DNA methylation alterations in response to pesticides exposure

农药暴露导致的 DNA 甲基化改变

• 批准号: 7833470
• 负责人: Lifang Hou
• 金额: $ 50万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-27 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7833470
• 关键词: Address; Affect; Aftercare; Agriculture; Area; Blood; Blood Cells; Blood specimen; Cancer Etiology; Carbon; Carcinogenicity Tests; Cell Line; Cells; Chemicals; Cohort Studies; Complement; Cross-Sectional Studies; DNA; DNA Methylation; Data; Dependence; Detection; Diet Modification; Dose; Environment; Environmental Exposure; Epidemiologic Studies; Epigenetic Process; Evaluation; Event; Exposure to; Folate; Funding; Gene Mutation; General Population; Genes; Genetic Polymorphism; Genomics; Health; Human; In Vitro; Incidence; Insecticides; Investigation; Iowa; Knowledge; Link; Malignant Neoplasms; Metabolism; Methionine; Methylation; Methyltransferase; North Carolina; Nutrient; Occupational Exposure; Organophosphates; Participant; Pattern; Pesticides; Plasma; Population; Population Study; Process; Prospective Studies; Public Health; Resources; Risk; Safety; Sampling; Screening procedure; Seminal; System; Testing; Tissues; Toxic Environmental Substances; Tumor Suppressor Genes; United States Environmental Protection Agency; Validation; Vitamin B 12; base; cancer risk; carcinogenicity; cohort; farmer; genome wide association study; genome-wide; human data; human subject; human tissue; innovation; insight; nervous system disorder; novel; pesticide exposure; promoter; public health relevance; response

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (08) Genomics and specific Challenge Topic, 08-ES-104: Identification of alterations in epigenetic marks related to environmental exposures. In the US, exposure to pesticides is ubiquitous, and over one million people are subjected to high occupational exposure. Pesticides and their residues are pervasive in our environment and our dependence upon pesticides is increasing. Although all pesticides sold in the US have passed Environmental Protection Agency (EPA) tests for carcinogenicity, exposure to pesticides have repeatedly been associated with increased human cancer incidence in epidemiologic studies. Our recent analysis of the Agricultural Health Study (AHS) cohort, the largest prospective study in the world of pesticide applicators from Iowa and North Carolina, also indicates that pesticide exposure increases risk for several cancers. The concern is that EPA's evaluation of chemical carcinogenicity is primarily based on the detection of mutagenic events. Altered DNA methylation, an emerging hallmark of cancer, is not considered in the EPA testing system. Emerging evidence suggests that promoter DNA methylation is affected by environmental exposures. Prior studies have shown that epigenetic information, including DNA methylation, contained in blood cell DNA represents a valuable predictive marker of cancer risk. Blood is a conduit between the external environment and human tissues, and as such constitutes a seminal target tissue to evaluate the effects of environmental toxicants on human health. Our preliminary data recently linked exposure to organophosphate pesticides (OPs), the most commonly used insecticides in the US, to increased promoter methylation of several tumor suppressor genes in blood DNA. We further confirmed this finding in vitro, using human blood cells treated with OPs. Taken together, we hypothesize that exposure to pesticides can induce promoter DNA methylation changes in blood cell DNA, and that this will provide currently unknown mechanistic insights into the association between pesticide exposure and cancer risk. We propose to study whether OP exposure alters gene promoter DNA methylation patterns in human subjects, and in OP-treated cell lines. We will first conduct a genome-wide screening in a subset of the population with the highest and lowest OP exposure, and in cell lines. Findings will then be validated using a gene-specific approach in an independent replication population, and after treatment of cells with varying doses of OP. We will also examine whether methyl donor-related nutrients and related genetic polymorphisms, two major factors in DNA methylation process, modify the associations between OP exposure and promoter DNA methylation levels. The investigations proposed in the current study will take advantage of the population and resources included in an existing NIEHS-funded cross-sectional study nested in AHS. PUBLIC HEALTH RELEVANCE: This study examines organophosphate pesticide (OP) exposure and neurological disorders in 700 AHS participants. Thus, we will have well-defined OP exposure data, DNA from blood samples, and comprehensive data for confounding and modifying effects that may impact data evaluation. Further, we have an established in-vitro system for evaluating epigenetic effects of pesticides. These are novel and innovative investigations, as DNA methylation studies with complementary human data and cell lines with pesticide treatment have not been done. This study will have high public health significance due to the widespread pesticide use in the US and worldwide. A major strength is the study population of farmers with well-characterized exposure assessment. Data on pesticide use, of this high quality and completeness, would be difficult to achieve in a general population cohort. Another major strength is that this study is guaranteed to be completed in a timely manner (if funded), since the DNA is ready for analysis, and other relevant data are also readily available. Pesticides are widely used in the US and worldwide, are pervasive in our environment. Our dependence upon pesticides is increasing. Although pesticides sold in the US have passed the Environmental Protection Agency (EPA) tests for their ability to cause cancer and been approved as safe, it has repeatedly been shown that some pesticides increased human cancer incidence. The concern is that EPA's evaluation on the safety of pesticides does not include the tests that examine DNA methylation alterations, a new emerging hallmark of cancer. Our proposed study is to investigate the effects of pesticides exposure on DNA methylation alterations in a subset of the population from the Agricultural Health Study (AHS), the largest prospective study in the world of pesticides applicators from Iowa and North Carolina. The results from this study will address a critical gap in our knowledge of pesticides and their ability to cause cancer.

