Potential Role for Sperm miRNAs 34c and 449a in the Transgenerational Effects of Trauma in Men

精子 miRNA 34c 和 449a 在男性创伤跨代影响中的潜在作用

• 批准号: 10359148
• 负责人: LARRY FEIG
• 金额: $ 27.68万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10359148
• 关键词: Accounting; Adult; Affect; Animals; Anxiety; Behavior; Brain; Child; Chronic; Daughter; Development; Disease; Disease susceptibility; Early-life trauma; Embryo; Embryonic Development; Environment; Epigenetic Process; Exposure to; Family; Fathers; Female; Fertility; Fertilization; Generations; Human; Inherited; Knockout Mice; Lead; Life; Male Adolescents; Mediating; Mental Depression; Mental disorders; MicroRNAs; Modeling; Mus; Parent-Child Relations; Parents; Phenotype; Post-Traumatic Stress Disorders; Predisposition; Process; Publications; Publishing; Questionnaires; Recording of previous events; Reporting; Risk; Role; Severities; Sister; Son; Stress; Symptoms; Testing; Time; Trauma; Work; adverse childhood events; anxiety symptoms; brain abnormalities; experience; male; men; mouse model; novel; offspring; social; sperm cell; stressor; trait; transgenerational epigenetic inheritance; transmission process; trauma exposure; zygote

Project(Summary( ( Exposure to trauma when young, or as and adult, enhances one's risk for a variety of stress-associated disorders, such as anxiety/depression and/or PTSD (A/D or P). These stressors also put one's offspring at risk for a variety of psychological disorders. The majority of this effect is likely due to trauma-associated alterations in the interactions of parents with children, but a growing body of evidence in mice suggests that at least some of this effect may be due to epigenetic inheritance of the effect of trauma, mediated by stress-induced changes in the levels of specific sperm micro-RNAs (miRNAs) that influence zygote development after fertilization. Our recent publications that drive this proposal raise the possibility that this concept applies to humans. We showed that exposure of adolescent male mice to chronic social instability (CSI) stress elevates anxiety specifically in their female offspring across at least three generations, even if offspring are never exposed to their fathers. We implicated two highly related and coordinately expressed sperm miRNAs, miR-34c and miR- 449a (miRs-34c/449a) in this process. In particular, we detected large decreases in both of their levels in sperm of F0 CSI stressed male mice, early F1 embryos derived from them, and sperm of F1 male offspring that transmit these stress phenotypes specifically to their F2 female offspring. We also found a negative correlation between the levels of the same sperm miRNAs and the degree of exposure of men to abusive and/or dysfunctional family experiences, revealed by the Adverse Childhood Experience (ACE) questionnaire. These miRNAs contribute to fertility in humans and sperm and brain development in mice. That both miRNAs are reduced in sperm of stressed mice and men is of particular significance because their redundant functions require that both be suppressed in knockout mice to observe these phenotypes. Thus, Aim1 will expand our recent study by testing whether adult exposure to trauma, assessed by the Trauma History Questionnaire (THQ), also reduces the levels of these sperm miRNAs. This aim will also test whether, just as in mice, stress- induced changes in men's sperm miRNAs are transmitted to their sons, which could lead to transmission of traits across multiple generations. Aim 2 will test whether reduced levels of sperm miRs-34c/449a, like elevated ACE scores, could be associated with the degree of men's experiences with A/D or P. We will also test whether transmission of reduced levels of these miRNAs is associated with A/D or P in offspring. Since our mouse model leads to anxiety only in female offspring, we will also test sisters of men expressing low levels of sperm miR-34c/449a “inherited” from their stressed fathers for these maladies. Overall, this proposal's findings may suggest that the levels of sperm miRNA levels can be markers for men's past experiences with abuse as well as their, or their sisters', recent experiences with A/D or P. They may also add support for the idea that transgenerational epigenetic inheritance of the effects of trauma occurs in humans. !

项目（摘要） ( 在年轻时或成年后暴露于创伤，会增加一个人患各种压力相关疾病的风险。 精神障碍，例如焦虑/抑郁和/或PTSD（A/D或P）。这些压力源也会使后代处于危险之中 治疗各种心理疾病这种影响的大部分可能是由于创伤相关的改变 在父母与孩子的互动中，但越来越多的小鼠证据表明，至少有一些 这种效应可能是由于创伤效应的表观遗传，由应激诱导的变化介导的 在特定的精子micro-RNAs（miRNAs）的水平，影响受精后受精卵的发育。我们 推动这一提议的最近出版物提出了这一概念适用于人类的可能性。我们 研究表明，青春期雄性小鼠暴露在慢性社会不稳定（CSI）压力下会增加焦虑， 特别是在至少三代的雌性后代中，即使后代从未接触过 他们的父亲我们发现两种高度相关且协调表达的精子miRNAs，miR-34 c和miR-24 c， 449a（miRs-34c/449a）。特别是，我们检测到他们的水平大幅下降， F0 CSI应激雄性小鼠的精子、源自它们的早期F1胚胎和F1雄性后代的精子 将这些应激表型特异性地传递给它们的F2雌性后代。我们还发现了一个负面的 相同精子miRNAs的水平与男性暴露于虐待的程度之间的相关性 和/或功能失调的家庭经历，通过不良童年经历（ACE）问卷调查。 这些miRNAs有助于人类的生育能力以及小鼠的精子和大脑发育。这两种miRNAs 在应激小鼠和男性精子中减少，这一点特别重要，因为它们的冗余功能 需要在基因敲除小鼠中抑制两者以观察这些表型。因此，Aim 1将扩展我们的 最近的一项研究通过测试成人是否暴露于创伤，通过创伤史问卷评估 (THQ)，也降低了这些精子miRNAs的水平。这个目标也将测试，就像在老鼠身上一样，压力- 男性精子miRNAs的诱导变化被传递给他们的儿子，这可能导致 几代人的性格特征目标2将测试精子miR-34 c/449 a水平的降低是否会导致精子miR-34 c/449 a水平的降低， 升高的ACE评分可能与男性A/D或P的经历程度有关。 测试这些miRNAs水平降低的传递是否与后代的A/D或P相关。由于我们 小鼠模型只在雌性后代中导致焦虑，我们还将测试表达低水平焦虑的男性姐妹篇。 精子miR-34 c/449 a“遗传”自他们的压力父亲，以获得这些疾病。总的来说，这个提案 研究结果可能表明，精子miRNA水平可以作为男性过去经历的标志， 虐待，以及他们，或他们的姐妹，最近的经验与A/D或P。 认为创伤影响的跨代表观遗传发生在人类身上。 !