Environmental Epigenetics of EDCs: From Germline to Brain

摘要 暴露于环境内分泌干扰化学品（EDCs），特别是在生命早期， 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。 胎儿（F1）暴露于EDC也会暴露生殖系，并导致可遗传的表观遗传变化， 传给后代。有一些限制，以前的工作，我将克服在目前的 RIVER应用程序。大多数EDC研究仅限于单一组织类型或单一机制， 目标的数量。这在大脑中特别复杂，因为它的异质性。该领域也是 由于比较性别差异的研究数量少得令人惊讶， 对发育中的男性和女性大脑、身体和生殖系的不同影响，这些影响受到性别特异性的影响。 表观遗传编程和性别特异性表型。最后，表观遗传编程 从配子传播到体细胞，并导致组织特异性疾病，如神经行为障碍 是一个根本性的问题，一个（据我所知）从未被解决过的问题。此RIVER应用程序具有 三大调查领域。1)环境内分泌干扰物通过什么表观遗传机制 在细胞水平上组织大脑发育，并导致暴露于 个人？2)哪种表观遗传机制负责种系的编程， 跨代传播？3)生殖系中的表观遗传编程如何表现为细胞特异性 体细胞（如脑）的表型？为了解决这些问题，我们将使用我们建立的大鼠EDC 暴露模型与人类相关的化学品，剂量和途径，其中直接（F1），代际（F2）， 多代（F3）工作将在大脑和配子中进行。我是唯一有资格 作为一名环境神经内分泌学家，领导这项研究计划， 表观遗传学研究我们将对大脑和配子的RNA、DNA和DNA进行单细胞多组学分析， 小的非编码RNA（sncRNA）水平，使我们能够确定受EDCs影响的细胞类型，以及如何 表型从配子传播到个体并跨越发育阶段。建立 生物信息学管道将分别介绍这些机制及其相互关系。关键是， 大脑和配子的工作线将通过将大脑和生殖细胞中的表观基因组图谱与 从而确定配子中的表观基因组标记如何反映在大脑中。这些数据将 建立明确的表观遗传特征，使我们能够确定EDC诱导的表观遗传起源 修饰并为人类的治疗提供潜在的靶点， 老鼠是高度保守的。RIVER程序的灵活性和安全性对于充分实现 这一可能的范式转变研究的承诺。

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.