Department of Neurology, Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, Pennsylvania 15260.
Department of Epidemiology, Fielding School of Public Health, UCLA, Los Angeles, California 90095.
Toxicol Sci. 2017 Jul 1;158(1):188-198. doi: 10.1093/toxsci/kfx086.
Exposure to certain pesticides induces oxidative stress and increases Parkinson's disease (PD) risk. Mitochondrial DNA (mtDNA) damage is found in dopaminergic neurons in idiopathic PD and following pesticide exposure in experimental models thereof. Base excision repair (BER) is the major pathway responsible for repairing oxidative DNA damage in cells. Whether single nucleotide polymorphisms (SNPs) in BER genes alone or in combination with pesticide exposure influence PD risk is unknown. We investigated the contributions of functional SNPs in 2 BER genes (APEX1 and OGG1) and mitochondrial dysfunction- or oxidative stress-related pesticide exposure, including paraquat, to PD risk. We also studied the effect of paraquat on levels of mtDNA damage and mitochondrial bioenergetics. 619 PD patients and 854 population-based controls were analyzed for the 2 SNPs, APEX1 rs1130409 and OGG1 rs1052133. Ambient pesticide exposures were assessed with a geographic information system. Individually, or in combination, the BER SNPs did not influence PD risk. Mitochondrial-inhibiting (OR = 1.79, 95% CI [1.32, 2.42]), oxidative stress-inducing pesticides (OR = 1.61, 95% CI [1.22, 2.11]), and paraquat (OR = 1.54, 95% CI [1.23, 1.93]) were associated with PD. Statistical interactions were detected, including for a genetic risk score based on rs1130409 and rs1052133 and oxidative stress inducing pesticides, where highly exposed carriers of both risk genotypes were at the highest risk of PD (OR = 2.21, 95% CI [1.25, 3.86]); similar interactions were estimated for mitochondrial-inhibiting pesticides and paraquat alone. Additionally, paraquat exposure was found to impair mitochondrial respiration and increase mtDNA damage in in vivo and in vitro systems. Our findings provide insight into possible mechanisms involved in increased PD risk due to pesticide exposure in the context of BER genotype variants.
接触某些杀虫剂会导致氧化应激，增加帕金森病 (PD) 的风险。在特发性 PD 患者的多巴胺能神经元中以及在实验模型中接触杀虫剂后，都会发现线粒体 DNA (mtDNA) 损伤。碱基切除修复 (BER) 是负责修复细胞中氧化 DNA 损伤的主要途径。BER 基因中的单个核苷酸多态性 (SNP) 是否单独或与杀虫剂暴露一起影响 PD 风险尚不清楚。我们研究了 2 个 BER 基因 (APEX1 和 OGG1) 中的功能 SNP 以及与线粒体功能障碍或氧化应激相关的杀虫剂暴露（包括百草枯）对 PD 风险的贡献。我们还研究了百草枯对 mtDNA 损伤和线粒体生物能的影响。对 619 名 PD 患者和 854 名基于人群的对照者进行了 APEX1 rs1130409 和 OGG1 rs1052133 这 2 个 SNP 的分析。使用地理信息系统评估环境杀虫剂暴露。BER SNP 单独或组合使用均不影响 PD 风险。线粒体抑制剂 (OR = 1.79, 95% CI [1.32, 2.42])、诱导氧化应激的杀虫剂 (OR = 1.61, 95% CI [1.22, 2.11]) 和百草枯 (OR = 1.54, 95% CI [1.23, 1.93]) 与 PD 相关。还检测到了统计学上的相互作用，包括基于 rs1130409 和 rs1052133 的遗传风险评分和诱导氧化应激的杀虫剂，其中两种风险基因型的高暴露携带者患 PD 的风险最高 (OR = 2.21, 95% CI [1.25, 3.86])；单独使用线粒体抑制剂和百草枯也估计了类似的相互作用。此外，百草枯暴露被发现会损害体内和体外系统中的线粒体呼吸并增加 mtDNA 损伤。我们的研究结果为 BER 基因型变异情况下由于杀虫剂暴露而导致 PD 风险增加的可能机制提供了深入了解。
