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)：翻译科学和具体的挑战主题，15-ES-101*：环境暴露对使用非人类模型的表型结果的影响。这项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、生育力受损和与激素相关的疾病状态。发育中的生物体，特别是胎儿和婴儿，特别容易受到内分泌干扰的影响。在这些早期生命阶段，荷尔蒙负责下丘脑的正常发育，下丘脑是调节内分泌和荷尔蒙系统的大脑区域，负责控制成人的生殖生理和行为。环境内皮细胞对这些系统的破坏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年表型受损。我们认为，多氯联苯(PCBS)等EDCs可以通过作用于下丘脑中类固醇激素受体基因和蛋白的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)。这项拟议的研究试图了解胎儿暴露于多氯联苯会导致下丘脑基因表达的永久性印记变化，从而导致成人功能障碍的机制。我们还将调查这些影响是如何传递给后代的。我们在胎儿暴露(F1)代的目标是测量多氯联苯和对照组动物下丘脑中类固醇激素受体基因表达的影响(目标1)；并通过DNA甲基化和组蛋白修饰的分析，探索和确定多氯联苯如何导致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)。总体而言，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紊乱的机械性洞察，成年发育紊乱表型的潜在表现，以及这一特征如何传递给后代。 公共卫生相关性：关于内分泌干扰的拟议研究与人类高度相关。对于目前的提案所选择的EDC，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类都有可检测到的多氯联苯的身体负担。因此，在大鼠模型中了解多氯联苯的跨代表观遗传效应可以为人类的公共政策、预防和医学干预提供信息。

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.