Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.
Children's Hospital Research Institute of Manitoba, Winnipeg, Manitoba, Canada.
Am J Physiol Lung Cell Mol Physiol. 2023 Nov 1;325(5):L552-L567. doi: 10.1152/ajplung.00192.2023. Epub 2023 Aug 29.
Prenatal and early-life exposure to cigarette smoke (CS) has repeatedly been shown to induce stable, long-term changes in DNA methylation (DNAm) in offspring. It has been hypothesized that these changes might be functionally related to the known outcomes of prenatal and early-life CS exposure, which include impaired lung development, altered lung function, and increased risk of asthma and wheeze. However, to date, few studies have examined DNAm changes induced by prenatal CS in tissues of the lung, and even fewer have attempted to examine the specific influences of prenatal versus early postnatal exposures. Here, we have established a mouse model of CS exposure which isolates the effects of prenatal and early postnatal CS exposures in early life. We have used this model to measure the effects of prenatal and/or postnatal CS exposures on lung function and immune cell infiltration as well as DNAm and expression of , a candidate gene previously observed to demonstrate DNAm differences on CS exposure in humans. Our study revealed that exposure to CS prenatally and in the early postnatal period causes long-lasting differences in offspring lung function, gene expression, and lung DNAm, which wane over time but are reestablished on reexposure to CS in adulthood. This study creates a testable mouse model that can be used to investigate the effects of prenatal and early postnatal CS exposures and will contribute to the design of intervention strategies to mediate these detrimental effects. Here, we isolated effects of prenatal from early postnatal cigarette smoke and showed that exposure to cigarette smoke early in life causes changes in offspring DNA methylation at that last through early adulthood but not into late adulthood. We also showed that smoking in adulthood reestablished these DNA methylation patterns at , suggesting that a mechanism other than DNA methylation results in long-term memory associated with early-life cigarette smoke exposures at this gene.
产前和生命早期接触香烟烟雾（CS）已反复表明会导致后代 DNA 甲基化（DNAm）的稳定、长期变化。据推测，这些变化可能与产前和生命早期 CS 暴露的已知结果具有功能相关性，其中包括肺发育受损、肺功能改变以及哮喘和喘息的风险增加。然而，迄今为止，很少有研究检查过产前 CS 引起的肺组织中的 DNAm 变化，甚至更少的研究试图检查产前与早期产后暴露的具体影响。在这里，我们建立了一个 CS 暴露的小鼠模型，该模型将产前和生命早期的产后 CS 暴露的影响隔离开来。我们使用该模型来测量产前和/或产后 CS 暴露对肺功能和免疫细胞浸润以及 DNAm 和 的影响， 是先前观察到的在人类 CS 暴露中表现出 DNAm 差异的候选基因。我们的研究表明，产前和生命早期的 CS 暴露会导致后代肺功能、基因表达和肺部 DNAm 的持久差异，这些差异会随着时间的推移而减弱，但在成年后重新暴露于 CS 时会重新建立。这项研究创建了一个可用于研究产前和早期产后 CS 暴露影响的可测试小鼠模型，并将有助于设计干预策略来减轻这些有害影响。在这里，我们从早期产后分离出了产前 CS 的影响，并表明生命早期接触香烟烟雾会导致后代 DNA 甲基化在 上发生变化，这些变化持续到成年早期，但不会持续到成年后期。我们还表明，成年后吸烟会重新建立这些 DNA 甲基化模式，这表明与该基因的生命早期香烟烟雾暴露相关的长期记忆不是由 DNA 甲基化以外的机制导致的。
