Pesticide Exposure and DNA Methylation in Pesticide Applicators

农药施用器中的农药接触和 DNA 甲基化

• 批准号: 7532468
• 负责人: Jennifer Ann Rusiecki
• 金额: $ 20.63万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-24 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7532468
• 关键词: Aberrant DNA Methylation; Address; Adherence; Age; Agriculture; Alcohol consumption; Alu Elements; American; Animals; Biological Assay; Blood Cells; Blood specimen; CDH1 gene; CDKN2A gene; Cell Cycle Regulation; Cells; Cereals; Characteristics; Chemicals; Class; Cohort Studies; DNA; DNA Methylation; DNA Repair; DNA Sequence; Data; Diet; Drug Metabolic Detoxication; Dust; Epidemiologic Studies; Epidemiology; Epigenetic Process; Event; Exposure to; Farming environment; GSTP1 gene; Gene Silencing; Genes; Genomics; Health; Human; Hypermethylation; In Vitro; Investigation; Knowledge; Licensing; Life Style; Link; Long Interspersed Nucleotide Elements; MGMT gene; Malignant Neoplasms; Marketing; Measures; Medical; Methylation; Occupational Exposure; Occupational/Environmental Epidemiology; Pattern; Pest Control; Pesticides; Population; Promoter Regions; Public Health; Research; Risk; Safety; Sampling; Solvents; Testing; Tobacco smoking; Today; Toxicology; United States Environmental Protection Agency; Welding; Whole Blood; base; cancer risk; carcinogenicity; cohort; genotoxicity; glutathione S-transferase pi; human study; pesticide exposure; prospective; response

DESCRIPTION (provided by applicant): The human carcinogenicity of almost all pesticides currently on the market is poorly evaluated and inadequately understood in spite of over 50 years of epidemiologic and toxicologic research. Most currently used pesticides are not overtly genotoxic or mutagenic in vitro and animal studies, however human studies have found suggestive evidence of increased risk for various cancers from exposure to specific pesticides. The objective of our study is to investigate whether pesticides act via an epigenetic mechanism, specifically by effecting aberrant DNA methylation, to confer increased cancer risk in humans. We hypothesize that high lifetime pesticide exposures will be associated with altered DNA methylation patterns, including global genomic hypomethylation and gene-specific hypermethylation, in a group of healthy pesticide applicators. We propose a study nested in a large, prospective cohort of licensed pesticide applicators, The Agricultural Health Study, which provides the unique opportunity afforded in few other studies to evaluate biologic responses to well characterized pesticide exposures in humans. There are no previous studies of DNA methylation measured in humans with respect to varying degrees of pesticide exposure. We will utilize blood samples from approximately 700 applicators, will extract genomic DNA, and will quantify both global DNA methylation and promoter region methylation for four of the most commonly silenced genes in cancers of concern to this cohort, p16INK4, MGMT, CDH-1, and GSTp1. Our primary aim is to investigate whether exposure to specific pesticides and chemical classes of pesticides predicts (1) hypermethylation of specific genes (p16INK4, MGMT, CDH-1, and GSTp1) and (2) decreased global genomic methylation (hypomethylation) estimated in Alu family of CpG repeats and LINE-1 (long interspersed nucleotide element-1) sequences of DNA in blood cells. Our secondary aims are to explore whether other farm related exposures, such as solvents, grain dust, welding fumes, and high pesticide exposure events modify the associations between pesticide exposures and gene specific or global methylation and to explore and elucidate patterns of gene specific and global methylation according to baseline characteristics, such as age, recent and past tobacco smoking, alcohol consumption and diet among a low pesticide exposure group. Our proposed study has the potential to identify a previously unexplored, potential mechanism of carcinogenicity through which pesticides may operate in humans. PUBLIC HEALTH RELEVANCE: The extent of worldwide pesticide usage and underscores the potential for these exposures to have enormous public health implications. Many pesticides currently on the market and in widespread use by the American public pass safety testing based on genotoxicity and mutagenicity assays, however epidemiologic studies suggest carcinogenicity in humans. Our proposed study will address a significant gap in our knowledge of pesticide carcinogenicity, specifically whether pesticides operate via an epigenetic mechanism, such as DNA methylation to confer increased cancer risk in humans.

描述（由申请人提供）：尽管进行了 50 多年的流行病学和毒理学研究，但目前市场上几乎所有农药的人类致癌性评估不足且了解不够。目前使用的大多数农药在体外和动物研究中并没有明显的基因毒性或诱变性，但人类研究发现有暗示证据表明接触特定农药会增加患各种癌症的风险。我们研究的目的是调查农药是否通过表观遗传机制发挥作用，特别是通过影响异常的 DNA 甲基化，从而增加人类患癌症的风险。我们假设，在一组健康的农药施用者中，高终生农药暴露与 DNA 甲基化模式的改变有关，包括整体基因组低甲基化和基因特异性高甲基化。我们提出了一项基于许可农药施用者的大型前瞻性队列的研究，即农业健康研究，该研究提供了其他几项研究中提供的独特机会，以评估人类对明确农药暴露的生物反应。之前没有针对不同程度的农药暴露对人类 DNA 甲基化进行测量的研究。我们将利用来自约 700 个施药器的血液样本，提取基因组 DNA，并对该队列所关注的癌症中四种最常见沉默基因（p16INK4、MGMT、CDH-1、和 GSTp1。我们的主要目的是调查暴露于特定农药和化学类别的农药是否会预测 (1) 特定基因（p16INK4、MGMT、CDH-1 和 GSTp1）的高甲基化和 (2) Alu 中估计的全球基因组甲基化降低（低甲基化）血细胞中 DNA 的 CpG 重复序列和 LINE-1（长散布核苷酸元件 1）序列。我们的次要目标是探索其他与农场相关的暴露，例如溶剂、谷物粉尘、焊接烟雾和高农药暴露事件是否会改变农药暴露与基因特异性或全球甲基化之间的关联，并探索和阐明基因特异性和全球甲基化的模式甲基化根据基线特征，例如低农药暴露组的年龄、最近和过去吸烟、饮酒和饮食。我们提出的研究有可能确定一种以前未探索过的潜在致癌机制，农药可以通过该机制对人类产生作用。公共卫生相关性：全球农药使用的范围强调了这些接触可能对公共卫生产生巨大影响。目前市场上并被美国公众广泛使用的许多农药都通过了基于遗传毒性和致突变性检测的安全测试，但流行病学研究表明对人类具有致癌性。我们提出的研究将解决我们对农药致癌性知识的重大空白，特别是农药是否通过表观遗传机制发挥作用，例如DNA甲基化，从而增加人类癌症风险。