有机磷农药暴露与全基因组 DNA 甲基化差异。
Organophosphate pesticide exposure and differential genome-wide DNA methylation.
机构信息
Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA, USA.
Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA, USA.
出版信息
Sci Total Environ. 2018 Dec 15;645:1135-1143. doi: 10.1016/j.scitotenv.2018.07.143. Epub 2018 Jul 21.
BACKGROUND
Organophosphates (OP) are widely used insecticides that acutely inhibit acetylcholinesterase enzyme activity. There is great interest in improving the understanding of molecular mechanisms related to chronic OP exposure induced toxicity. We aim to elucidate epigenetic changes associated with OP exposure, using untargeted analysis of genome-wide DNA methylation data.
METHODS
In a population-based case control study of Parkinson's disease (PD), we assessed ambient OP exposure via residential and workplace proximity to commercial applications. We investigated associations between OP exposure and genome-wide DNA methylation (Illumina 450 k) in 580 blood samples (342 PD patients, 238 controls) and 259 saliva samples (128 patients, 131 controls). To identify differential methylation related to OP exposure, we controlled for age, sex, European ancestry, and PD status; in addition, we stratified by disease status.
RESULTS
We identified 70 genome-wide significant CpGs, including cg01600516 in ALOX12 (cor = 0.27, p = 1.73E-11) and two CpGs in HLA genes, cg01655658 (cor = -0.24, p = 2.80E-09) in HLA-L (pseudogene) and cg15680603 (cor = 0.20, p = 7.94E-07) in HLA-DPA1. Among the 70 CpGs located in 41 genes, 14 were also differentially methylated in saliva samples. The most overrepresented pathway was the nicotinic acetylcholine receptor signaling pathway (fold enrichment = 15.63, p = 1.01E-03, FDR = 1.64E-01). Expanding to a larger number of genes (CpG p < 5E-04, FDR < 2.25E-01; 1077 CpGs, 662 genes), the most enriched pathway shifted to the muscarinic acetylcholine receptor 1 and 3 signaling pathway (p-value = 5.36E-04, FDR = 4.73E-02). When we stratified by PD status, results were similar. Of the 70 significant CpGs, 63 were detected among both patients and controls and 7 were only associated with OP exposure among patients.
CONCLUSIONS
This study finds chronic low-level OP exposure is associated with differential DNA methylation in blood and saliva, both in elderly population controls and PD patients. Our study results suggest that long-term sub-acute OP exposure influences methylation in genes enriched for muscarinic and nicotinic acetylcholine receptor pathways.
背景
有机磷化合物（OP）是广泛使用的杀虫剂，可急性抑制乙酰胆碱酯酶的活性。人们对了解与慢性 OP 暴露诱导的毒性相关的分子机制非常感兴趣。我们旨在通过全基因组 DNA 甲基化的非靶向分析来阐明与 OP 暴露相关的表观遗传变化。
方法
在一项基于人群的帕金森病（PD）病例对照研究中，我们通过居住和工作场所与商业应用的接近程度来评估环境 OP 暴露。我们研究了 580 份血液样本（342 名 PD 患者，238 名对照）和 259 份唾液样本（128 名患者，131 名对照）中 OP 暴露与全基因组 DNA 甲基化（Illumina 450k）之间的关联。为了确定与 OP 暴露相关的差异甲基化，我们控制了年龄、性别、欧洲血统和 PD 状态；此外，我们还根据疾病状态进行了分层。
结果
我们确定了 70 个具有全基因组意义的 CpG，包括 ALOX12 中的 cg01600516（cor = 0.27，p = 1.73E-11）和 HLA 基因中的两个 CpG，cg01655658（cor = -0.24，p = 2.80E-09）在 HLA-L（假基因）和 cg15680603（cor = 0.20，p = 7.94E-07）在 HLA-DPA1。在位于 41 个基因中的 70 个 CpG 中，有 14 个在唾液样本中也存在差异甲基化。最具代表性的途径是烟碱型乙酰胆碱受体信号通路（折叠富集= 15.63，p = 1.01E-03，FDR = 1.64E-01）。扩展到更多数量的基因（CpG p < 5E-04，FDR < 2.25E-01；1077 个 CpGs，662 个基因），最富集的途径转移到毒蕈碱乙酰胆碱受体 1 和 3 信号通路（p 值= 5.36E-04，FDR = 4.73E-02）。当我们按 PD 状态进行分层时，结果相似。在 70 个显著的 CpG 中，有 63 个在患者和对照者中均有检测到，有 7 个仅在患者中与 OP 暴露相关。
结论
这项研究发现，慢性低水平 OP 暴露与血液和唾液中的 DNA 甲基化差异有关，包括老年人群对照者和 PD 患者。我们的研究结果表明，长期亚急性 OP 暴露会影响富含毒蕈碱和烟碱型乙酰胆碱受体的基因的甲基化。
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