Transgenerational epigenetic effects of PCBs on neuroendocrine systems

PCBs对神经内分泌系统的跨代表观遗传效应

• 批准号: 7941807
• 负责人: ANDREA C GORE
• 金额: $ 44.18万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-28 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7941807
• 关键词: Address; Adult; Animals; Area; Behavior; Biological Assay; Body Burden; Brain region; Budgets; Chemical Exposure; Control Animal; DNA Methylation; Development; Disease; Endocrine; Endocrine Disruptors; Endocrine disruption; Endocrine system; Environmental Exposure; Epigenetic Process; Equipment; Experimental Models; Exposure to; Female; Fertility; Fetus; Functional disorder; Future Generations; Gene Expression; Gene Proteins; Generations; Genes; Goals; Harvest; Health; Hormones; Human; Human Resources; Hypothalamic structure; Impairment; Individual; Infant; Intervention; Laboratories; Life; Maintenance; Measures; Medical; Modeling; Modification; Molecular Biology; Neurosecretory Systems; Organism; Outcome; Perinatal Exposure; Phenotype; Physiology; Play; Polychlorinated Biphenyls; Prevention; Preventive Intervention; Procedures; Process; Public Policy; Publications; Publishing; Radioimmunoassay; Rattus; Receptor Gene; Reproduction; Reproductive Physiology; Research; Research Proposals; Role; Sampling; Serum; Staging; Students; System; Testing; Time; Translational Research; Work; brain tissue; design; exposed human population; fetal; fetal polychlorinated biphenyl exposure; histone modification; imprint; insight; male; offspring; pregnant; protein expression; public health relevance; reproductive; reproductive development; research study; statistics; steroid hormone receptor; trait; transmission process

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (15): Translational Science and specific Challenge Topic, 15- ES-101*: Effects of Environmental Exposures on Phenotypic Outcomes Using Non-human Models. The overall goal of this research proposal is to study transgenerational, epigenetic effects of endocrine- disrupting chemicals (EDCs) on neuroendocrine function. Environmental EDC exposures can result in permanent dysfunctions in reproductive development, impaired fertility, and hormonally-related disease states. Developing organisms, particularly fetuses and infants, are especially vulnerable to endocrine disruption. During these early life periods, hormones are responsible for normal development of the hypothalamus, the brain region that regulates endocrine and hormonal systems and is responsible for the control of adult reproductive physiology and behavior. Disruptions of these systems by environmental EDCs can interfere with the acquisition and maintenance of these processes, resulting in aberrant neuroendocrine development and a compromised adult phenotype. We propose that EDCs such as polychlorinated biphenyls (PCBs) can effect these changes in the fetally exposed (F1) individuals through actions on steroid hormone receptor gene and protein expression in the hypothalamus. Additionally, effects may be transmitted to future generations (F2, F3) through transgenerational, epigenetic mechanisms. The proposed studies seek to understand the mechanisms by which fetal exposures to PCBs cause permanent imprinting changes on gene expression in the hypothalamus to cause adult dysfunction. We will also investigate how these effects are transmitted to subsequent generations. Our goals in the fetally-exposed (F1) generation are to measure effects of expression of genes for steroid hormone receptors in the hypothalamus of PCB vs. control animals (Aim 1); and to explore and identify how PCBs may cause epigenetic modifications to these genes through analyses of DNA methylation and histone modifications (Aim 2). Then, comparisons will be made among the F1, F2 and F3 generations of rats to determine the manifestation of transgenerational, epigenetic effects and to ascertain the mechanism for transmission (Aim 3). As a whole, these experiments are designed to provide mechanistic insight into endocrine disruption of hypothalamic function during critical developmental life stages, the latent manifestation of a disrupted adult phenotype, and the transmission of this trait to subsequent generations. PUBLIC HEALTH RELEVANCE: The proposed studies on endocrine disruption are highly relevant to humans. The EDC chosen for the current proposal, PCBs are a persistent and continuing problem, as virtually all living humans have a detectable body burden of PCBs. Therefore, understanding the transgenerational epigenetic effects of PCBs in a rat model can provide information about public policy, prevention, and medical interventions in humans.

描述（由申请人提供）：本申请涉及广泛的挑战领域 (15)：转化科学和具体挑战主题，15-ES-101*：使用非人类模型的环境暴露对表型结果的影响。该研究计划的总体目标是研究内分泌干扰化学物质（EDC）对神经内分泌功能的跨代、表观遗传效应。环境中的 EDC 暴露可能导致生殖发育永久性功能障碍、生育能力受损以及与激素相关的疾病状态。发育中的有机体，特别是胎儿和婴儿，特别容易受到内分泌干扰。在生命的早期阶段，激素负责下丘脑的正常发育，下丘脑是调节内分泌和激素系统的大脑区域，并负责控制成人生殖生理和行为。环境 EDC 对这些系统的破坏可能会干扰这些过程的获得和维持，导致神经内分泌发育异常和成人表型受损。我们认为，多氯联苯 (PCB) 等 EDC 可以通过作用于下丘脑中的类固醇激素受体基因和蛋白质表达来影响胎儿暴露 (F1) 个体的这些变化。此外，影响可能通过跨代、表观遗传机制传递给后代（F2、F3）。拟议的研究旨在了解胎儿接触多氯联苯导致下丘脑基因表达永久性印记变化从而导致成人功能障碍的机制。我们还将研究这些影响如何传递给后代。我们在胎儿暴露 (F1) 代中的目标是测量 PCB 与对照动物下丘脑中类固醇激素受体基因表达的影响（目标 1）；通过分析 DNA 甲基化和组蛋白修饰，探索和确定 PCB 如何引起这些基因的表观遗传修饰（目标 2）。然后，将在F1、F2和F3代大鼠之间进行比较，以确定跨代、表观遗传效应的表现并确定传播机制（目标3）。总的来说，这些实验旨在提供对关键发育生命阶段下丘脑功能内分泌破坏、成年表型破坏的潜在表现以及这种性状向后代的传递的机制见解。 公共卫生相关性：拟议的内分泌干扰研究与人类高度相关。 EDC 当前提案所选择的 PCB 是一个持续存在的问题，因为几乎所有活着的人体内都有可检测到的 PCB 负荷。因此，了解多氯联苯在大鼠模型中的跨代表观遗传效应可以提供有关人类公共政策、预防和医疗干预的信息。