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.

母亲一生都面临压力、感染、营养不良和高龄等干扰， 与后代疾病风险增加有关，包括与神经精神疾病密切相关 失调。虽然怀孕期间母亲的侮辱会直接影响胎儿的发育，但其机制是 哪些终生经历可以改变生殖细胞编程并影响后代神经发育？ 已知。令人惊讶的是，很少有动物模型被开发出来来检查编程机制 先入为主的干扰。在这项提案中，我们利用了母亲孕前压力的小鼠模型 （MPS）其中女性（而非男性）后代表现出较高的应激敏感性，以检查性别 有助于神经发育编程的特定机制。基于我们激动人心的已发表和 根据初步数据，我们假设 MPS 会导致卵母细胞储存的母体 mRNA 发生变化，这些 mRNA 会相互作用 在囊胚和胎盘发育过程中，对发育中的下丘脑进行性别特异性变化。 我们的假设将在本提案中得到检验，并在 3 个不同的机制层面进行检验：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反式 胎盘向发育中的大脑发出信号，从性染色体开始。我们的研究和其他人已经 鉴定出 X 连锁基因在女性胎盘中表达水平较高。通过全基因组 在母体应激后的筛查中，我们发现 X 连锁基因 OGT 是性别编程的因果因素。 特定的应激表型。胎盘 OGT 已做好应对环境变化的准备 对发育中的胚胎很重要，最终作为下丘脑的性别特异性调节剂 发展。因此，我们的建议将侧重于定义有助于 MPS 编程的机制 检查：1) 卵母细胞：识别因受孕前反应而发生的持久分子变化 受精时存在的应激及其繁殖雌性后代表型的必要性，2) 胎盘：确定女性受孕前应激的性别特异性机制 后代表型侧重于胎盘的贡献，3) 下丘脑：确定性别特异性 母亲孕前压力后下丘脑的编程发生变化，及其作为 女性神经精神疾病风险的潜在因素。