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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

基本信息

批准号：
10656492
负责人：
Tracy L Bale
金额：
$ 68.91万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
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/10656492
关键词：
Adolescence Adolescent Adverse event Affect Behavioral Biology Brain Cell Culture System Cell Nucleus Cells Child Chronic stress Communities Development Elderly Electrophysiology (science)Embryo Embryo Transfer Embryonic Development Environment Epididymis Epigenetic Process Epithelial Cells Exposure to Extracellular Matrix Fertilization Fetal Development Fiber Functional disorder Future Generations Generations Germ Cells Glucocorticoid Receptor Glutamates Hearing Histones Home Human Hypothalamic dysfunction Hypothalamic structure In Vitro Infection Intracytoplasmic Sperm Injections Link Malnutrition MicroRNAs Microinjections Mitochondria Modeling Mus Neurodevelopmental Disorder Neurons Oocytes Outcome Performance Phenotype Photometry Pregnancy Proteins Reaction Time Recovery Regulation Reproductive Techniques Research Risk Role Signal Transduction Slice Smell Perception Social isolation Specificity Stress Structural Protein Technology Testing Transfer RNA Transgenic Mice allostasis assisted reproduction blood-brain barrier permeabilization disorder risk executive function experience extracellular vesicles fetal gamma-Aminobutyric Acid gene environment interaction in vivo insight intergenerational juvenile animal male mouse model neurodevelopment neuropsychiatric disorder next generation novel offspring piRNA reproductive tract response sperm cell stress reactivity synaptic function tool transcriptome transmission process zygote

项目摘要

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。

项目成果

期刊论文数量（29）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Germ Cell Drivers: Transmission of Preconception Stress Across Generations.

DOI：
10.3389/fnhum.2021.642762
发表时间：
2021
期刊：
Frontiers in human neuroscience
影响因子：
2.9
作者：
Duffy KA;Bale TL;Epperson CN
通讯作者：
Epperson CN

Repeated sampling facilitates within- and between-subject modeling of the human sperm transcriptome to identify dynamic and stress-responsive sncRNAs.

DOI：
10.1038/s41598-020-73867-7
发表时间：
2020-10-15
期刊：
Scientific reports
影响因子：
4.6
作者：
Morgan CP;Shetty AC;Chan JC;Berger DS;Ament SA;Epperson CN;Bale TL
通讯作者：
Bale TL

Paternal stress exposure alters sperm microRNA content and reprograms offspring HPA stress axis regulation.

DOI：
10.1523/jneurosci.0914-13.2013
发表时间：
2013-05-22
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Rodgers AB;Morgan CP;Bronson SL;Revello S;Bale TL
通讯作者：
Bale TL

Parental Advisory: Maternal and Paternal Stress Can Impact Offspring Neurodevelopment.