Pesticides And Parkinson s Disease In The Agricultural Health Study

农业和运动评估研究（FAME）是一项嵌套在农业健康研究中的PD病例对照研究，这是一项针对89，000名持牌农药施用者及其配偶的队列研究，旨在评估农业相关暴露在慢性疾病中的作用。FAME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）生活方式因素，包括饮食、吸烟和咖啡因;（iv）皮肤黑色素，以检查种族/民族差异;以及（v）涉及多巴胺能神经传递、异源生物质代谢或异源生物质特异性膜转运的基因多态性。 我们招募了115例病例和384例对照。PD诊断由运动障碍专家验证。对照组是从剩余队列中随机抽取的样本，频率与年龄、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了评估：（一）关于农药使用、其他暴露和AHS中已经收集的生活方式的访谈信息;（二）用于测量有机氯和金属以及DNA库的血液样本;以及（三）新的电话访谈，其中获得了与PD有关的特定农药以及其他神经毒物的信息。 农药和PD：线粒体功能障碍和氧化应激是实验模型和遗传形式的PD中涉及的病理生理机制。某些杀虫剂可能会影响这些机制，但没有杀虫剂与人类PD明确相关。使用FAME数据，我们发现PD与使用一组抑制线粒体复合物I的农药有关。（OR 1.7，95% CI，1.02.8），包括鱼藤酮（OR 2.5，95% CI，1.34.7），并使用一组可引起氧化应激的农药（OR 2.0，95% CI，1.23.6），包括百草枯（OR 2.5; 95% CI，1.44.7）。这是第一项显示PD与鱼藤酮相关的研究，鱼藤酮是一种已知的线粒体毒物，用于PD最强大的动物模型之一。该研究还扩展了先前关于PD和百草枯的工作，提供了更详细的数据，例如显示了剂量反应。我们的发现，PD与两组农药定义的机制，以前实验牵连支持这些机制在PD病理生理学的作用。 百草枯、谷胱甘肽转移酶和PD：百草枯是全世界使用最广泛的除草剂之一。它通过氧化还原循环和氧化应激在啮齿动物中产生PD模型，并与人类PD风险相关。谷胱甘肽转移酶提供细胞抗氧化应激保护，并可能调节百草枯毒性。我们研究了与百草枯使用相关的PD风险，在编码谷胱甘肽-S-转移酶M1（GSTM 1）或T1（GSTT 1）的基因纯合缺失的个体中。百草枯与GSTM 1之间没有相互作用。相反，GSTT 1基因型显著改变了百草枯与帕金森病的相关性（p-相互作用=0.027）。在具有功能性GSTT 1的男性中，百草枯的OR为1.5（95% CI 0.63.6），而在具有纯合GSTT 1缺失的男性中，OR为11.1（95% CI 3.044.6）。虽然需要复制，但我们的研究结果表明，百草枯暴露的PD风险可能在缺乏GSTT 1的个体中特别高。GSTT 1缺失很常见，可能会发现大量因氧化应激（如百草枯）而患PD的高风险亚群。 膳食脂肪、农药暴露和PD：膳食脂肪摄入可能直接或通过改变对环境神经毒物（包括农药）的反应来改变PD风险。使用FAME的数据，我们评估了89例病例诊断前10年的饮食和农药使用情况，或336例频率匹配的对照组的相应日期。PD与N-3多不饱和脂肪酸（PUFA）（OR 0.4，95% CI 0.2-0.8，最高与最低三分位数）和N-3前体-亚麻酸（0.4，0.2-0.8）呈负相关。此外，PD与百草枯和鱼藤酮的关联被脂肪摄入量改变。对于多不饱和脂肪酸摄入量低于中位数的个体，百草枯的OR为4.2（1.5-12），而对于摄入量较高的个体，百草枯的OR为1.2（0.4-3.4）（p-相互作用=0.10）。在饱和脂肪摄入量高于中位数的人群中，鱼藤酮的OR为5.8（2.3-15），而在摄入量较低的人群中，OR为1.5（0.5-4.2）（p-相互作用=0.02）。因此，多不饱和脂肪酸摄入量高，这可能会减轻神经炎症，缓和与百草枯相关的PD风险。相反，高饱和脂肪摄入，这可能会增加氧化应激，增加与鱼藤酮相关的PD风险。 α-突触核蛋白、头部损伤和PD：散发性PD与头部损伤和SNCA Rep 1（编码α-突触核蛋白基因启动子区的多态性二核苷酸微卫星）相关。我们评估了SNCA Rep 1改变偶发病例中头部损伤与PD风险之间关联的假设。来自FAME的数据与来自PD的第二个病例对照研究的数据相结合，使用病例对照历史访谈的环境相关性和帕金森病风险研究（Study of Environmental Association and Risk of Parkinsonism using Case-Control Historical Interviews，简称CRIS）。与以前的报道一致，相对于中等长度的Rep 1，短Rep 1基因型与PD风险降低相关，而长Rep 1基因型与风险增加相关。头部损伤与PD总体无显著相关性（OR 1.3，95% CI 0.91.8），在短或中等长度Rep 1的患者中也是如此。然而，在Rep 1较长的患者中，头部损伤与PD密切相关（OR 3.5，95% CI 1.49.2，p-相互作用=0.02）。头部受伤和长Rep 1的个体比没有危险因素的人早诊断4.9年（p=0.03）。虽然单独的头部损伤与PD风险无关，但我们的数据表明，当α-突触核蛋白水平较高时，头部损伤可能会引发和/或加速神经退行性变，如Rep 1扩增的患者。

The Farming and Movement Evaluation Study (FAME) is a case-control study of PD nested in the Agricultural Health Study, a cohort study of 89,000 licensed pesticide applicators and spouses designed to evaluate the role of farming-related exposures in chronic disease. The specific aims of FAME were to examine the relationship of PD to (i) pesticide exposure; (ii) other neurotoxicants, particularly metals; (iii) lifestyle factors including diet, smoking, and caffeine; (iv) skin melanin, to examine racial/ethnic differences; and (v) polymorphisms in genes involved in dopaminergic neurotransmission, xenobiotic metabolism, or xenobiotic-specific membrane transport. We enrolled 115 cases and 384 controls. PD diagnosis was verified by movement disorder specialists. Controls were a random sample from the remaining cohort, frequency matched to cases by age, sex, and state. Exposure was evaluated using data from three complementary sources: (i) interview information on pesticide use, other exposures, and lifestyle already collected in the AHS; (ii) blood samples to measure organochlorines and metals and for DNA banking; and (iii) new telephone interviews which obtained information on specific pesticides implicated in PD as well as other neurotoxicants. Pesticides and PD: Mitochondrial dysfunction and oxidative stress are pathophysiologic mechanisms implicated in experimental models and genetic forms of PD. Certain pesticides may affect these mechanisms, but no pesticide has been definitively associated with PD in humans. Using FAME data, we found that PD was associated with use of a group of pesticides that inhibit mitochondrial complex I (OR 1.7, 95% CI, 1.02.8), including rotenone (OR 2.5, 95% CI, 1.34.7), and with use of a group of pesticides that cause