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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：
10487840
负责人：
Tracie R Baker
金额：
$ 52.99万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-11-01 至 2024-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10487840
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 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 diagnostic strategy epigenetic regulation epigenome evidence base fighting glucose metabolism gonad development grasp histone methyltransferase histone modification human male insight lipid metabolism male prevent prototype reproductive reproductive system disorder 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.

项目总结