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: 10376276
• 负责人: ANDREA C GORE
• 金额: $ 62.05万
• 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/10376276
• 关键词: Address; Adult; Affect; Age; Animals; Body Burden; Breeding; Chemical Exposure; Competence; Consumption; DNA Methylation; Development; 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; dietary; 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 outcome; 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 接触环境内分泌干扰化学物质 (EDC)，尤其是在生命早期，会严重影响 与不良生殖结果有关。多氯联苯 (PCB) 是一个成熟的家族 EDC 在工业应用中使用了数十年。尽管几十年前就被禁止，但人类仍然接触多氯联苯 今天主要通过食物链。在人类和动物中，较高的 PCB 身体负担都与之相关 患有内分泌和生殖功能障碍。然而，这方面的知识存在几个重要的空白 我们建议填写的字段。首先，虽然多氯联苯会干扰下丘脑-垂体-性腺 (HPG) 轴的各个水平 当单独评估时，这些级别之间的相互影响尚未被探索。二、趁早 发育（胎儿、婴儿）被认为是易受 EDC 影响的时期，孕前期是 另一个尚未研究 PCB 对 HPG 系统作用的关键窗口，尤其是在女性中， 我们建议纠正一些问题。第三，绝大多数 EDC 暴露后的表型分析都是在 EDC 暴露后进行的 在一个生命阶段，通常是在成人阶段。然而，生殖系统正在经历巨大的动态变化 整个生命周期的结构和功能，强调了对表型的生命周期方法的需要。这 第四个也许是最大的差距是孕前暴露是否以及如何重新编程种系 表观基因组，以及是否会导致躯体效应。在本提案中，我们将开发并利用一种新颖的 孕前接触 PCB 的代际模型。我们将喂养怀孕的斯普拉格-道利大鼠母鼠 （F0 祖母）当生殖细胞表观遗传时，来自 E8-18 的 PCB 混合物或媒介物的人类相关水平 F1 胎儿性腺中的标记正在被擦除；和/或在哺乳期间，当 F1 幼崽为 P1-21 且 当生殖细胞表观遗传标记重新建立时。 F1 雌性与未经处理的雄性大鼠交配 产生F2代。 F2 雌性后代（孙子）将在 3 个生殖寿命时进行表型分析 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 参与生殖能力的控制以及潜在的分子表观遗传标记（DNA 和组蛋白） 甲基化）将被评估。此外，我们将使用一种新方法来分离原始生殖细胞（PGC） PCB 和车辆谱系的新生 F1 和 F2 雌性大鼠，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。因此，这个提议是 预计将为孕前 PCB 暴露对女性 HPG 的影响提供新的见解 生理学、功能和潜在的表观遗传调节机制，其结果直接相关 为了妇女的环境健康。