Paternal stress epigenetic programming of offspring neurodevelopment

父母一生暴露在诸如压力、感染、营养不良和高龄等扰动中 与其子女患神经发育障碍的风险增加有关。而母性的侮辱 怀孕期间会直接影响胎儿发育，父亲终生的机制 经验可以改变生殖细胞编程，并影响后代的神经发育，目前尚不清楚。然而， 将这些表观遗传标记传递给下一代会显著增加疾病风险，如果 植入生殖系的程序也会影响后代。以男性的压力体验为榜样 我们可以研究与后代神经发育编程有关的机制，我们发现 父亲的压力显著改变了后代HPA应激轴的调节，并对下丘脑进行了重新编程。 从机制上讲，我们在应激雄性成熟精子中鉴定出9个特定的miRNAs，它们参与了 后代的表型。此外，我们能够通过以下方式完全概括后代的表型 将这9个miRNAs显微注射到受精卵中。利用单细胞扩增技术，我们 发现了这些miRNAs显著影响受精后胚胎发育的新角色，提供了 大量证据表明精子miRNAs可由环境编程并能够传播 允许父系指导胚胎发育的信息。因此，我们的提案将利用我们的鼠标 父系应激模型：1)应激改变父系生殖细胞miRNA的机制 影响神经发育并产生后代表型，2)跨代传递 由父亲应激和精子miRNAs编程的第二代应激失调，以及3) 子代大脑中通过增加血脑屏障促进父系应激表型的机制 渗透性和抑制性组蛋白表观遗传编程。

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.