Epigenetic links from oocyte to postnatal health

卵母细胞和植入前的胚胎对它们的环境非常敏感，甚至很小。 变化会对成年人的健康产生重大影响(例如，。母亲低蛋白血症所致的成人高血压 植入前的饮食)。了解卵母细胞/早期胚胎中微小的、短暂的变化 环境能产生如此长期、持久和严重的影响对改善人类健康至关重要。这 提出的建议基于三个中心假设：(1)为了暂时处理卵母细胞/早期 胚胎要对成体表型产生长期影响，必须发生可遗传的、稳定的、表观遗传的变化 修改基因表达、发育和生理~(2)，因为这些变化是由于 卵母细胞/早期胚胎暴露，并持续存在，它们应该存在于成人身体的所有细胞和组织中，并将 可能会影响广泛的特征。(3)由于胎盘功能是决定出生后表型的关键， 胎盘也会发生表观遗传变化，影响其功能，进而影响出生后的健康。这个 这项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 基因及其影响的过程。显微外科卵母细胞操作和胚胎培养操作 媒体共同提供了一个独特的系统来实现这一点。我们在小鼠身上观察到菌株间生发泡 转移(IGVT)导致很大一部分雌性后代明显的生长缺陷。另外， 通过改变培养基中丙酮酸和乳酸的含量来改变合子氧化还原状态(ZRs) 10h的培养可导致短暂或持久的出生后生长效应。总而言之，这些结果确立了 IGVT和ZRS手法是研究脑出血起源和本质的理想方法 由早期效应引起的异常胎儿、产后和成人表型的表观遗传学变化 对卵母细胞和受精卵的影响，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ZRs)之间的机械联系 出生发育，以确定表观遗传变化的性质、时机和稳定性以及受影响的基因阵列， 并确定可能与人类辅助生殖和其他观察到的表观遗传效应重叠 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.