余队列中随机抽取的样本，与年龄、性别和州的病例相匹配。使用来自三个补充来源的数据对暴露进行评估。我们利用采访信息农药的使用，其他风险，和生活方式已经收集在AHS。此外，我们收集血液样本来测量有机氯，金属和诺卡氏菌的暴露和DNA库。我们收集房屋和农场设备灰尘样本，以测量某些农药和金属。我们还进行了额外的采访，以获得有关终身使用的特定农药涉及PD的病例报告或动物研究，以及暴露于其他神经毒物的信息。 这项研究是第一次使用前瞻性收集的暴露信息，以评估农药暴露与PD风险相关的假设。它利用了《美国卫生标准》提供的独特机会，将严格的病例调查方法与几种补充的接触评估方法相结合，在按农药使用情况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作为结局。我们使用了来自农业健康研究（AHS）的约84，000名持牌私人农药施用者及其配偶的数据，以评估自我报告的PD与农药暴露的关系。队列成员在入组时提供了关于终生农药使用的详细信息，并在入组时（流行病例，n=83）和5年后（事件病例，n=78）报告了医生诊断的PD;将自我报告的PD病例与其余队列进行比较。流行病例更有可能报告帕金森病症状，包括手震颤;事件病例在报告PD前5年入组时也报告了手震颤增加。PD事件与入组时农药使用累积天数相关[比值比（OR）= 2.3; 95%置信区间（CI）：1.2，最高与最低四分位数为4.5;趋势p为0.009]，个人使用农药的时间超过一半（OR = 1.9; 95% CI：0.7，4.7），某些特定农药（OR> 1.4）。接受与农药有关的医疗护理与风险增加有关，使用个人防护设备减少潜在接触与风险降低有关。这项研究进一步支持了暴露于某些农药会增加PD风险的假设。对特定化学品的发现必须谨慎解释，但可能为进一步调查提供富有成效的线索。这项分析受到自我报告的PD诊断的限制，这一问题将在我们的病例对照研究中解决，该研究将有神经学家证实的病例。

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 complete; we have enrolled 115 cases and 381 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. Incident PD was associated with cumulative days of pesticide use at enrollment [odds ratio (OR) = 2.3; 95% confidence interval (CI): 1.2, 4.5 for highest vs lowest quartile; p for trend 0.009], with personally applying pesticides more than half the time (OR = 1.9; 95% CI: 0.7, 4.7), and with some specific pesticides (ORs > 1.4). Receiving pesticide-related medical care was associated with increased risk, and using personal protective equipment to reduce potential exposure was associated with decreased risk. 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.