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

基本信息

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
项目类别：
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

项目摘要

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，会严重影响多氯联苯 (PCB) 是一个成熟的家族，与不良生殖后果有关。 EDC 在工业应用中使用了数十年，虽然几十年前就已被禁止，但人类仍会接触 PCB。如今，人类和动物体内的多氯联苯含量主要通过食物链传播。然而，这方面的知识存在一些重要的空白。首先，PCBs 会干扰下丘脑-垂体-性腺 (HPG) 轴的各个层面。其次，在单独评估时，尚未探索这些级别之间的相互影响。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，第三，绝大多数表型分析都是在 EDC 暴露后进行的。然而，在一个生命阶段，通常是在成人阶段，生殖系统会经历巨大的动态变化。在整个结构和功能生命周期中，强调需要采用生命周期方法进行表型分析。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，如果这会导致体细胞效应，在这个提案中，我们将开发和利用一种新颖的方法。孕前接触多氯联苯的代际模型我们将喂养怀孕的斯普拉格-道利大鼠。（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当 F1 幼崽处于 P1-21 时，F1 胎儿的性腺中的标记被擦除；当生殖细胞表观遗传标记重新建立时，F1 雌性与未经治疗的雄性大鼠交配。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、青春期和成人的生理结果、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）此外，我们将使用一种新方法来分离原始生殖细胞（PGC）。 PCB 和媒介物谱系的新生 F1 和 F2 雌性大鼠，以量化基因表达和甲基化这使我们能够将 HPG 表型与先前的生殖细胞编程联系起来。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。