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: 7935479
• 负责人: Jennifer Ann Rusiecki
• 金额: $ 15.98万
• 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 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7935479
• 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; Cohort Studies; DNA; DNA Methylation; DNA Repair; DNA Sequence; Data; Diet; Drug Metabolic Detoxication; Dust; Environmental Epidemiology; 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; Occupational Exposure; Pattern; Pest Control; Pesticides; Promoter Regions; Public Health; Research; Risk; Sampling; Solvents; Tobacco smoking; Toxicology; United States Environmental Protection Agency; Welding; Whole Blood; base; cancer risk; carcinogenicity; cohort; genotoxicity; human study; pesticide exposure; population based; prospective; public health relevance; response; safety testing

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）：尽管经过50多年的流行病学和毒理学研究，目前市场上几乎所有农药的人类致癌性都受到评估不足，并且不充分理解。当前使用的大多数使用农药在体外和动物研究中不是公开的遗传毒性或诱变，但是人类研究发现了暗示性的证据，证明了暴露于特定农药的各种癌症风险增加。我们研究的目的是研究农药是否通过表观遗传机制，特别是通过影响异常的DNA甲基化来起作用，以赋予人类癌症的风险增加。我们假设在一组健康的农药施用剂中，高终生农药暴露将与改变的DNA甲基化模式改变，包括全球基因组低甲基化和基因特异性高甲基化。我们提出了一项研究，该研究嵌套在一批有执照的农药施用者的大量，农业健康研究中，该研究提供了其他一些研究提供的独特机会，以评估人类对良好特征的农药暴露的生物学反应。先前没有针对人类在不同程度的农药暴露中测量的DNA甲基化的研究。我们将利用大约700名施加剂的血液样本，将提取基因组DNA，并将在该同龄人所关注的癌症中量化四个最常见的沉默基因，p16ink4，mgmt，cdh-1和gSTP1，量化全球DNA甲基化和启动子区域甲基化。我们的主要目的是调查暴露于特定的农药和化学类别的农药（1）（1）特定基因（P16INK4，MGMT，MGMT，CDH-1和GSTP1）的高甲基化以及（2）降低全球基因组甲基化（次甲基化（低甲基化），在CPG重复和sequle-1元素中估计的Alu nu sequletse nuble-e元素中的估计值（holds nefna e元素）中的元素（均为nuble-nepsed nupsed nupsed nubletiide）。我们的次要目的是探索其他与农场相关的暴露，例如溶剂，谷物粉尘，焊接烟雾以及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，并根据基准的特征和全球甲基化的特征和饮食量，以及过去的饮食，以及过去的饮食，探索和阐明了基因特异性和全球甲基化的模式。我们提出的研究有可能识别一种先前未开发的致癌性机制，通过该机制在人类中可以通过该机制进行。公共卫生相关性：全球农药使用的程度，并强调了这些暴露具有巨大公共卫生影响的潜力。目前市场上的许多农药以及基于遗传毒性和诱变性测定的美国公共通行证安全测试广泛使用，但是流行病学研究表明人类的致癌性。我们提出的研究将解决我们对农药致癌性知识的巨大差距，特别是农药是否通过表观遗传机制运作，例如DNA甲基化以增加人类的癌症风险增加。

项目成果

High pesticide exposure events and DNA methylation among pesticide applicators in the agricultural health study.

• DOI: 10.1002/em.22067
• 发表时间: 2017-01
• 期刊: Environmental and molecular mutagenesis
• 影响因子: 2.8
• 作者: Rusiecki JA;Beane Freeman LE;Bonner MR;Alexander M;Chen L;Andreotti G;Barry KH;Moore LE;Byun HM;Kamel F;Alavanja M;Hoppin JA;Baccarelli A
• 通讯作者: Baccarelli A