Environmental Epigenetics of EDCs: From Germline to Brain

EDC 的环境表观遗传学：从种系到大脑

• 批准号: 10641202
• 负责人: ANDREA C GORE
• 金额: $ 27.71万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-06 至 2031-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641202
• 关键词: Address; Affect; Agriculture; Animal Experiments; Area; Brain; Cells; Chemical Exposure; Chemical Industry; Chemicals; DNA; Data; Development; Disease; Endocrine; Endocrine Disruptors; Epigenetic Process; Exposure to; Female; Fetus; Functional disorder; Future Generations; Generations; Germ Cells; Health; Heritability; Heterogeneity; Hormones; Human; Individual; Intervention; Knowledge; Lead; Life; Link; Modeling; Modification; Molecular; Neurobiology; Outcome; Phenotype; Plastics; Qualifying; RNA; Rattus; Research; Route; Security; Sex Differences; Somatic Cell; Time; Tissues; Untranslated RNA; Work; bioinformatics pipeline; brain cell; cell type; dosage; egg; epidemiologic data; epigenomics; exposed human population; flexibility; intergenerational; male; multiple omics; neurobehavioral; neurobehavioral disorder; offspring; programs; reproductive; sex; sperm cell; targeted treatment; transmission process

ABSTRACT Exposures to environmental endocrine-disrupting chemicals (EDCs), especially during early life, are strongly linked to adverse health outcomes including neurobehavioral, reproductive, and other endocrine dysfunctions. EDC exposures to a fetus (F1) also exposes the germline and causes heritable epigenetic changes that are passed to future generations. There are a number of limitations to prior work that I will overcome in the current RIVER application. Most EDC research is limited to a single tissue type or a single mechanism with a limited number of targets. This is particularly complicated in the brain because of its heterogeneity. The field is also limited by a surprisingly small number of studies that compare sex differences, yet EDCs have profoundly different effects on the developing male and female brain, body, and germline, which are subject to sex-specific epigenetic programming and therefore sex-specific phenotypes. Finally, how epigenetic programming propagates from gamete to somatic cells and causes tissue-specific diseases such as neurobehavioral disorders is a fundamental question, one that (to my knowledge) has never been addressed. This RIVER application has three overarching areas of inquiry. 1) What are the epigenetic mechanisms by which environmental EDCs organize brain development at the cellular level, and lead to functional neurobiological deficits in exposed individuals? 2) Which epigenetic mechanism(s) is responsible for programming of the germline to enable transmission across generations? 3) How does epigenetic programming in the germline manifest as cell-specific phenotypes in somatic cells (e.g. brain)? To address these questions we will use our established rat EDC exposure model with human-relevant chemicals, dosages, and route, in which direct (F1), intergenerational (F2), and multigenerational (F3) work will be performed in both the brain and the gametes. I am uniquely qualified to lead this research program as an environmental neuroendocrinologist doing groundbreaking multigenerational epigenetic work. We will do single-cell multiomic profiling of both the brain and gametes at the RNA, DNA, and small-noncoding RNA (sncRNA) level, enabling us to pinpoint the cell types influenced by EDCs, and how phenotypes are propagated from gametes to individuals and across developmental stages. Established bioinformatic pipelines will inform on these mechanisms individually, as well as their relationships. Crucially, the lines of work in brain and gametes will be connected by relating epigenomic profiles in brain and germ cells to one another, thereby determining how epigenomic marks in gametes are reflected in the brain. These data will establish definitive epigenetic profiles that will allow us to identify the origin of EDC induced epigenetic modifications and provide potential targets for therapeutics in humans, with which the mechanisms studied in rats are highly conserved. The flexibility and security of the RIVER program is necessary to fully realize the promise of this likely paradigm-shifting research.

抽象的 对环境内分泌中断化学物质（EDC）的暴露，尤其是在早期生命中 与不良健康结果有关，包括神经行为，生殖和其他内分泌功能障碍。 EDC暴露于胎儿（F1）也暴露了种系，并引起可遗传的表观遗传变化 传递给子孙后代。先前的工作有许多局限性，我将在当前中克服 河流应用。大多数EDC研究仅限于单一组织类型或有限的单个机制 目标数。由于其异质性，这在大脑中尤其复杂。该领域也是 受到比较性别差异的少数研究的限制 对发展的男性和女性大脑，身体和种系的不同影响，这些影响受性别特异性的影响 表观遗传编程，因此特定于性别的表型。最后，表观遗传编程如何 从配子到体细胞传播，并引起组织特异性疾病，例如神经行为疾病 是一个基本问题，据我所知，这是一个从未得到解决的问题。该河流应用有 询问的三个总体领域。 1）环境EDC的表观遗传机制是什么 在细胞水平上组织大脑发育，并导致暴露的功能性神经生物学缺陷 个人？ 2）哪种表观遗传机制负责种系的编程以实现 几代人的传播？ 3）种系中的表观遗传编程如何表现为细胞特异性 体细胞中的表型（例如大脑）？为了解决这些问题，我们将使用我们已建立的老鼠EDC 与人相关的化学物质，剂量和途径的暴露模型，其中直接（F1），代际（F2）， 多代（F3）的工作将在大脑和配子中进行。我很有资格 领导该研究计划作为一名开创性多代的环境神经内分泌学家 表观遗传学工作。我们将在RNA，DNA和 小型非编码RNA（SNCRNA）水平，使我们能够确定受EDC影响的细胞类型，以及如何 表型从配子到个体以及跨发育阶段传播。已确立的 生物信息学的管道将单独告知这些机制及其关系。至关重要的是 通过将大脑和生殖细胞中的表观基因组谱与 彼此之间，确定了在大脑中如何反映配子中的表观基因组痕迹。这些数据将 建立确定的表观遗传剖面，使我们能够识别EDC诱导的表观遗传学的起源 修改并为人类的治疗剂提供潜在的靶标，并与之相关的机制 大鼠是高度保守的。河流计划的灵活性和安全性是必要的 希望这种范式转移研究的承诺。