Preconception Stress Effects on Oogenesis

孕前应激对卵子发生的影响

基本信息

批准号：
10414873
负责人：
CHARLES L CHAFFIN
金额：
$ 62.16万
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/10414873
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

抽象的受孕前的母亲压力与不良代谢和神经发育有关对孩子的影响。我们成长的环境为我们一生的身心健康奠定了基础健康。在整个发育过程中，快速生长和系统可塑性使器官系统对环境因素的影响可以赋予适应性优势或持久的脆弱性。有我们对孕期期间孕产妇压力相关机制的理解存在根本差距儿童逆境风险增加的孕前期。母亲压力可能产生的具体影响涉及胎儿和母体因素之间复杂的相互作用，表观遗传修饰肯定会发挥作用在这些过程中表现突出。该提案的中心假设是，怀孕期间母亲的压力孕前期将通过皮质醇的改变来改变卵泡内的分子环境水平、代谢和基因表达，最终影响卵母细胞和胚胎质量总体上并通过 DNA 甲基化涉及影响终生健康和后代的健康。由于这些研究无法在人类身上进行，并且啮齿动物模型缺乏为了回答这些问题的复杂性，我们将利用非人类灵长类动物模型。恒河猴的用途通过压力干预和完善的方法来研究卵泡发生提供了精确度已被验证用于发展规划的研究。我们将描述先入为主的影响对卵母细胞质量的压力；皮质醇、代谢标志物和卵巢卵泡微基因表达环境;以及所得卵母细胞和胚胎中的 DNA 甲基化。采用独特的纵向设计，我们将检查自然和人工刺激循环中的这些变化并采用尖端技术这将允许评估单个卵泡内的材料来检验我们的假设。这部作品是可能会显着推动该领域朝着确定可改变的根本原因和调解因素的目标迈进通过产妇压力促进孕前发展规划并提出目标预防策略