Epigenetic links from oocyte to postnatal health

卵母细胞与产后健康的表观遗传联系

• 批准号: 9189638
• 负责人: Keith E Latham
• 金额: $ 31.85万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-25 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9189638
• 关键词: Adult; Affect; Age; Animal Model; Birth; Cells; Characteristics; DNA Methylation; Development; Embryo; Environment; Epigenetic Process; Exposure to; Female; Fertilization; Gene Expression; Genes; Genome; Goals; Growth; Health; Heritability; Histones; Human; Hypertension; In Vitro; Lead; Learning; Life; Link; Long-Term Effects; Maternal Health; Maternal Physiology; Minor; Mus; Nature; Neonatal; Ontology; Oocytes; Pathway Analysis; Phenotype; Physiology; Placenta; Process; Production; Protein-Restricted Diet; Publishing; Pyruvate; Reporting; Reproducibility; Stress; Surveys; System; Testing; Time; Tissues; Vesicle; analytical method; assisted reproduction; cost effective; deep sequencing; embryo culture; environmental agent; epigenome; fetal; genome-wide; human disease; improved; male; meetings; mother nutrition; postnatal; preimplantation; prevent; public health relevance; zygote

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.

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，即使是较小的改变也会对成人健康产生重大影响（例如，在植入前植入前，孕产妇低蛋白质饮食后成人高血压）。 了解卵母细胞/早期胚胎环境中的较小，短暂的变化如何具有如此长期，持久和严重的影响对于改善人类健康至关重要。 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可能会影响BROD的特征范围。 （3）由于胎盘功能是产后表型的关键，因此胎盘中也会出现表观遗传变化，以影响其功能，这反过来影响产后健康。该提案的目标是确定何时发生表观遗传变化，其稳定性，受影响的基因及其受影响的过程。微型外科卵母细胞操纵和对胚胎培养基的操纵共同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，晶体间生发囊泡转移（IGVT）导致大量雌性后代的显着生长缺乏。 此外，通过在培养基中改变丙酮酸和乳酸含量10小时的培养物中，改变二元氧化还原状态（ZRS）可以导致短暂或持续的产后生长效应。总之，这些结果将IGVT和ZRS操纵作为理想方法，可以合并，以研究表观遗传变化的起源和性质，这些变化是胎儿异常，产后和成人表型是由对卵母细胞和Zygotes的早期影响以及测试是否可以预防这种影响的早期作用而产生的。我们的目的是确定卵母细胞（IGVT）与胚胎（ZRS改变）在修饰后生长的扰动中的机械联系，以确定表观遗传变化的性质，时机和稳定性以及受影响基因的阵列的性质，时间和稳定性，并确定对人类辅助疗法的可能重叠和其他影响的培育和其他培养物的重叠。