Cao Fangjie, Souders Ii Christopher L, Perez-Rodriguez Veronica, Martyniuk Christopher J
Department of Physiological Sciences, Center for Environmental and Human Toxicology, University of Florida Genetics Institute, College of Veterinary Medicine, University of Florida Interdisciplinary Program in Biomedical Sciences Neuroscience, University of Florida, Gainesville, FL, United States.
Front Genet. 2019 Jan 25;9:701. doi: 10.3389/fgene.2018.00701. eCollection 2018.
While a number of genetic mutations are associated with Parkinson's disease (PD), it is also widely acknowledged that the environment plays a significant role in the etiology of neurodegenerative diseases. Epidemiological evidence suggests that occupational exposure to pesticides (e.g., dieldrin, paraquat, rotenone, maneb, and ziram) is associated with a higher risk of developing PD in susceptible populations. Within dopaminergic neurons, environmental chemicals can have an array of adverse effects resulting in cell death, such as aberrant redox cycling and oxidative damage, mitochondrial dysfunction, unfolded protein response, ubiquitin-proteome system dysfunction, neuroinflammation, and metabolic disruption. More recently, our understanding of how pesticides affect cells of the central nervous system has been strengthened by computational biology. New insight has been gained about transcriptional and proteomic networks, and the metabolic pathways perturbed by pesticides. These networks and cell signaling pathways constitute potential therapeutic targets for intervention to slow or mitigate neurodegenerative diseases. Here we review the epidemiological evidence that supports a role for specific pesticides in the etiology of PD and identify molecular profiles amongst these pesticides that may contribute to the disease. Using the Comparative Toxicogenomics Database, these transcripts were compared to those regulated by the PD-associated neurotoxicant MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). While many transcripts are already established as those related to PD (alpha-synuclein, caspases, leucine rich repeat kinase 2, and parkin2), lesser studied targets have emerged as "pesticide/PD-associated transcripts" [e.g., phosphatidylinositol glycan anchor biosynthesis class C (Pigc), allograft inflammatory factor 1 (Aif1), TIMP metallopeptidase inhibitor 3, and DNA damage inducible transcript 4]. We also compared pesticide-regulated genes to a recent meta-analysis of genome-wide association studies in PD which revealed new genetic mutant alleles; the pesticides under review regulated the expression of many of these genes (e.g., ELOVL fatty acid elongase 7, ATPase H+ transporting V0 subunit a1, and bridging integrator 3). The significance is that these proteins may contribute to pesticide-related increases in PD risk. This review collates information on transcriptome responses to PD-associated pesticides to develop a mechanistic framework for quantifying PD risk with exposures.
虽然许多基因突变与帕金森病（PD）相关，但环境在神经退行性疾病病因中起重要作用这一点也得到广泛认可。流行病学证据表明，职业性接触农药（如狄氏剂、百草枯、鱼藤酮、代森锰和福美锌）会使易感人群患帕金森病的风险升高。在多巴胺能神经元内，环境化学物质会产生一系列导致细胞死亡的不利影响，如异常的氧化还原循环和氧化损伤、线粒体功能障碍、未折叠蛋白反应、泛素 - 蛋白质组系统功能障碍、神经炎症和代谢紊乱。最近，计算生物学加深了我们对农药如何影响中枢神经系统细胞的理解。人们对转录组和蛋白质组网络以及受农药干扰的代谢途径有了新的认识。这些网络和细胞信号通路构成了干预以减缓或减轻神经退行性疾病的潜在治疗靶点。在此，我们综述支持特定农药在帕金森病病因中起作用的流行病学证据，并确定这些农药中可能导致该疾病的分子特征。利用比较毒理基因组学数据库，将这些转录本与帕金森病相关神经毒素1 - 甲基 - 4 - 苯基 - 1,2,3,6 - 四氢吡啶（MPTP）调控的转录本进行比较。虽然许多转录本已被确定与帕金森病相关（α - 突触核蛋白、半胱天冬酶、富含亮氨酸重复激酶2和帕金2），但研究较少的靶点已作为“农药/帕金森病相关转录本”出现[例如，磷脂酰肌醇聚糖锚定生物合成C类（Pigc）、同种异体移植炎症因子1（Aif1）、金属蛋白酶组织抑制因子3和DNA损伤诱导转录本4]。我们还将受农药调控的基因与最近一项帕金森病全基因组关联研究的荟萃分析进行比较，该分析揭示了新的基因突变等位基因；所审查的农药调控了其中许多基因的表达（例如，超长链脂肪酸延伸酶7、H⁺转运ATP酶V0亚基a1和衔接整合子3）。其意义在于这些蛋白质可能导致与农药相关的帕金森病风险增加。本综述整理了关于转录组对帕金森病相关农药反应的信息，以建立一个通过接触来量化帕金森病风险的机制框架。
