Functional and epigenetic effects of preconceptional EDCs on the female HPG axis

孕前 EDC 对女性 HPG 轴的功能和表观遗传影响

• 批准号: 9910877
• 负责人: ANDREA C GORE
• 金额: $ 7.97万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9910877
• 关键词: Address; Adult; Affect; Age; Animals; Body Burden; Breeding; Chemical Exposure; Competence; Consumption; DNA Methylation; Development; Diet; Endocrine; Endocrine Disruptors; Environmental Health; Epigenetic Process; Exposure to; Family; Female; Fetus; Food Chain; Functional disorder; Gene Expression; Gene Proteins; Generations; Genes; Germ Cells; Gonadal structure; Heritability; Human; Hypothalamic structure; Ice; Individual; Industrialization; Infant; Intervention; Knowledge; Lactation; Lead; Life; Life Cycle Stages; Link; Mammals; Methods; Methylation; Modeling; Modification; Molecular; Morphology; Neonatal; Newborn Animals; Newborn Infant; Outcome; Ovarian; Ovary; Phenotype; Physiological; Physiology; Pituitary Gland; Polychlorinated Biphenyls; Pregnancy; Rattus; Regulation; Reproductive Health; Reproductive system; Research; Role; Soil; Sprague-Dawley Rats; Structure; Structure of primordial sex cell; System; Tissues; Water; Woman; Work; climate change; critical developmental period; design; environmental chemical; epigenetic profiling; epigenome; exposed human population; functional outcomes; histone methylation; hypothalamic pituitary gonadal axis; hypothalamic pituitary ovarian axis; insight; intergenerational; lactation period; male; novel; offspring; pregnant; pup; reproductive; reproductive toxicity

ABSTRACT Exposures to environmental endocrine-disrupting chemicals (EDCs), especially during early life, are strongly linked to adverse reproductive outcomes. Polychlorinated biphenyls (PCBs) are a well-established family of EDCs, used for decades in industrial applications. While banned decades ago, humans are exposed to PCBs today primarily through the food chain. In both humans and animals, higher PCB body burdens are associated with endocrine and reproductive dysfunctions. However, there are several important gaps in knowledge in this field that we propose to fill. First, while PCBs perturb each level of the hypothalamic-pituitary-gonadal (HPG) axis when assessed individually, the cross-talk among these levels has not been explored. Second, while early development (fetus, infant) is recognized as a period of vulnerability to EDCs, the preconceptional period is another critical window that has not been studied for PCB actions on HPG systems, especially in females, something we propose to redress. Third, the vast majority of phenotyping following EDC exposures is conducted at a single life stage, typically in the adult. Yet, the reproductive system undergoes enormous dynamic change in structure and function throughout life, underscoring the need for a lifecycle approach to phenotyping. The fourth and perhaps largest gap is whether and how preconceptional exposures reprogram the germline epigenome, and if that leads to somatic effects. In this proposal, we will develop and utilize a novel intergenerational model of preconceptional exposure to PCBs. We will feed pregnant Sprague-Dawley rat dams (F0 grandmothers) human-relevant levels of a PCB mixture, or vehicle, from E8-18, when germ cell epigenetic marks are being erased in the gonads of the F1 fetuses; and/or during lactation when F1 pups are P1-21 and when germ cell epigenetic marks are re-established. The F1 females are bred with untreated male rats to generate the F2 generation. The F2 female offspring (grandchildren) will be phenotyped at 3 reproductive life stages: neonatal, pubertal, and adult. Physiological outcomes, expression of key HPG genes and proteins involved in the control of reproductive competence, and underlying molecular epigenetic marks (DNA and histone methylation) will be assessed. In addition, we will use a novel method to isolate primordial germ cells (PGCs) of newborn F1 and F2 females rats of the PCB and vehicle lineage, to quantify gene expression and methylation marks. This allows us to relate HPG phenotypes to prior germ cell programming. Thus, this proposal is anticipated to provide novel insights into the effects of preconceptional PCB exposures on female HPG physiology, function, and underlying epigenetic mechanisms of regulation, results of which are directly relevant to women’s environmental health.

抽象的 对环境内分泌化学物质（EDC）的暴露，尤其是在早期生命中，很强 与不良生殖结果有关。多氯联苯（PCB）是一个完善的家族 EDCS，用于工业应用数十年。几十年前被禁止，人类暴露于PCB 今天，主要通过食物链。在人类和动物中，较高的PCB身体燃烧是相关的 内分泌和生殖功能障碍。但是，知识中有几个重要差距 我们建议填充的字段。首先，PCB扰动下丘脑 - 垂体 - 基达尔（HPG）轴的每个级别 当单独评估时，尚未探索这些级别之间的串扰。第二，早点 发育（胎儿，婴儿）被认为是EDC的脆弱时期 尚未研究HPG系统的PCB操作的另一个关键窗口，尤其是在女性中， 我们建议补救的事情。第三，进行EDC暴露后的绝大多数表型 在一个生命阶段，通常在成年人中。然而，生殖系统经历了巨大的动态变化 在整个生命的结构和功能中，强调了对表型生命周期方法的需求。这 第四，也许最大的差距是，是否以及如何看前暴露重新编程了种系 表观基因组，如果导致躯体作用。在此提案中，我们将开发和利用小说 对PCB的预感暴露的代际模型。我们将喂养怀孕的sprague-dawley大鼠大坝 （F0祖母）当生殖细胞表观遗传学 在F1胎儿的性腺中删除了痕迹；和/或哺乳期F1幼崽为P1-21时 重新建立生殖细胞表观遗传标记时。 F1女性育种未经处理的雄性大鼠 生成F2代。 F2女子后代（孙子）将在3种生殖生活中表现出来 阶段：新生儿，青春期和成人。生理结果，关键HPG基因和蛋白质的表达 涉及控制生殖能力和潜在的分子表观遗传标记（DNA和组蛋白 将评估甲基化）。此外，我们将使用一种新颖的方法来分离原始生殖细胞（PGC） 新生儿F1和F2雌性大鼠PCB和媒介物谱系，以量化基因表达和甲基化 标记。这使我们能够将HPG表型与先前的生殖细胞编程联系起来。那是 预计会提供对孕前PCB暴露对女性HPG的影响的新见解 调节的生理学，功能和潜在的表观遗传机制，其结果是直接相关的 妇女的环境健康。