Epigenetic links from oocyte to postnatal health

卵母细胞和植入前阶段的胚胎对它们的环境非常敏感， 改变可导致对成人健康的显著影响（例如，母体低蛋白血症后成人高血压 在胚胎植入前的饮食）。 了解卵母细胞/早期胚胎的微小、短暂变化 环境可能具有如此长期、持久和严重的影响，这对改善人类健康至关重要。 这 该建议基于三个中心假设：（1）为了对卵母细胞/早期 胚胎对成人表型产生长期影响，必须出现可遗传的、稳定的表观遗传变化， 改变基因表达、发育和生理~（2）由于这些变化是 卵母细胞/早期胚胎暴露，并持续存在，他们应该存在于所有细胞和组织的成年人的身体，并将 可能影响广泛的特征。(3)因为胎盘功能是产后表型的关键， 胎盘也会出现表观遗传变化，影响其功能，进而影响产后健康。的 该提案的目标是确定表观遗传变化何时发生，它们的稳定性，它们的影响， 基因及其影响过程。卵母细胞显微操作与胚胎培养操作 媒体一起提供了一个独特的系统来做到这一点。 我们在小鼠中观察到， 转移（iGVT）导致大部分雌性后代的显著生长缺陷。 此外，本发明还 通过改变培养基中的丙酮酸和乳酸含量来改变合子的氧化还原状态（ZRS）， 10小时的培养可导致短暂或持续的出生后生长效应。这些结果共同确立了 iGVT和ZRS操作作为理想的方法，可以结合起来研究的起源和性质， 表观遗传学变化是由早期效应引起的异常胎儿、出生后和成人表型的基础 卵母细胞和受精卵，并测试是否可以防止这种影响。我们的目标是确定 卵母细胞（iGVT）和胚胎（改变的ZRS）扰动之间的机械联系， 纳塔尔生长，以确定性质，时间和表观遗传变化的稳定性和受影响的基因阵列， 并确定与人类辅助生殖和其他生殖系统中观察到的表观遗传效应的可能重叠， 影响后代生长的变量。

Oocytes and preimplantation stage embryos are exquisitely sensitive to their environments, and even minor alterations can lead to significant effects on adult health (e.g,. adult hypertension following maternal low-protein diet during the preimplantation period). Learning how minor, transient changes in the oocyte/early embryo environment can have such long-term, persistent, and serious effects is vital for improving human health. This proposal is founded on three central hypotheses: (1) in order for transient treatments of oocytes/early embryos to exert long-term effects on adult phenotype, heritable, stable, epigenetic changes must arise that modify gene expression, development, and physiology~ (2) Because these changes arise a result of oocyte/early embryo exposure, and persist, they should exist in all cells and tissues of the adult body, and will likely affect a broad range of characteristics. (3) Because placental function is key to post-natal phenotype, epigenetic changes also arise in the placenta to affect its function, which in turn affects post-natal health. The objectives of this proposal are to determine when epigenetic changes occur, their stability, their affected genes, and their affected processes. Microsurgical oocyte manipulation and manipulation of embryo culture medium together provide a unique system to do this. We observed in mice that inter-strain germinal vesicle transfer (iGVT) results in a pronounced growth deficiency in a large fraction of female progeny. Additionally, altering the zygotic REDOX state (ZRS) by changing the pyruvate and lactate content in the culture medium for 10 h of culture can lead to transient or persistent post-natal growth effects. Together, these results establish iGVT and ZRS manipulation as ideal approaches that can be combined for studying the origins and nature of epigenetic changes that underlie abnormal fetal, post-natal and adult phenotypes that arise from early effects on oocytes and zygotes, and testing whether such effects can be prevented. Our Aims are to determine the mechanistic connections between oocyte (iGVT) and embryo (altered ZRS) perturbations in modifying post- natal growth, to identify the nature, timing, and stability of epigenetic changes and the array of affected genes, and to determine possible overlap with epigenetic effects observed for human assisted reproduction and other variables affecting progeny growth.