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: 7815355
• 负责人: ANDREA C GORE
• 金额: $ 39.58万
• 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 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7815355
• 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）：此申请应解决广泛的挑战领域（15）：转化科学和特定挑战主题，15- ES-101*：环境暴露对使用非人类模型的表型结果的影响。该研究建议的总体目的是研究内分泌破坏化学物质（EDC）对神经内分泌功能的跨代，表观遗传作用。环境EDC暴露会导致生殖发育，生育不良和荷尔蒙相关疾病状态的永久性功能障碍。发展中的生物，尤其是胎儿和婴儿，特别容易受到内分泌干扰的影响。在这些早期生命周期中，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对这些系统的破坏会干扰这些过程的获取和维护，从而导致异常的神经内分泌发展和受损的成人表型。我们提出，诸如多氯联苯（PCB）之类的EDC可以通过对下丘脑中类固醇激素受体基因和蛋白质表达的作用来影响胎儿暴露（F1）个体的这些变化。另外，效应可以通过转世，表观遗传机制传播到子孙后代（F2，F3）。拟议的研究试图理解胎儿暴露于PCB的机制，导致下丘脑中基因表达的永久性变化导致成人功能障碍。我们还将研究这些效果如何传输到后代。我们在胎儿暴露（F1）的生成中的目标是测量基因在PCB下丘脑和对照动物下丘脑中基因表达的影响（AIM 1）；并通过分析DNA甲基化和组蛋白修饰来探索和确定PCB如何引起对这些基因的表观遗传修饰（AIM 2）。然后，将在F1，F2和F3代的大鼠中进行比较，以确定跨代，表观遗传效应的表现并确定传播机制（AIM 3）。总体而言，这些实验旨在提供机械洞察力，以了解在关键发育生命阶段下丘脑功能的内分泌破坏，破坏成人表型的潜在表现以及将这种性状传播到随后的一代。 公共卫生相关性：拟议的有关内分泌干扰的研究与人类高度相关。为当前提案选择的EDC，PCB是一个持续且持续的问题，因为几乎所有活人都有可检测到的PCB的身体负担。因此，了解大鼠模型中PCB的跨代表观遗传效应可以提供有关人类公共政策，预防和医疗干预措施的信息。