Preconception Stress Effects on Oogenesis

孕前应激对卵子发生的影响

基本信息

批准号：
9917282
负责人：
CHARLES L CHAFFIN
金额：
$ 65.43万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9917282
关键词：
Animals Antral Attention deficit hyperactivity disorder Behavioral Cell physiology Child Child Health Complex Conceptions Consensus Couples Critical Pathways DNA Methylation Development Diabetes Mellitus Disease Embryo Embryonic Development Environment Environmental Risk Factor Epigenetic Process Estradiol Evaluation Exposure to Fertility Fertilization Fertilization in Vitro Fetal Development Follicular Fluid Foundations Future Gene Expression Genes Glucose Glycolysis Goals Health Health behavior Hormones Human Hydrocortisone Hypertension Immune Impairment Individual Intervention Life Style Macaca mulatta Measurable Mediator of activation protein Medical Mental Health Metabolic Metabolic Marker Metabolism Methods Methylation Modeling Modification Molecular Molecular Analysis Mus Neurologic Neurosecretory Systems Obesity Oocytes Oogenesis Outcome Ovarian Ovarian Follicle Phase Physiological Plant Roots Pregnancy Prevention Prevention strategy Process Production Psychosocial Stress Recommendation Reporting Reproducibility Research Research Design Retrieval Risk Rodent Model Role Sampling Stress System Technology Testing Time Tissues Translating Up-Regulation Woman Work autism spectrum disorder blastocyst body system childhood adversity critical period discrete time embryo quality experience fatty acid oxidation fetal folliculogenesis genome wide methylation glucose metabolism granulosa cell hypothalamic-pituitary-adrenal axis innovation longitudinal design maternal stress methylation pattern methylome nonhuman primate offspring oocyte maturation oocyte quality physical conditioning psychologic rapid growth response

项目摘要

ABSTRACT Maternal stress prior to conception has been associated with adverse metabolic and neurodevelopmental outcomes in the child. The milieu in which we develop lays the foundation for a lifetime of physical and mental health. Throughout development, rapid growth and system plasticity render organ systems sensitive to the effects of environmental factors that can confer adaptive advantages or lasting vulnerability. There are fundamental gaps in our understanding of the mechanisms that connect maternal stress during the preconception period with enhanced risk for childhood adversity. Specific effects of maternal stress likely involve a complex interaction between fetal and maternal factors, and epigenetic modification is sure to feature prominently in these processes. The central hypothesis of this proposal is that maternal stress during the preconception period will alter the intrafollicular molecular environment through alterations in cortisol levels, metabolism, and gene expression, with ultimate impacts on oocyte and embryo quality both grossly and through DNA methylation involving critical pathways that influence lifelong health and wellness in offspring. As these studies cannot be performed in humans and because rodent models lack the complexity to answer these questions, we will utilize a nonhuman primate model. Use of the rhesus macaque affords precision with a stress intervention and well-honed methods for the study of folliculogenesis that have been validated for the study of developmental programming. We will characterize the effects of preconception stress on oocyte quality; cortisol, metabolic markers and gene expression in the ovarian follicular micro- environment; and DNA methylation in the resulting oocyte and embryo. Using a unique longitudinal design, we will examine these changes in natural and artificially-stimulated cycles and employ cutting edge technology that will allow for evaluation of materials within individual ovarian follicles to test our hypotheses. This work is likely to move the field measurably towards the goal of identifying modifiable root causes and mediators that contribute to preconception developmental programming through maternal stress and suggesting targets for prevention strategies

抽象的受孕之前的孕产妇压力与不良代谢和神经发育有关孩子的结果。我们开发的环境为一生的身心奠定了基础健康。在整个开发中，快速生长和系统可塑性使器官系统对可以赋予适应性优势或持久脆弱性的环境因素的影响。有我们对在孕产妇压力中的机制的理解中的基本差距先入为主时期，童年逆境风险增加。孕产妇压力的特定影响可能涉及胎儿和母体因素之间的复杂相互作用，并且表观遗传修饰肯定具有特征在这些过程中显着。该提议的核心假设是先选期会通过改变皮质醇的变化来改变流体内分子环境水平，代谢和基因表达，对卵母细胞和胚胎质量产生最终影响严重并通过DNA甲基化，涉及影响终身健康和的关键途径后代健康。由于这些研究不能在人类中进行，并且由于啮齿动物模型缺乏回答这些问题的复杂性，我们将利用非人类的灵长类动物模型。豪华猕猴的使用通过应力干预和良好的方法提供精确的研究，以研究卵泡发生已被验证用于研究发展节目。我们将表征先入之见的影响压力卵母细胞质量；卵巢卵泡微微体中的皮质醇，代谢标记和基因表达环境;以及所得的卵母细胞和胚胎中的DNA甲基化。使用独特的纵向设计，我们将检查自然和人为刺激周期的这些变化，并采用尖端技术这将允许评估各个卵巢卵泡中的材料来检验我们的假设。这项工作是可能会以衡量可修改的根本原因和调解人的目标来衡量地将现场移动通过孕产妇的压力为孕前的发展编程做出贡献，并提出目标的目标预防策略