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: 8626607
• 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/8626607
• 关键词: Adult; Affect; Age; Animal Model; Birth; Cells; Characteristics; Culture Media; DNA Methylation; Development; Embryo; Embryo Transfer; Environment; Epigenetic Process; Exposure to; Female; Fertilization; Gene Expression; Genes; Genome; Goals; Growth; Health; 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; Staging; 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

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.

卵母细胞和着床前胚胎对环境非常敏感，甚至很小