Department of Emergency Medicine, Stanford University School of Medicine, Palo Alto, California, United States.
Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Oregon Health and Science University, Portland, Oregon, United States.
Am J Physiol Lung Cell Mol Physiol. 2023 Dec 1;325(6):L776-L787. doi: 10.1152/ajplung.00103.2023. Epub 2023 Oct 10.
Asthma susceptibility is influenced by environmental, genetic, and epigenetic factors. DNA methylation is one form of epigenetic modification that regulates gene expression and is both inherited and modified by environmental exposures throughout life. Prenatal development is a particularly vulnerable time period during which exposure to maternal asthma increases asthma risk in offspring. How maternal asthma affects DNA methylation in offspring and what the consequences of differential methylation are in subsequent generations are not fully known. In this study, we tested the effects of grandmaternal house dust mite (HDM) allergen sensitization during pregnancy on airway physiology and inflammation in HDM-sensitized and challenged second-generation mice. We also tested the effects of grandmaternal HDM sensitization on tissue-specific DNA methylation in allergen-naïve and -sensitized second-generation mice. Descendants of both allergen- and vehicle-exposed grandmaternal founders exhibited airway hyperreactivity after HDM sensitization. However, grandmaternal allergen sensitization significantly potentiated airway hyperreactivity and altered the epigenomic trajectory in second-generation offspring after HDM sensitization compared with HDM-sensitized offspring from vehicle-exposed founders. As a result, biological processes and signaling pathways associated with epigenetic modifications were distinct between lineages. A targeted analysis of pathway-associated gene expression found that Smad3 was significantly dysregulated as a result of grandmaternal allergen sensitization. These data show that grandmaternal allergen exposure during pregnancy establishes a unique epigenetic trajectory that reprograms allergen responses in second-generation offspring and may contribute to asthma risk. Asthma susceptibility is influenced by environmental, genetic, and epigenetic factors. This study shows that maternal allergen exposure during pregnancy promotes unique epigenetic trajectories in second-generation offspring at baseline and in response to allergen sensitization, which is associated with the potentiation of airway hyperreactivity. These effects are one mechanism by which maternal asthma may influence the inheritance of asthma risk.
哮喘易感性受环境、遗传和表观遗传因素的影响。DNA 甲基化是一种表观遗传修饰形式，可调节基因表达，并且在整个生命周期中都受到遗传和环境暴露的影响。产前发育是一个特别脆弱的时期，在此期间，母亲哮喘的暴露会增加后代患哮喘的风险。母亲哮喘如何影响后代的 DNA 甲基化，以及差异甲基化在后代中产生的后果尚不完全清楚。在这项研究中，我们测试了怀孕期间祖母尘螨（HDM）过敏原致敏对 HDM 致敏和挑战的第二代小鼠气道生理学和炎症的影响。我们还测试了祖母 HDM 致敏对变应原-naive 和致敏的第二代小鼠组织特异性 DNA 甲基化的影响。致敏和载体暴露的祖母祖代的后代在 HDM 致敏后均表现出气道高反应性。然而，与来自载体暴露祖代的 HDM 致敏后代相比，祖母过敏原致敏显著增强了 HDM 致敏后的第二代后代的气道高反应性，并改变了其表观遗传轨迹。结果，与表观遗传修饰相关的生物过程和信号通路在谱系之间存在明显差异。对通路相关基因表达的靶向分析发现，Smad3 由于祖母过敏原致敏而显著失调。这些数据表明，怀孕期间祖母过敏原暴露会建立一个独特的表观遗传轨迹，该轨迹可重新编程第二代后代的过敏原反应，并可能导致哮喘风险。哮喘易感性受环境、遗传和表观遗传因素的影响。本研究表明，母亲在怀孕期间暴露于过敏原会在基线和对过敏原致敏时促进第二代后代的独特表观遗传轨迹，这与气道高反应性的增强有关。这些影响是母亲哮喘可能影响哮喘风险遗传的一种机制。
