Germline transmission of epigenetic alterations to offspring

表观遗传改变的种系传递给后代

• 批准号: 10876750
• 负责人: Ramji Kumar Bhandari
• 金额: $ 21.56万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10876750
• 关键词: 20 year old; Adult; Age; Androgen Receptor; Animal Model; Chemical Exposure; Chemicals; Clustered Regularly Interspaced Short Palindromic Repeats; CpG Islands; Crossbreeding; DNA; DNA Methylation; Databases; Defect; Development; Disease; Embryo; Endocrine Disruptors; Environment; Epigenetic Process; Exposure to; Failure; Female; Fertility; Fertilization; Fishes; Future; Future Generations; Gender; Generations; Germ Cells; Goals; Gonadal structure; Health; Histologic; Human; Impairment; Incidence; Individual; Inherited; Japanese Killifish; Libraries; Life; Literature; Mammals; Meiosis; Mitotic; Modeling; Modification; Oryziinae; Outcome; Partner in relationship; Pattern; Phenotype; Predisposition; Puberty; Publishing; RNA; Recording of previous events; Reproduction; Reproductive Health; Research; Research Project Grants; Resistance; Risk; Role; Sexual Maturation; Site; Spermatids; Spermatocytes; Spermatogenesis; Spermatogonia; Structure of primordial sex cell; Testing; Time; Tissues; Vertebrates; bisphenol A; bisulfite sequencing; comparative; dietary supplements; egg; environmental chemical; epigenome; epigenome editing; epitranscriptome; estrogenic; gastrulation; genome-wide; histone modification; in vivo; insight; interest; life history; male; methylome; neuronal cell body; next generation; offspring; programs; promoter; pyrosequencing; reproductive; reproductive development; sex; sperm cell; subfertility; success; tool; trait; transcriptome; transmission process; whole genome; young adult

ABSTRACT: The overall goal of this research program is to delineate the role of germline epigenetic alterations (epimutations) in the onset and progression of inter-and transgenerational reproductive defects. So far, published scientific literature suggests that environmentally induced epigenetic alterations, mainly DNA methylation, histone modifications, and RNA modifications (epitranscriptome), are transmitted to subsequent generations via germline (eggs or sperm)1. However, the role of observed epimutations in the development of reproductive phenotypes is not well understood because of a lack of clear understanding of PGC to germline and germline-to soma transfer of reprogramming-resistant epimutations during the turnover of generations. Here in the proposed study, we are asking three big questions: a) Do germline epimutations establish age and developmental stage specifically in males? b) Do ancestrally established transgenerational epimutations predispose future generations to increased risks for reproductive impairment if exposed again to emerging environmental chemicals of concern? c) Is the role of the observed epimutations in the development of progression of phenotypic traits causative or correlative? This R01 research project will systematically answer these questions in three different aims. BPA will be used as a ubiquitous model endocrine-disrupting chemical (EDC), and Bisphenol S (BPS) will be used as an emerging contaminant of concern, and medaka fish as a comparative vertebrate animal model. Aim 1 will test the hypothesis that male germ cells at all stages of development are susceptible to BPA, the model EDC. Aim 2 will test the hypothesis that exposure of the F3 generation offspring with pre-existing epimutations to emerging contaminants will result in an increased incidence of reproductive impairment. Aim 3 will test the hypothesis that the EDC-induced epimutations are associated with reduced fertility in males and females and that these epimutations can be corrected by reprogrammable CRISPR-dCas9 epigenome editing in vivo. The project will identify footprints of the past exposure, determine the role of epimutations in reproductive impairment, determine whether inherited epimutations predispose current and future generations to increased risks of reproductive health due to exposure to emerging contaminants of concern, and provide significant insights into mechanisms underlying germline transmission of the epigenome and longitudinal health risks of exposure. Understanding of key time points during which epimutations transfer would provide insights into strategies for the mitigation of future estrogenic chemical-induced reproductive health effects in humans.

摘要：该研究项目的总体目标是描述生殖细胞的作用。 代间和跨代遗传的发生和进展中的表观遗传改变（表观突变） 生殖缺陷。到目前为止，已发表的科学文献表明，环境引起的 表观遗传改变，主要是DNA甲基化、组蛋白修饰和RNA修饰 （外转录组）通过种系（卵子或精子）传递给后代1。 然而，观察到的表突变在生殖表型发展中的作用并不明确。 由于缺乏对 PGC 到种系和种系到种系的清晰了解，所以很好理解 在世代更替过程中，体细胞转移了重编程抗性表突变。这里 在拟议的研究中，我们提出三个大问题：a）种系表突变是否建立 特别是男性的年龄和发育阶段？ b) 做祖传的事 跨代表突变使后代面临更高的生殖风险 如果再次接触新兴环境化学品会造成损害吗？ c) 的作用是 在表型性状的进展过程中观察到的表突变导致或 相关的？这个R01研究项目将从三个不同的方面系统地回答这些问题 目标。 BPA 将被用作一种普遍存在的内分泌干扰化学品 (EDC) 模型，并且 双酚 S (BPS) 将被用作新出现的令人关注的污染物，青鳉鱼将被用作 比较脊椎动物模型。目标 1 将检验男性生殖细胞是否存在的假设 发育阶段容易受到 BPA（EDC 模型）的影响。目标 2 将检验以下假设： 已存在表突变的 F3 代后代暴露于新出现的污染物 会导致生殖障碍发生率增加。目标 3 将检验假设 EDC 诱导的表突变与男性和女性生育能力下降有关 这些表观突变可以通过可重编程的 CRISPR-dCas9 表观基因组编辑来纠正 体内。该项目将识别过去暴露的足迹，确定 生殖障碍中的表突变，确定遗传性表突变是否易诱发 当代和子孙后代因接触环境而增加生殖健康风险 关注的新出现的污染物，并提供对潜在机制的重要见解 表观基因组的种系传播和暴露的纵向健康风险。理解 表突变转移的关键时间点将提供对策略的见解 减轻未来雌激素化学物质引起的人类生殖健康影响。