Maternal exposures modify offspring allergic airway disease risk via epigenetic reprogramming

项目摘要 哮喘是美国和全球儿童中最常见的慢性疾病，其患病率为 增加。子宫内暴露已被证明会改变后代哮喘的风险，但控制哮喘的机制 这种影响尚不清楚。令人信服的数据表明，胎儿肺的结构和功能可能 母亲的暴露会改变，因此在出生前易患哮喘。我们之前的工作 表明产前暴露于屋尘螨（HDM）提取物，一种普遍存在的室内过敏原， 在没有二次暴露的情况下，小鼠后代的肺反应性。在产前暴露的后代中， 随后在成年期暴露，气道反应性进一步增加。这些变化伴随着 肺中DNA甲基化的基因组范围和基因特异性变化，这意味着表观遗传改变 可能在这一现象中发挥了作用。本研究的目的是探讨产妇的影响， 在整个发育过程中对后代肺部健康的影响。我们假设母体过敏原 暴露改变了胎儿甲基化，导致胎儿肺生长和发育失调， 导致在以后的生活中气道高反应性增加， 富含甲基供体的饮食可改变母体变应原暴露对后代的影响。这 这一现象将通过两个具体目标进行研究。具体目标1：审查产妇死亡率的影响 屋尘螨和/或富甲基食物暴露对肺功能和肺表观遗传标记影响 从胎儿肺到成人肺的生长、发育和防御。此外，我们假设， 母体暴露对胎儿的影响是通过胎盘介导的，因此胎盘失调 母体暴露引起的辐射可导致胎儿生长和功能改变。为了研究这个问题，我们建议 具体目标2：研究母体/胎儿界面对胎儿表观遗传调控的影响， 胎儿肺部发育。我们将研究母体屋尘螨暴露对 母体氧化应激、炎症和胎盘功能。这些目标的完成将使我们了解 了解母体暴露如何改变后代哮喘风险，包括过敏原暴露是否直接针对 并通过改变胎盘功能改变肺发育和/或间接影响后代哮喘风险。

PROJECT SUMMARY Asthma is the most common chronic disease among children in the US and globally, and its prevalence is increasing. In utero exposures have been shown to alter offspring asthma risk, but the mechanisms governing this effect are unclear. Compelling data has demonstrated that the structure and function of the fetal lung may be altered by maternal exposures and thus predisposed to asthma before birth. Our previous work has demonstrated that prenatal exposure to house dust mite (HDM) extract, a ubiquitous indoor allergen, increases offspring lung reactivity in the absence of a secondary exposure in mice. In offspring exposed prenatally and then later exposed in adulthood, airway reactivity was further increased. These changes were accompanied by genome wide and gene-specific changes in DNA methylation in the lung, implying that epigenetic alterations may play a role in this phenomenon. The objective of this research is to investigate the effects of maternal exposures on offspring lung health throughout development. We hypothesize that maternal allergen exposure alters the fetal methylome, leading to dysregulated fetal lung growth and development, resulting in increased airway hyperresponsiveness in later life, and that concurrent exposure with a methyl donor enriched diet may alter the effect of maternal allergen exposure on offspring. This phenomenon will be investigated via two specific aims. Specific aim 1: examine the effects of maternal house dust mite and/or methyl-enriched diet exposure on lung function and epigenetic markers of lung growth, development, and defense from the fetal lung to the adult lung. Additionally, we hypothesize that the effects of maternal exposures on the fetus are mediated by the placenta, thus placental dysregulation induced by maternal exposures can result in altered fetal growth and function. To investigate this, we propose Specific aim 2: investigate the influence of the maternal/fetal interface on fetal epigenetic regulation of fetal lung development in offspring. We will examine the effect of maternal house dust mite exposure on maternal oxidative stress, inflammation, and placental function. The completion of these aims will offer insight into how maternal exposures alter offspring asthma risk, including whether allergen exposure directly target and modify lung development, and/or indirectly affect offspring asthma risk by altering placenta functions.