Genetic and epigenetic mechanisms of infertility caused by endocrine disrupting chemicals

项目总结 在发育过程中接触一种单一的毒物会在成年后及以后造成生殖缺陷。 这是预防和治疗人类不孕不育的一大障碍。尽管它的 然而，调解这一过程的机制却鲜为人知。内分泌紊乱 化学品(EDCs)在世界范围内男性不育发病率的上升中发挥了作用，而且越来越多的证据表明 提示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，使循证预防策略 并且可以治疗成人发病和跨代疾病。这项NIEHS的总体目标 R01奖(PA-19-056)的应用是确定基因组功能改变和表观遗传调节 受环境影响的不孕症。中心假设是在男性性腺期间接触亚致死性EDC 发育导致基因组和表观遗传失调，改变睾丸线粒体功能 暴露的一代和后代人。提出这项研究的理由是 EDC导致不孕的机制的研究将促进预防、风险评估、诊断、 以及人类男性不育的治疗策略。在强劲的初步数据的指引下，这一假设将是 通过追求三个具体目标进行测试：1)确定睾丸细胞类型的特异性和生命阶段的特异性变化 在基因组功能方面，以确定影响生物标记物和基因关系的关键窗口；2)识别 表观基因组与表型和遗传终点有关的变化；3)决定多代和 由祖先暴露引起的跨代细胞特异性转录和表观遗传学变化。 最终，这些结果将确定生物标志物的关键作用窗口，告知 调节有毒终点的途径。

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.