描述（由申请人提供）：此申请解决广泛的挑战领域（08）基因组学和特定挑战主题，08-ES-104：识别与环境暴露有关的表观遗传标记的变化。在美国，接触农药无处不在，超过一百万的人受到高职业接触。农药及其残留物在我们的环境中普遍存在，我们对农药的依赖正在增加。尽管美国出售的所有农药都通过环境保护局（EPA）的致癌性测试，但在流行病学研究中，暴露于农药的暴露与人类癌症发病率增加有关。我们最近对农业健康研究（AHS）队列的分析，这是来自爱荷华州和北卡罗来纳州的农药施用者世界上最大的前瞻性研究，也表明，农药的暴露会增加几种癌症的风险。关注的是，EPA对化学致癌性的评估主要是基于对诱变事件的检测。 EPA测试系统中未考虑改变DNA甲基化是癌症的新兴标志。新兴证据表明，启动子DNA甲基化受环境暴露的影响。先前的研究表明，血细胞DNA中包含在内的表观遗传信息（包括DNA甲基化）代表了癌症风险的宝贵预测标志。血液是外部环境和人体组织之间的管道，因此构成了精确的目标组织，以评估环境有毒物质对人类健康的影响。我们的初步数据最近将暴露于美国最常用的杀虫剂的有机磷酸盐农药（OPS），以增加血液DNA中几种肿瘤抑制基因的启动子甲基化。我们进一步使用用OP处理的人类血细胞在体外证实了这一发现。综上所述，我们假设暴露于农药可以诱导血细胞DNA中的启动子DNA甲基化变化，这将为当前对农药暴露与癌症风险之间关联的机械洞察提供目前未知的洞察力。我们建议研究OP暴露是否会改变人类受试者中的基因启动子DNA甲基化模式，以及在经过处理的细胞系中。我们将首先在OP暴露最高和最低的人群中以及细胞系中的一部分中进行全基因组筛查。然后，将在独立复制群中使用基因特异性方法以及用不同剂量的OP处理细胞后对发现进行验证。我们还将检查与甲基供体相关的养分和相关的遗传多态性（DNA甲基化过程中的两个主要因素）是否改变了OP暴露与启动子DNA甲基化水平之间的关联。当前研究中提出的调查将利用嵌套在AHS中的现有NIEHS资助的横断面研究中的人口和资源。 公共卫生相关性：这项研究检查了700名AHS参与者的有机磷酸盐农药（OP）暴露和神经系统疾病。因此，我们将拥有明确定义的OP暴露数据，来自血液样本的DNA以及可能影响数据评估的混淆和修改效果的综合数据。此外，我们建立了一个既定的体外系统，用于评估农药的表观遗传作用。这些都是新颖的创新研究，因为尚未进行使用补充人类数据和细胞系进行农药治疗的DNA甲基化研究。由于在美国和全球范围内广泛使用农药，这项研究将具有很高的公共卫生意义。一个主要优势是对经过良好暴露评估的农民的研究人群。在普通人群中，很难获得有关这种高质量和完整性的农药使用的数据。另一个主要优势是，由于DNA已准备好进行分析，并且还很容易获得这项研究（如果资助），可以及时完成这项研究。农药在美国和全球广泛使用，在我们的环境中普遍存在。我们对农药的依赖正在增加。尽管在美国出售的农药已经通过了环境保护局（EPA）的测试，以使其引起癌症的能力并被批准为安全，但已反复证明某些农药增加了人类癌症的发病率。关注的是，EPA对农药安全的评估不包括检查DNA甲基化改变的测试，这是癌症的新出现标志。我们提出的研究是研究农药暴露于农业健康研究（AHS）的一部分人群中DNA甲基化改变的影响，这是来自爱荷华州和北卡罗来纳州的农药施用者中最大的前瞻性研究。这项研究的结果将解决我们对农药知识及其引起癌症的能力的关键差距。