Genetic and epigenetic mechanisms of infertility caused by endocrine disrupting chemicals

项目摘要 在发育过程中接触一次有毒物质会导致成年期和随后的生殖缺陷。 这是预防和治疗人类不育症的一个主要障碍。尽管 然而，重要的是，介导这一过程的机制知之甚少。内分泌干扰 化学物质（内分泌干扰物）在全球男性不育症发病率上升中发挥作用， 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， 和治疗成人发病和跨代疾病可以制定。本NIEHS的总体目标 R 01奖（PA-19-056）的应用是为了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，在雄性性腺发育过程中， 发育导致基因组和表观遗传失调，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诱导不孕症的潜在机制将促进预防，风险评估，诊断， 以及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 在基因组功能中识别效应和基因关系的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的变化; 3）确定多代和 由祖先暴露引起的跨代细胞特异性转录组学和表观遗传学变化。 最终，这些结果将确定生物标志物效应的关键窗口，为生物标志物之间的相互作用提供信息。 介导毒性终点的途径。

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.