The Epigenetics Crossroads of Environmental Exposures and Early-Life Adversity

环境暴露与早年逆境的表观遗传学十字路口

• 批准号: 10490289
• 负责人: Keith Bein
• 金额: $ 18.94万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10490289
• 关键词: Address; Adult; Air Pollution; Area; Behavior; Behavioral; Biological; Cardiovascular Diseases; Characteristics; Childhood; Chronic; DNA Methylation; Data; Development; Disease; Dorsal; Environment; Environmental Exposure; Environmental Risk Factor; Epidemiology; Epigenetic Process; Event; Exposure to; Fracture; Functional disorder; Future; Gene Expression; Genetic; Glucocorticoid Receptor; Goals; Health; Health behavior; Heavy Metals; Hippocampus (Brain); Human; Hyperactivity; Impaired cognition; Incidence; Inflammation; Intervention; Lead; Life; Life Experience; Link; Malignant Neoplasms; Medical; Mental disorders; Methods; Modeling; Modification; Molecular; Mus; Neurodevelopmental Disorder; Neurologic; Obesity; Outcome; Pathway interactions; Pesticides; Phenotype; Physiological; Pregnancy; Prevalence; Psyche structure; Public Health; Rattus; Regulation; Reporting; Research; Risk; Skin; Untranslated RNA; adverse outcome; base; behavioral outcome; behavioral phenotyping; caregiving; disease phenotype; early life adversity; early life stress; epigenome; epigenomics; experience; histone modification; in vivo; interest; maternal stress; molecular phenotype; mortality; mother nutrition; mouse model; nervous system disorder; neurodevelopment; postnatal development; receptor expression; traffic-related air pollution; traumatic stress

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.

抽象的 我们的健康和疾病能力与环境和经验密切相关 裸露。因此，生活经历可以对发展，行为和健康产生持久的后果。那些 在生命早期敏感时期发生可能特别潜力。早期的冒险（ELA）很高，并且 普遍普遍，并说明死亡率增加，以及提高的精神和身体率 病理生理学。这表明了精神健康障碍和慢性医疗状况的事件 成年，以及心血管疾病，感染，肥胖和癌症。研究表明 据报道，有60.9％的成年人至少经历过一种不良儿童暴露（ACE），即 和15.9％的经历了多个A。这一最近的统计强调了纯粹的流行和深远的角度 ELA对人类健康和行为的后果，并强调研究的重要性 考虑多个现代王牌。 环境暴露协会（包括空气污染和创伤性ELA）和表观基因组变化 已被众所周知。但是，为了告知有效解决公共卫生问题的干预措施， 关于ACE的病理生理基础的tantamount问题 - 它们如何通过 表观基因组的修饰，以及这些表观基因组的变化如何以及功能相关 观察到的疾病表型 - 仍然很了解。在此提案中，我们将确定表观遗传 在ACE的小鼠模型中发生了具有强大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，在开发过程中，小鼠暴露于与交通相关的空气污染（陷阱）， 代表已知与神经发育风险增加有关的环境因素 疾病，包括认知障碍，精神病缺陷和多动症。作为当代王牌， 我们将应用有限的床上用品和筑巢（LBN）骨折的护理范式，与几个相关 类似的表型结果。我们假设这两个ACE将对 分子和行为结果。对这些研究的补充，我们将研究以下假设。 表观遗传信息的变化是慢性不良儿童时期的重要物理组成部分 暴露会在以后的生活中表现出后果。该项目以研究糖皮质激素的兴趣为基础 背部海马的受体（GR）表达和调节 - 特定基因表达是否改变 尚未确定诱导特定的结构和功能变化。我们希望确定独特的 并在功能上值得注意的表观遗传学“签名”与这些表型特征有关 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鲁棒表型 将实现未来的研究，其中特定表观遗传信息的功能意义可以是 通过表观遗传编辑进行了研究。因此，本探索性建议中收集的数据将形成 研究表观遗传学与ACE诱导的行为表型之间的因果关系的基础。