Female preconception stress programming of offspring neurodevelopment

女性孕前压力编程对后代神经发育的影响

• 批准号: 9360959
• 负责人: Tracy L Bale
• 金额: $ 45.59万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9360959
• 关键词: Adult; Affect; Animal Model; Brain; Cells; Chromatin; Chronic stress; Conceptions; Data; Development; Disease; Elderly; Embryo; Embryo Transfer; Environment; Epigenetic Process; Exposure to; Female; Fertilization; Fetal Development; Genes; Genetic; Germ Cells; Histones; Hypothalamic structure; Infection; Life Experience; Link; Malnutrition; Mass Spectrum Analysis; Maternal Messenger RNA; Modeling; Molecular; Mus; N-Acetylglucosaminyltransferases; Oocytes; Outcome; Phenotype; Placenta; Placentation; Play; Population; Post-Translational Protein Processing; Predictive Factor; Pregnancy; Publishing; Regulation; Risk; Role; Sex Characteristics; Sex Chromosomes; Signal Transduction; Stress; Testing; Transcriptional Regulation; Transgenic Mice; UDP-N-acetylglucosamine-peptide beta-N-acetylglucosaminyltransferase; base; blastocyst; disorder risk; endophenotype; experience; genome-wide analysis; in utero; male; maternal stress; mouse model; neurodevelopment; neuropsychiatric disorder; novel; offspring; programs; resilience; response; sex; transcriptome sequencing; transcriptomics; transmission process; trophoblast; zygote

Maternal lifetime exposures to perturbations such as stress, infection, malnutrition, and advanced age have been linked with an increased risk for offspring disease, including a strong association with neuropsychiatric disorders. While maternal insults during pregnancy can directly impact fetal development, the mechanisms by which lifelong experiences can alter germ cell programming and affect offspring neurodevelopment are not known. Surprisingly few animal models have been developed to examine programming mechanisms of preconception perturbations. In this proposal, we utilize our mouse model of maternal preconception stress (MPS) in which female, but not male, offspring present with elevated stress sensitivity, to examine the sex- specific mechanisms contributing to neurodevelopmental programming. Based on our exciting published and preliminary data, we hypothesize that MPS imparts changes in oocyte stored maternal mRNAs that interact during blastocyst and placental development to program sex-specific changes in the developing hypothalamus. Our hypothesis will be tested in this proposal and examined at 3 distinct mechanistic levels: the oocyte, the placenta, and the hypothalamus. Sex differences in the placenta are likely to produce sex-specific trans- placental signals to the developing brain and begin with sex chromosomes. Our studies and others have identified X-linked genes that are expressed at higher levels in the female placenta. Through a genome-wide screen following maternal stress, we identified the X-linked gene, OGT, as causal in programming a sex- specific stress phenotype. Placental OGT is poised to respond to changes in the environment that are important to the developing embryo, ultimately serving as a sex-specific regulator of hypothalamic development. Therefore, our proposal will focus on defining mechanisms contributing to MPS programming examining the: 1) oocyte: To identify the lasting molecular changes that occur in response to preconception stress that are present at fertilization and their necessity for reproducing the female offspring phenotype, 2) placenta: To determine the maternal preconception stress sex-specific mechanisms involved in the female offspring phenotype focusing on the placental contribution, and 3) hypothalamus: To determine the sex-specific hypothalamic programming changes following maternal preconception stress and the role this plays as an underlying factor in female neuropsychiatric disease risk.

孕产妇终生暴露于压力，感染，营养不良和高龄等扰动 与增加后代疾病的风险增加有关，包括与神经精神病的牢固联系 疾病。虽然怀孕期间的孕产妇侮辱会直接影响胎儿发育，但这种机制是通过 哪些终身经历可以改变生殖细胞编程并影响后代神经发育不是 已知。令人惊讶的是，很少开发动物模型来检查 先选的扰动。在此提案中，我们利用了母体祖母应力的小鼠模型 （MPS）女性而非男性的后代具有升高的压力敏感性，以检查性别 有助于神经发育编程的特定机制。根据我们令人兴奋的发表和 初步数据，我们假设MPS赋予卵母细胞储存的母体mRNA的变化 在胚泡和胎盘发育过程中，下丘脑发展的性别特定变化。 我们的假设将在该提案中进行检验，并以3个不同的机械水平进行检查：卵母细胞，卵母细胞， 胎盘和下丘脑。胎盘的性别差异可能会产生性别特异性的跨性别 发育中的大脑的胎盘信号，从性别染色体开始。我们的研究和其他人有 鉴定出在雌性胎盘中以较高水平表达的X连锁基因。通过全基因组 在母体压力之后，我们确定X连锁基因OGT是在编程性别的因果关系。 特定的应力表型。胎盘OGT有望应对环境的变化 对于发展中的胚胎至关重要，最终充当下丘脑的性别特定调节剂 发展。因此，我们的建议将着重于定义有助于国会议员编程的机制 检查：1）卵母细胞：确定响应于先入的持久分子变化 施肥中存在的压力及其重现女性后代表型的必要性，2） 胎盘：确定女性涉及的母体孕前应力特异性机制 后代表型的重点是胎盘贡献，3）下丘脑：确定性别特定的 孕产妇的看法压力和这种作用作为一种，下丘脑编程的变化以及这种作用作为一种 女性神经精神疾病风险的基本因素。