The Epigenetics Crossroads of Environmental Exposures and Early-Life Adversity

摘要 我们的健康和疾病能力与我们所处的环境和经历密切相关 暴露了。因此，生活经历可以对发展、行为和健康产生持久的影响。那些 发生在生命早期的敏感期可能特别有效。早期生活逆境(ELA)是高度和 普遍流行，并解释了死亡率增加以及精神和身体疾病比率增加的原因 病理生理学。这表现在精神健康障碍和慢性疾病的发生率上。 进入成年期，以及心血管疾病、炎症、肥胖和癌症。研究表明， 据报告，60.9%的成年人至少经历过一种儿童时期的不良暴露(ACE)， 15.9%的人经历过多个A级。最近的统计数据强调了这一现象的广泛流行和深远影响 ELA对人类健康和行为的影响，以及强调以下研究的重要性 考虑一下多个同时代的王牌。 环境暴露(包括空气污染和创伤性ELA)与表观基因组变化的关系 已经广为人知。然而，为了向有效解决公共卫生问题的干预措施提供信息， 关于ACEs的病理生理学基础的问题--它们是如何通过 表观基因组修饰，以及这些表观基因组变化如何以及哪些是因果或功能相关的 对观察到的疾病表型-仍然知之甚少。在这项提案中，我们将确定表观遗传学 以及发生在ACE小鼠模型中的具有强健表型后果的遗传事件。我们将使用 加州大学戴维斯分校的独特模型，在该模型中，小鼠在发育过程中暴露在与交通相关的空气污染(TRAP)中， 代表一种已知与神经发育风险增加相关的环境因素 精神障碍，包括认知障碍、精神运动障碍和多动症。作为同时代的ACE， 我们将应用有限床上用品和嵌套(LBN)范式的破裂护理，相关的几个 相似的表型结果。我们假设这两个A对……有相加或协同作用。 分子和行为结果。作为对这些研究的补充，我们将调查以下假设 表观遗传信息的变化是儿童时期慢性不良的重要生理成分 暴露会在以后的生活中表现出后果。这个项目建立在对糖皮质激素研究的兴趣之上。 受体(GR)在背侧海马区的表达和调节--特定基因表达是否发生变化 引起特定的结构和功能变化尚未确定。我们希望能识别出不同的 以及与这些表型特征相关的功能上值得注意的表观遗传“签名”，基于相关的 学习。这项研究的长期目标是识别表观遗传事件和稳健的表型，并对其进行优先排序 将使未来的研究成为可能，在这些研究中，特定表观遗传信息的功能意义可以 通过表观遗传编辑进行调查。因此，在这份探索性提案中收集的数据将形成 研究表观遗传学与血管紧张素转换酶诱导的行为表型之间的因果关系。

ABSTRACT Our capacity for health and disease is intimately tied with the environment and the experiences to which we are exposed. Life experiences, then, can yield lasting consequences on development, behavior, and health. Those occurring during the sensitive period early in life can be especially potent. Early life adversity (ELA) is highly and universally prevalent, and accounts for increased mortality, as well as increased rates of mental and physical pathophysiology. This is manifested in the incidence of mental health disorders and chronic medical conditions well into adulthood, as well as cardiovascular disease, inflammation, obesity, and cancer. Studies suggest that 60.9% of adults reported to have experienced a minimum of one type of adverse childhood exposures (ACE), and 15.9% experienced multiple ACEs. This recent statistic underscores the sheer prevalence and far-reaching consequences of ELA on human health and behavior, as well as emphasizing the importance of studies that consider multiple contemporaneous ACEs. The association of environmental exposures (including air pollution and traumatic ELA) and epigenomic changes has been well-recognized. However, in order to inform interventions that address public health issues effectively, the tantamount question regarding the pathophysiological bases of ACEs – how they “get under the skin” via epigenome modification, and how and which of these epigenomic changes are causally or functionally relevant to the disease phenotypes observed – remains poorly understood. In this proposal, we will identify epigenetic and genetic events with robust phenotypic consequences occurring in a mouse model of ACE. We will use a unique model at UC Davis in which mice are exposed to traffic-related air pollution (TRAP) during development, representing an environmental factor known to be associated with increased risk of neurodevelopmental disorders, including cognitive impairment, psychomotor deficits, and hyperactivity. As a contemporaneous ACE, we will apply the limited bedding and nesting (LBN) paradigm of fractured caregiving, associated with several similar phenotypic outcomes. We hypothesize that the two ACEs will have additive or synergistic effects on molecular and behavioral outcomes. Complementary to these studies, we will investigate the hypothesis that changes in epigenetic information are an important physical component of how chronic adverse childhood exposures manifests consequences later in life. This project builds upon an interest in studying glucocorticoid receptor (GR) expression and regulation in the dorsal hippocampus – whether specific gene expression changes induce specific structural and functional changes has not yet been ascertained. We expect to identify distinct and functionally noteworthy epigenetic “signatures” related to these phenotypic characteristics, based on related studies. The long-term goal of this study is to identify and prioritize epigenetic events and robust phenotypes that will enable future studies in which the functional significance of specific epigenetic information can be investigated through epigenetic editing. Therefore, the data collected in this exploratory proposal will form the basis to investigate causal relevance between epigenetics and ACE-induced behavioral phenotypes.