Preconception Stress Effects on Oogenesis

摘要 怀孕前的母亲压力与不利的代谢和神经发育有关 对孩子的影响。我们发展的环境为我们一生的身心发展奠定了基础 健康。在整个发育过程中，快速的生长和系统的可塑性使器官系统对 可赋予适应性优势或持久脆弱性的环境因素的影响。确实有 在我们对母体应激的机制的理解上存在根本性的差距 儿童时期遭遇逆境的风险增加的先入期。母体压力可能产生的特定影响 涉及胎儿和母体因素之间的复杂相互作用，表观遗传修饰肯定会成为特征 尤其是在这些过程中。这一建议的中心假设是母体应激在 未孕期将通过皮质醇的改变改变卵泡内的分子环境 水平、新陈代谢和基因表达，最终影响卵母细胞和胚胎的质量 大体上和通过DNA甲基化涉及影响终身健康和 子孙后代健康。由于这些研究不能在人类身上进行，而且啮齿动物模型缺乏 复杂性为了回答这些问题，我们将利用一个非人类灵长类动物模型。恒河猴的使用 为研究卵泡发生提供了精确的压力干预和完善的方法，这些方法具有 已被证实可用于发展规划研究。我们将描述先入为主的影响 应激对卵母细胞质量的影响；卵泡内皮质醇、代谢标志物和基因表达 以及由此产生的卵母细胞和胚胎中的DNA甲基化。采用独特的纵向设计，我们 将在自然和人工刺激的循环中检查这些变化，并使用尖端技术 这将允许对单个卵泡内的材料进行评估，以检验我们的假设。这项工作是 可能会使该领域朝着确定可修改的根本原因和介体的目标方向发展 通过母体应激促进预想发展规划，并为 预防策略

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