Paternal stress epigenetic programming of offspring neurodevelopment

父系应激对后代神经发育的表观遗传编程

• 批准号: 10755571
• 负责人: Tracy L Bale
• 金额: $ 42.75万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10755571
• 关键词: Paternal; stress; epigenetic; programming; offspring

Parental lifetime exposures to perturbations such as stress, infection, malnutrition, and to advanced age have been linked with an increased risk for neurodevelopmental disorders in their children. While maternal insults during pregnancy can directly impact fetal development, the mechanisms by which paternal lifelong experiences can alter germ cell programming and affect offspring neurodevelopment are not known. However, transmission of these epigenetic marks to the next generation can significantly elevate disease risk, and if programmed into the germline can affect future generations as well. Using male stress experience as a model in which we can examine mechanisms involved in offspring neurodevelopmental programming, we found that paternal stress significantly altered offspring HPA stress axis regulation and reprogrammed the hypothalamus. Mechanistically, we identified 9 specific miRNAs in the mature sperm from stressed males that contributed to the offspring phenotype. Further, we were able to completely recapitulate the offspring phenotype by microinjection of these 9 miRNAs into fertilized zygotes. Using single-cell amplification technology, we were identified a novel role for these miRNAs to significantly affect post-fertilization embryo development, providing substantial evidence that sperm miRNAs are programmable by the environment and are able to transmit this information allowing for paternally directed embryo development. Therefore, our proposal will utilize our mouse model of paternal stress to examine: 1) the mechanisms whereby stress alters paternal germ cell miRNA that affect neurodevelopment and give rise to the offspring phenotype, 2) the transgenerational transmission of stress dysregulation to a second generation programmed by paternal stress and sperm miRNAs, and 3) the mechanism within the offspring brain that promotes the paternal stress phenotype through increased BBB permeability and repressive histone epigenetic programming.

父母一生都面临压力、感染、营养不良和高龄等干扰， 与儿童神经发育障碍风险增加有关。当母亲受到侮辱时 怀孕期间可以直接影响胎儿的发育，父亲终身的机制 经验是否会改变生殖细胞编程并影响后代神经发育尚不清楚。然而， 这些表观遗传标记传递给下一代会显着增加疾病风险，如果 编程到种系中也会影响后代。以男性压力经历为模型 我们可以在其中检查涉及后代神经发育编程的机制，我们发现 父亲的压力显着改变了后代 HPA 应激轴调节并重新编程了下丘脑。 从机制上讲，我们在压力男性的成熟精子中发现了 9 个特定的 miRNA，这些 miRNA 有助于 后代表型。此外，我们能够通过以下方式完全重现后代表型： 将这 9 个 miRNA 显微注射到受精卵中。利用单细胞扩增技术，我们 确定了这些 miRNA 显着影响受精后胚胎发育的新作用，提供 大量证据表明精子 miRNA 可以通过环境进行编程并且能够传递这种信息 允许父方指导胚胎发育的信息。因此，我们的建议将使用我们的鼠标 父亲压力模型来检查：1）压力改变父亲生殖细胞 miRNA 的机制 影响神经发育并产生后代表型，2）跨代传递 由父系压力和精子 miRNA 编程的第二代应激失调，以及 3) 子代大脑内通过增加血脑屏障促进父亲应激表型的机制 通透性和抑制性组蛋白表观遗传编程。