Transgenerational epigenetic effects of PCBs on neuroendocrine systems

描述（由申请人提供）：本申请涉及广泛的挑战领域（15）：转化科学和特定的挑战主题，15- ES-101*：环境暴露对使用非人类模型的表型结果的影响。本研究计划的总体目标是研究内分泌干扰物（EDCs）对神经内分泌功能的跨代、表观遗传效应。环境EDC暴露可导致生殖发育的永久性功能障碍、生育能力受损和生殖相关疾病状态。发育中的生物，特别是胎儿和婴儿，特别容易受到内分泌干扰。在这些生命早期，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，负责控制成年生殖生理和行为。环境内分泌干扰物对这些系统的破坏会干扰这些过程的获得和维持，导致异常的神经内分泌发育和受损的成人表型。我们认为，内分泌干扰物，如多氯联苯（PCBs）可以影响这些变化的胎儿暴露（F1）的个人通过行动类固醇激素受体基因和蛋白质的表达在下丘脑。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暴露于多氯联苯导致下丘脑基因表达永久印记变化，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（Aim 1）;并通过分析DNA甲基化和组蛋白修饰（Aim 2）探索和确定PCB如何引起这些基因的表观遗传修饰。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（目的3）。作为一个整体，这些实验的目的是提供机制的洞察下丘脑功能的内分泌干扰在关键的发育生命阶段，一个中断的成人表型的潜在表现，以及这种特性的传递给后代。 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选择为当前的提案，多氯联苯是一个持久和持续的问题，因为几乎所有活着的人都有可检测的多氯联苯的身体负担。因此，了解大鼠模型中多氯联苯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。

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.