Epigenetic links from oocyte to postnatal health

描述(由申请人提供)：卵母细胞和植入前胚胎对环境非常敏感，即使是微小的改变也会对成年人的健康造成重大影响(例如。植入前母亲低蛋白饮食导致的成人高血压)。了解卵母细胞/早期胚胎环境中微小的、短暂的变化如何能够产生如此长期、持久和严重的影响，对于改善人类健康至关重要。这一建议基于三个中心假设：(1)为了使卵母细胞/早期胚胎的瞬时处理对成体表型产生长期影响，必须出现可遗传的、稳定的、表观遗传的改变，以改变基因的表达、发育和生理~(2)因为这些改变是卵母细胞/早期胚胎暴露的结果，并且持续存在，它们应该存在于成人身体的所有细胞和组织中，并可能影响一系列特征。(3)由于胎盘功能是出生后表型的关键，胎盘也会发生表观遗传学变化，影响其功能，进而影响出生后健康。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、它们受影响的基因和它们受影响的过程。显微手术的卵母细胞操作和胚胎培养液的操作一起提供了一个独特的系统来完成这项工作。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。此外，通过改变培养液中丙酮酸和乳酸的含量来改变受精卵的氧化还原状态(ZRs)10h可以导致短暂或持久的出生后生长效应。综上所述，这些结果确立了iGVT和ZRS操作是一种理想的方法，可以结合起来研究表观遗传变化的起源和性质，这些表观遗传变化是由于早期对卵母细胞和受精卵的影响而引起的异常胎儿、出生后和成年表型的基础，并测试这种影响是否可以预防。我们的目标是确定卵母细胞(IGVT)和胚胎(改变的ZRs)扰动在改变出生后生长方面的机制联系，识别表观遗传变化的性质、时间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的表观遗传效应和其他影响后代生长的变量重叠。

DESCRIPTION (provided by applicant): 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 brod 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.