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）：卵母细胞和植入前阶段的胚胎对其环境非常敏感，即使是微小的改变也会对成年人的健康产生重大影响（例如，着床前母体低蛋白饮食后的成人高血压）。 了解卵母细胞/早期胚胎环境的微小、短暂变化如何产生长期、持久和严重的影响，对于改善人类健康至关重要。 这一建议基于三个核心假设：（1）为了使卵母细胞/早期胚胎的瞬时处理对成人表型产生长期影响，必须出现可遗传的、稳定的、表观遗传的变化，这些变化改变基因表达、发育和生理学~（2）由于这些变化是卵母细胞/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，并且将可能影响广泛的特性。(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，影响其功能，进而影响产后健康。该提案的目标是确定表观遗传变化何时发生，其稳定性，受影响的基因及其受影响的过程。显微手术卵母细胞操作和胚胎培养基的操作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，品系间生发囊泡转移（iGVT）导致大部分雌性后代明显的生长缺陷。 此外，通过改变培养基中培养10小时的丙酮酸盐和乳酸盐含量来改变合子氧化还原状态（ZRS）可导致短暂或持续的出生后生长效应。总之，这些结果确立了iGVT和ZRS操作作为理想的方法，可以结合用于研究表观遗传变化的起源和性质，这些表观遗传变化是由对卵母细胞和受精卵的早期影响引起的异常胎儿，出生后和成人表型的基础，并测试这种影响是否可以预防。我们的目的是确定卵母细胞（iGVT）和胚胎（改变的ZRS）扰动在改变纳塔尔后生长方面的机制联系，以确定表观遗传变化的性质、时间和稳定性以及受影响基因的阵列，并确定与人类辅助生殖观察到的表观遗传效应和影响后代生长的其他变量可能重叠。