Preconception Stress Effects on Oogenesis

摘要 怀孕前的母亲压力与不良的代谢和神经发育有关 孩子的结果。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生长因子敏感。 可赋予适应优势或持久脆弱性的环境因素的影响。有 我们对母亲在怀孕期间承受压力的机制的理解存在根本性的差距。 孕前时期，儿童期逆境的风险增加。可能是母亲压力的具体影响 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 在这些过程中，这一建议的核心假设是，母亲的压力，在 孕前期将通过皮质醇的改变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， 严重和通过DNA甲基化，涉及影响终身健康的关键途径， 子孙的幸福。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 为了回答这些问题，我们将利用非人类灵长类动物模型。使用恒河猴 为研究卵泡发生提供了精确的压力干预和完善的方法， 已经被验证用于发展规划的研究。我们将描述先入为主的影响 压力对卵母细胞质量;皮质醇，代谢标志物和基因表达在卵巢卵泡微 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， 将研究自然和人工刺激周期中的这些变化，并采用尖端技术 这将允许对单个卵泡内的物质进行评估，以验证我们的假设。这项工作是 有可能使该领域朝着确定可改变的根源和调解人的目标迈进， 通过产妇压力促进孕前发展规划，并提出目标， 预防战略

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