Molecular biomarkers of exposure to an endocrine disrupting herbicide

接触内分泌干扰性除草剂的分子生物标志物

• 批准号: 8496349
• 负责人: Jennifer L Freeman
• 金额: $ 45.01万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-10 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8496349
• 关键词: Adult; Agriculture; Atrazine; Automobile Driving; Biological Assay; Biological Markers; Biological Models; Brain; Carcinogens; Chemical Exposure; Chemicals; Coupled; DNA Methylation; Data; Development; Disease; Dose; Elderly; Embryo; Endocrine Disruptors; Endocrine disruption; Epidemiologic Studies; Epigenetic Process; European Union; Exhibits; Exposure to; Female; Fertilization; Gene Expression Alteration; Gene Proteins; Genes; Genetic; Genome; Goals; Health; Herbicides; Hour; Human; Hypothalamic structure; Individual; Knowledge; Laboratories; Laboratory Study; Link; Literature; Longevity; MicroRNAs; Molecular; Neurosecretory Systems; Pituitary Gland; Play; Property; Public Health; Regimen; Reporting; Research; Research Design; Risk; Rodent; Rodent Model; Role; Safety; Sex Ratio; Signal Pathway; Signal Transduction; Small RNA; Testing; Tissue Differentiation; Tissues; Toxic effect; Toxicology; United States; Vertebrates; Water Supply; Zebrafish; brain tissue; comparative; critical period; drinking water; experience; graduate student; life history; male; novel; offspring; pituitary gonadal axis; public health relevance; reproductive; reproductive development; reproductive function; research study; response; sex; trait; transcriptomics; undergraduate student

DESCRIPTION (provided by applicant): Public concern about the potential effects of endocrine disrupting chemicals (EDCs) on human health has heightened the need for research that assesses the mechanistic effects of exposure to these chemicals. EDC exposure during critical periods of development can result in irreversible changes in tissue differentiation alterig the sex and long-term reproductive potential of offspring supporting a developmental origin of these later lifespan impacts. The later lifespan impacts in many studies are attributed to epigenetic changes in the genome. While a number of studies have focused on DNA methylation as an epigenetic mechanism of toxicity, few studies have investigated the role of microRNAs (miRNAs). miRNAs are small RNAs that regulate expression of genes and proteins. miRNAs play a role in neuroendocrine and reproductive function and disease and are altered following chemical exposure in toxicology studies, but have yet to be investigated as an epigenetic mechanism of atrazine (ATR) toxicity. ATR is an agricultural herbicide commonly reported to contaminate drinking water supplies throughout the United States. ATR is implicated as an endocrine disruptor and a potential carcinogen. ATR is reported to act upon the hypothalamus-pituitary-gonadal (HPG) axis, but the endocrine disrupting properties of ATR are not completely understood. In our ongoing study, transcriptomic analysis immediately following a developmental ATR exposure from 1 to 72 hours post fertilization (hpf) in the zebrafish model system supports alterations in the HPG axis and neuroendocrine control of ATR endocrine disruption alterations. Furthermore, adult zebrafish developmentally exposed to ATR and allowed to mature under normal laboratory conditions exhibited significant alterations in life history traits and reproductive function. Our central hypothesis is that alterations in the HPG axi from a developmental ATR exposure are driven by epigenetic mechanisms. In addition, we hypothesize that ATR endocrine disruption alterations are under neuroendocrine control. The long term goal of our study is to define and link the genetic and epigenetic mechanisms governing the developmental origin of ATR-induced alterations on the HPG axis. In this study we will first identify miRNA expression alterations immediately following a developmental ATR exposure to define epigenetic targets of ATR toxicity. In the second and third aims, we will perform comparative transcriptomic analysis of brain/pituitary and gonadal tissue isolated from adult female and male zebrafish developmentally exposed to ATR. Preliminary transcriptomic data with adult zebrafish brain tissue further supports alterations in HPG signaling. A multitude of confirmation and targeted assays will also be performed to further investigate mechanisms of ATR toxicity on the HPG axis. The data collected in aims 2 and 3 will be coupled to that of aim 1 to link genetic and epigenetic mechanisms of the developmental origin of ATR-induced alterations to the HPG axis. Moreover, throughout this study graduate and undergraduate students will play an active role and gain extensive experience in all aspects of conducting a scientific research study.

描述（由申请人提供）：公众对内分泌干扰化学品（EDCs）对人类健康的潜在影响的关注，增加了对评估暴露于这些化学品的机械影响的研究的需求。在发育的关键时期暴露于EDC可导致组织分化的不可逆变化，改变后代的性别和长期生殖潜力，支持这些后期寿命影响的发育起源。在许多研究中，后期寿命的影响归因于基因组中的表观遗传变化。虽然许多研究集中在DNA甲基化作为毒性的表观遗传机制，但很少有研究调查microRNA（miRNAs）的作用。miRNA是调节基因和蛋白质表达的小RNA。miRNAs在神经内分泌和生殖功能以及疾病中发挥作用，并且在毒理学研究中随着化学暴露而改变，但尚未将其作为阿特拉津（ATR）毒性的表观遗传机制进行研究。ATR是一种农业除草剂，通常被报道污染整个美国的饮用水供应。ATR被认为是一种内分泌干扰物和潜在的致癌物质。据报道ATR作用于下丘脑-垂体-性腺（HPG）轴，但ATR的内分泌干扰特性尚不完全清楚。在我们正在进行的研究中，转录组学分析后立即发育ATR暴露从1至72小时后受精（hpf）在斑马鱼模型系统中支持HPG轴的改变和ATR内分泌干扰改变的神经内分泌控制。此外，成年斑马鱼发育暴露于ATR，并允许在正常的实验室条件下成熟表现出显着的生活史特征和生殖功能的改变。我们的中心假设是，在HPG轴从发展ATR曝光的变化是由表观遗传机制驱动。此外，我们假设ATR内分泌干扰的改变是在神经内分泌控制下。我们研究的长期目标是确定和连接的遗传和表观遗传机制，管理ATR诱导的HPG轴上的改变的发育起源。在这项研究中，我们将首先确定发育ATR暴露后立即发生的miRNA表达变化，以确定ATR毒性的表观遗传靶点。在第二个和第三个目标，我们将进行比较转录组学分析的脑/垂体和性腺组织分离成年女性和男性斑马鱼发育暴露于ATR。成年斑马鱼脑组织的初步转录组学数据进一步支持HPG信号转导的改变。还将进行大量的确认和靶向测定，以进一步研究ATR对HPG轴的毒性机制。目标2和3中收集的数据将与目标1的数据相结合，以将ATR诱导的改变的发育起源的遗传和表观遗传机制与HPG轴联系起来。此外，在整个研究中，研究生和本科生将发挥积极作用，并在进行科学研究的各个方面获得丰富的经验。