oxidative stress (OR 2.0, 95% CI, 1.23.6), including paraquat (OR 2.5; 95% CI, 1.44.7). This is the first study to show an association of PD with rotenone, a known mitochondrial toxicant used in one of the most robust animal models of PD. The study also extends previous work on PD and paraquat with more detailed data, showing for example a dose-response. Our finding that PD was positively associated with two groups of pesticides defined by mechanisms previously implicated experimentally supports a role for these mechanisms in PD pathophysiology. Paraquat, glutathione transferases, and PD: Paraquat is one of the most widely used herbicides worldwide. It produces a PD model in rodents through redox cycling and oxidative stress and is associated with PD risk in humans. Glutathione transferases provide cellular protection against oxidative stress and could potentially modulate paraquat toxicity. We investigated PD risk associated with paraquat use in individuals with homozygous deletions of the genes encoding glutathione-S-transferase M1 (GSTM1) or T1 (GSTT1). There was no interaction of paraquat with GSTM1. In contrast, GSTT1 genotype significantly modified the association of paraquat with PD (p-interaction=0.027). In men with functional GSTT1, the OR for paraquat was 1.5 (95% CI 0.63.6), while in men with homozygous GSTT1 deletion, the OR was 11.1 (95% CI 3.044.6). Although replication is needed, our results suggest that PD risk from paraquat exposure might be particularly high in individuals lacking GSTT1. The GSTT1 deletion is common and could potentially identify a large subpopulation at high risk of PD from oxidative stressors such as paraquat. Dietary fat, pesticide exposure, and PD: Dietary fat intake may modify PD risk directly or by altering the response to environmental neurotoxicants including pesticides. Using data from FAME, we evaluated diet and pesticide use 10 years before diagnosis in 89 cases or a corresponding date in 336 frequency-matched controls. PD was inversely associated with N-3 polyunsaturated fatty acids (PUFAs) (OR 0.4, 95% CI 0.2-0.8 for highest vs lowest tertile) and the N-3 precursor -linolenic acid (0.4, 0.2-0.8). Moreover, associations of PD with paraquat and rotenone were modified by fat intake. The OR for paraquat was 4.2 (1.5-12) in individuals with PUFA intake below the median but 1.2 (0.4-3.4) in those with higher intake (p-interaction=0.10). The OR for rotenone was 5.8 (2.3-15) in those with saturated fat intake above the median but 1.5 (0.5-4.2) in those with lower intake (p-interaction=0.02). Thus, high PUFA intake, which may mitigate neuroinflammation, moderated the PD risk associated with paraquat. In contrast, high saturated fat intake, which may increase oxidative stress, increased PD risk associated with rotenone. alpha-synuclein, head injury, and PD: Sporadic PD is associated with both head injury and SNCA Rep1, a polymorphic dinucleotide microsatellite in the promoter region of the gene encoding alpha-synuclein. We evaluated the hypothesis that SNCA Rep1 modifies the association between head injury and PD risk in sporadic cases. Data from FAME were combined with data from a second case-control study of PD, the Study of Environmental Association and Risk of Parkinsonism using Case-Control Historical Interviews (SEARCH). Consistent with prior reports, short Rep1 genotype was associated with reduced PD risk and long Rep1 with increased risk, relative to medium-length Rep1. Head injury was not significantly associated with PD overall (OR 1.3, 95% CI 0.91.8), nor among those with short or medium-length Rep1. However, head injury was strongly associated with PD in those with long Rep1 (OR 3.5, 95% CI 1.49.2, p-interaction=0.02). Individuals with both head injury and long Rep1 were diagnosed 4.9 years earlier than those with neither risk factor (p=0.03). While head injury alone was not associated with PD risk, our data suggest head injury may initiate and/or accelerate neurodegeneration when levels of alpha-synuclein are high, as in those with Rep1 expansion.