Environmental Epigenetics of EDCs: From Germline to Brain

摘要 暴露于环境内分泌干扰物(EDCs)，特别是在生命早期， 与不良健康后果有关，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)也会暴露生殖系，并导致可遗传的表观遗传学变化 传给子孙后代。以前的工作有一些限制，我将在当前克服这些限制 河流应用。大多数EDC研究局限于单一组织类型或单一机制 目标数量。这在大脑中尤其复杂，因为它的异质性。这一领域也是 由于比较性别差异的研究令人惊讶地少之又少，然而EDC却深刻地 对发育中的男性和女性大脑、身体和生殖系的不同影响，这些都受性别差异的影响 表观遗传编程，因此是性别特有的表型。最后，表观遗传编程是如何 从配子传播到体细胞，并导致组织特有的疾病，如神经行为障碍 这是一个根本性的问题，据我所知，这个问题从未得到解决。这个River应用程序具有 三个主要的调查领域。1)环境内分泌细胞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 个体？2)哪种表观遗传机制(S)负责对生殖系进行编程以使 跨代传播？3)胚系中的表观遗传编程是如何表现为细胞特异性的 体细胞(如脑)的表型？为了解决这些问题，我们将使用我们已建立的RAT EDC 与人类相关的化学品、剂量和路线的暴露模型，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，他具有开创性的多代 表观遗传学的工作。我们将对大脑和配子的RNA、DNA和 小非编码RNA(SncRNA)水平，使我们能够精确定位受内皮细胞影响的细胞类型，以及如何 表型从配子传播到个体，并跨越发育阶段。已建立 生物信息管道将单独告知这些机制以及它们之间的关系。至关重要的是， 大脑和配子的工作线将通过将大脑和生殖细胞的表观基因组图谱联系起来 相互作用，从而决定配子中的表观基因组标记如何在大脑中反映。这些数据将 建立明确的表观遗传学图谱，使我们能够确定EDC诱导的表观遗传学的起源 修饰并为人类的治疗提供潜在的靶点，其中研究的机制 老鼠是高度保守的。河流项目的灵活性和安全性是充分实现 这项可能改变范式的研究的前景。

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.