Preconception Stress Effects on Oogenesis

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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