Genetic and epigenetic mechanisms of infertility caused by endocrine disrupting chemicals

内分泌干扰物引起不孕症的遗传和表观遗传机制

基本信息

批准号：
9911309
负责人：
Tracie R Baker
金额：
$ 35.19万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-20 至 2024-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9911309
关键词：
Adult Agonist Agriculture Aryl Hydrocarbon Receptor Award Biological Markers Cells Characteristics Chemical Exposure Chromatin Clinical Critical Pathways DNA Modification Methylases Data Defect Development Diagnostic Disease Elderly Endocrine Disruptors Epidemic Epidemiology Epigenetic Process Exposure to Female Fishes Food Chain Food Supply Gene Expression Generations Genes Genetic Genome Genomics Goals Heritability Human Incidence Industrialization Infertility Investigation Knowledge Laboratories Lead Life Male Infertility Mediating Metabolic Metabolism Methylation Mitochondria Modification Molecular Mutation National Institute of Environmental Health Sciences Outcome Pathway interactions Pharmacologic Substance Phenotype Play Pollution Population Predisposition Prevention Process Public Health Reproductive Health Reproductive system Research Risk Assessment Role Self Care Sentinel Series Spermatogenesis Structure Testicular Tissue Testing Testis Tetrachlorodibenzodioxin Therapeutic Time Tissues Toxic Environmental Substances Toxicant exposure Toxin Transgenic Organisms Zebrafish cell type epigenetic regulation epigenome evidence base fighting glucose metabolism gonad development grasp histone methyltransferase histone modification human male insight lipid metabolism male prevent prototype reproductive response single cell sequencing sperm cell toxicant transcriptomics treatment strategy

项目摘要

PROJECT SUMMARY A single toxicant exposure during development can produce reproductive defects in adulthood and subsequent generations, presenting a major hurdle in the prevention and treatment of human infertility. Despite its significance, however, the mechanisms that mediate this process are poorly understood. Endocrine disrupting chemicals (EDCs) play a role in the increasing incidence of male infertility worldwide, and mounting evidence suggests that EDC exposure can alter gene expression and the epigenome. Our long-term goal is to determine how environmental toxicants interfere with reproductive health so that evidence-based strategies to prevent and treat adult-onset and transgenerational disease can be developed.!The overall objective for this NIEHS R01 Award (PA-19-056) application is to determine genome function alterations and epigenetic regulation of environmentally-influenced infertility. The central hypothesis is that sublethal EDC exposure during male gonad development leads to genomic and epigenetic dysregulation that alters testicular mitochondrial function in exposed generation and subsequent generations. The rationale for the proposed research is that investigation of the mechanisms underlying EDC induced infertility will advance prevention, risk-assessment, diagnostic, and treatment strategies for human male infertility. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Determine testicular cell-type specific and life stage specific changes in genome function to identify critical windows for biomarkers of effect and gene relationships; 2) Identify changes in the epigenome related to phenotypic and genetic endpoints; 3) Determine multigenerational and transgenerational cell-specific transcriptomic and epigenetic changes induced by ancestral exposure. Ultimately, these results will identify critical windows for biomarkers of effect, inform the interplay among pathways mediating toxic endpoints.

项目概要发育过程中接触单一有毒物质可能会导致成年期和随后的生殖缺陷几代人，这是预防和治疗人类不孕症的一个主要障碍。尽管其然而，人们对介导这一过程的机制知之甚少。内分泌干扰化学品 (EDC) 在全球男性不育发病率上升中发挥着重要作用，并且越来越多的证据表明表明 EDC 暴露可以改变基因表达和表观基因组。我们的长期目标是确定环境毒物如何干扰生殖健康，以便制定基于证据的预防策略可以开发治疗成人发病和跨代疾病的方法。！本次 NIEHS 的总体目标 R01奖（PA-19-056）申请旨在确定基因组功能改变和表观遗传调控环境影响的不孕症。中心假设是男性性腺期间亚致死的 EDC 暴露发育导致基因组和表观遗传失调，从而改变睾丸线粒体功能暴露的一代和后代。拟议研究的理由是调查 EDC 诱发不孕症的潜在机制的研究将促进预防、风险评估、诊断、人类男性不育症的治疗策略。在强有力的初步数据的指导下，这一假设将是通过追求三个特定目标进行测试：1）确定睾丸细胞类型特异性和生命阶段特异性变化在基因组功能中确定效应和基因关系生物标志物的关键窗口； 2）识别与表型和遗传终点相关的表观基因组变化； 3）确定多代和由祖先暴露引起的跨代细胞特异性转录组和表观遗传变化。最终，这些结果将确定生物标志物作用的关键窗口，并告知它们之间的相互作用介导毒性终点的途径。