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）：公众对内分泌破坏化学物质（EDC）对人类健康的潜在影响的关注增强了研究的需求，以评估暴露于这些化学物质的机械作用。在关键发展期间的EDC暴露会导致组织分化的不可逆转变化。许多研究的寿命影响归因于基因组的表观遗传变化。尽管许多研究集中在DNA甲基化作为毒性的表观遗传机制上，但很少有研究研究microRNA（miRNA）的作用。 miRNA是调节基因和蛋白质表达的小RNA。 miRNA在神经内分泌和生殖功能和疾病中发挥作用，在毒理学研究中化学暴露后会改变，但尚未作为阿特拉津（ATR）毒性的表观遗传机制进行研究。 ATR是一种农业除草剂，通常据报道在美国各地污染饮用水供应。 ATR被视为内分泌破坏者和潜在的致癌物。据报道，ATR对下丘脑 - 垂体 - 基达（HPG）轴作用，但是尚未完全了解ATR的内分泌破坏特性。在我们正在进行的研究中，在斑马鱼模型系统中受精后1至72小时的发育ATR暴露后立即进行转录组分析支持HPG轴的改变和神经内分泌控制ATR内分泌干扰改变的改变。此外，在正常实验室条件下允许成熟的成年斑马鱼在发育中暴露于ATR，在生活史特征和生殖功能上表现出重大改变。我们的中心假设是，HPG AXI从发育ATR暴露中的改变是由表观遗传机制驱动的。此外，我们假设ATR内分泌干扰改变受神经内分泌控制。我们研究的长期目标是定义和联系统治ATR诱导的HPG轴改变起源的遗传和表观遗传机制。在这项研究中，我们将首先在发育ATR暴露后立即确定miRNA表达改变，以定义ATR毒性的表观遗传靶标。在第二和第三目标中，我们将对从成年女性和雄性斑马鱼中分离出的大脑/垂体和性腺组织进行比较转录组分析，从而暴露于ATR。成人斑马鱼脑组织的初步转录组数据进一步支持HPG信号的改变。还将进行大量确认和靶向测定，以进一步研究HPG轴上ATR毒性的机制。 AIM 2和3中收集的数据将与AIM 1的数据耦合，以将ATR诱导的改变与HPG轴的变化的发育起源的遗传和表观遗传机理联系起来。此外，在整个研究中，毕业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。