The Epigenetics Crossroads of Environmental Exposures and Early-Life Adversity

摘要 我们的健康和疾病的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）是非常重要的， 普遍流行，并造成死亡率增加，以及精神和身体疾病的发病率增加， 病理生理学这表现在精神健康障碍和慢性病的发病率上 以及心血管疾病、炎症、肥胖和癌症。研究表明 60.9%的成年人报告至少经历过一种儿童期不良暴露（ACE）， 15.9%经历过多次ACE。这一最新统计数据强调了艾滋病的普遍性和深远影响。 ELA对人类健康和行为的后果，以及强调研究的重要性， 考虑多个同期ACE。 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 得到了广泛认可。然而，为了提供有效解决公共卫生问题的干预措施的信息， 关于ACE的病理生理学基础的同等问题-它们如何通过 表观基因组修饰，以及这些表观基因组变化如何以及哪些与因果关系或功能相关 对所观察到的疾病表型-仍然知之甚少。在这个建议中，我们将确定表观遗传 以及在ACE小鼠模型中发生的具有稳健表型后果的遗传事件。我们将使用一个 加州大学戴维斯分校的独特模型，其中小鼠在发育期间暴露于交通相关的空气污染（TRAP）， 代表已知与神经发育风险增加相关的环境因素 包括认知损害、精神缺陷和多动症的疾病。作为同时代的ACE， 我们将应用有限层理和嵌套（LBN）的断裂褶皱范例，与几个 相似的表型结果。我们假设这两种ACE将对 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慢性不良儿童期 暴露会在以后的生活中显现出后果。这个项目建立在对糖皮质激素研究的兴趣之上 受体（GR）的表达和调节在背海马-是否特定的基因表达的变化 诱导特异性结构和功能变化。我们希望能找出 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”， 问题研究这项研究的长期目标是确定和优先考虑表观遗传事件和强大的表型， 这将使未来的研究，其中特定的表观遗传信息的功能意义， 通过表观遗传编辑进行研究。因此，本探索性提案中收集的数据将构成 研究表观遗传学和ACE诱导的行为表型之间因果关系的基础。

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.