Human Pesticide Exposure and Epigenetic Changes in Sperm DNA

人类农药暴露与精子 DNA 的表观遗传变化

• 批准号: 9302776
• 负责人: TIMOTHY D HOWARD
• 金额: $ 35.71万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9302776
• 关键词: 2,4-Dichlorophenoxyacetic Acid; Acids; Address; Adverse effects; Affect; Agriculture; Andrology; Area; Binding Proteins; Biological; Biological Markers; Centers for Disease Control and Prevention (U.S.); Chlorpyrifos; Chronic; Clinic; Controlled Study; DNA; DNA Methylation; Data; Environmental Impact; Environmental and Occupational Exposure; Epidemiology; Epigenetic Process; Exposure to; Family member; Fertility; Genes; Genome; Goals; Health; Health Policy; Herbicides; Human; Immigrant; Impairment; Individual; Infertility; Insecticides; Laboratory Animal Models; Latino; Methods; Methylation; Morphology; Occupational; Occupational Exposure; Occupations; Pattern; Pesticides; Population; Precipitation; Prevention strategy; Public Health; Publishing; Reporting; Reproductive Health; Research; Review Literature; Risk; Route; Seasons; Seminal fluid; Site; Sperm Count Procedure; Spermatogenesis; Time; United States; agricultural pesticide; base; case control; cell motility; clinically relevant; design; dichlorodiphenyltrichloroethane; epigenomics; experience; exposed human population; farm worker; genome wide methylation; genome-wide; imprint; longitudinal design; male; male health; men; men' s group; methylation pattern; next generation sequencing; pesticide exposure; public health relevance; pyrethroid; reproductive; socioeconomics; sperm cell; sperm function; sperm quality; urinary

 DESCRIPTION (provided by applicant): Human populations are exposed to a variety of pesticides. Much of the research documenting the detrimental effects of pesticide exposure on sperm quality has been extrapolated on laboratory and animal models with limited results from studies of direct human pesticide exposure. Many of the human studies focus on the use of persistent pesticides, such as DDT (dichlorodiphenyltrichloroethane), whose use is thankfully decreasing in the developed world. However, increasing studies suggest deleterious effects of contemporary, non-persistent pesticides on human semen parameters, including decreased sperm concentration and motility. Latino immigrant farmworkers, most of whom are men, are a health disparate population with direct and frequent exposure to pesticides. These men provide an opportunity to examine the mechanisms and effects of exposure to contemporary, non-persistent pesticides on human sperm quality. A promising new area of reproductive research relates the epigenetic state of spermatozoa to sperm quality. In humans, clinic-based studies indicate that levels of DNA methylation are abnormal in spermatozoa of men with reduced fertility. A significant gap exists in our understanding of the genes that are epigenetically alterd following exposure to non-persistent pesticides. Data documenting the association of exposure to contemporary, non-persistent pesticides on the reproductive health of male farmworkers is needed to inform prevention strategies and public health policy surrounding the use of agricultural pesticides. The goal of this project is to document the association of pesticide exposure with epigenetic changes in spermatogenesis. We will compare 50 male immigrant Latino farmworkers, a group that experiences repeated pesticide exposure, with 50 immigrant Latinos living in urban, non-agricultural communities, without occupational exposure to pesticides. The proposed project will address three specific aims: 1. Methylation binding protein precipitation will be used to enrich imprinted DNA and Next Generation sequencing will be used for genome wide annotation of spermatozoa genes in high- (farmworkers) and low- (non-farmworker) pesticide exposed Latino men. 2. We will correlate biomarkers of non-persistent pesticide exposure (urinary metabolites of organophosphorus pesticides [3,5,6-trichloropyridinol, TCPy/chlorpyrifos], pyrethroid insecticides [3-phenoxybenzoic acid, 3PBA], and herbicides [2,4- dichlorophenoxyacetic acid, 2,4-D]) with the methylation status of spermatozoa genes. 3. Associations among clinically relevant semen parameters (sperm concentration, motility and morphology), urinary pesticide metabolite concentrations and DNA methylation patterns within spermatozoa genes in both groups of men will be determined. This research will combine epidemiology, andrology and epigenomics. The unique longitudinal design of this study will allow us to evaluate cross-sectional differences between high- and low-exposure groups, and changes within populations and individuals across an agricultural season.

 描述(申请人提供)：人类人群暴露于各种杀虫剂。记录农药暴露对精子质量有害影响的大部分研究都是在实验室和动物模型上推断的，对人类直接接触杀虫剂的研究结果有限。许多人体研究的重点是持久性杀虫剂的使用，如DDT(二氯二苯基三氯乙烷)，谢天谢地，它的使用量在发达国家正在减少。然而，越来越多的研究表明，当代非持久性杀虫剂对人类精液参数的有害影响，包括降低精子密度和活力。拉丁裔移民农场工人，其中大多数是男性，是一个健康状况迥异的群体，直接和频繁地接触杀虫剂。这些人提供了一个机会来研究接触当代非持久性杀虫剂对人类精子质量的机制和影响。生殖研究的一个很有前途的新领域将精子的表观遗传状态与精子质量联系起来。在人类中，基于临床的研究表明，生育力下降的男性精子中的DNA甲基化水平是异常的。在我们对暴露于非持久性杀虫剂后发生表观遗传变化的基因的理解上存在着显著的差距。需要记录接触当代非持久性农药对男性农场工人生殖健康影响的数据，以便为有关使用农业农药的预防战略和公共卫生政策提供信息。该项目的目标是证明农药暴露与精子发生的表观遗传学变化之间的联系。我们将比较50名拉丁裔男性移民农场工人和50名生活在城市非农业社区、没有职业接触农药的拉丁裔移民。拟议的项目将解决三个具体目标：1.甲基化结合蛋白沉淀将用于丰富印迹DNA，下一代测序将用于高(农场工人)和低(非农场工人)农药暴露的拉丁裔男子的精子基因的全基因组注释。2.我们将把非持久性农药暴露的生物标志物(有机磷农药的尿代谢物[3，5，6-三氯吡啶，TCPy/毒死蜱]、拟除虫菊酯[3-苯氧基苯甲酸，3PBA]和除草剂[2，4-二氯苯氧乙酸，2，4-D])与精子基因甲基化状态相关联。3.将确定两组男性的临床相关精液参数(精子密度、活动率和形态)、尿中农药代谢产物浓度和精子基因DNA甲基化模式之间的关系。这项研究将结合流行病学、男科学和表观基因组学。这项研究的独特纵向设计将使我们能够评估高暴露组和低暴露组之间的横截面差异，以及整个农业季节人群和个人的变化。