BACKGROUND Fetal growth restriction (FGR) is a major risk factor for bronchopulmonary dysplasia (BPD). Maternal stress and poor diet are linked to FGR. Effect of perinatal stress on lung development remains unknown. OBJECTIVE Using a murine model of adverse early life environment (AELE), we hypothesized that maternal exposure to perinatal environmental stress and high-fat diet (Western diet) lead to impaired lung development in the offspring. METHODS Female mice were placed on either control diet or Western diet before conception. Those exposed to Western diet were also exposed to perinatal environmental stress, the combination referred to as AELE. Pups were either euthanized at postnatal day 21 (P21) or weaned to control diet and environment until adulthood (8-14 wk old). Lungs were harvested for histology, gene expression by quantitative RT-PCR, microRNA profiling, and immunoblotting. RESULTS AELE increased the mean linear intercept and decreased the radial alveolar count and secondary septation in P21 and adult mice. Capillary count was also decreased in P21 and adult mice. AELE lungs had decreased vascular endothelial growth factor A (VEGFA), VEGF receptor 2, endothelial nitric oxide synthase, and hypoxia inducible factor-1α protein levels and increased expression of genes that regulate DNA methylation and upregulation of microRNAs that target genes involved in lung development at P21. CONCLUSION AELE leads to impaired lung alveolar and vascular growth, which persists into adult age despite normalizing the diet and environment at P21. AELE also alters the expression of genes involved in lung remodeling.

中文翻译：

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不良的早期生活环境会损害小鼠的产后肺发育。

背景技术胎儿生长受限（FGR）是支气管肺发育不良（BPD）的主要危险因素。产妇压力和不良饮食与森林遗传资源有关。围产期应激对肺发育的影响仍然未知。目的使用不利的早期生活环境（AELE）的鼠模型，我们假设孕妇暴露于围产期环境压力和高脂饮食（西方饮食）会导致后代的肺发育受损。方法雌性小鼠在受孕前接受对照饮食或西式饮食。那些暴露于西方饮食的人也暴露于围产期环境压力，这种组合被称为AELE。在出生后第21天（P21）对幼犬实施安乐死，或者断奶以控制饮食和环境，直到成年（8-14周龄）。收集肺以进行组织学检查，通过定量RT-PCR，microRNA分析和免疫印迹进行基因表达。结果AELE增加了P21和成年小鼠的平均线性截距，并降低了径向肺泡计数和继发性分隔。在P21和成年小鼠中，毛细血管数量也减少了。AELE肺的血管内皮生长因子A（VEGFA），VEGF受体2，内皮一氧化氮合酶和低氧诱导因子-1α蛋白水平降低，并且调节DNA甲基化的基因表达增加，并且靶向涉及肺发育的基因的microRNA上调在P21。结论AELE导致肺泡和血管生长受损，尽管在P21时饮食和环境恢复正常，该现象一直持续到成年年龄。AELE还可以改变参与肺重构的基因的表达。结果AELE增加了P21和成年小鼠的平均线性截距，并降低了径向肺泡计数和继发性分隔。在P21和成年小鼠中，毛细血管数量也减少了。AELE肺的血管内皮生长因子A（VEGFA），VEGF受体2，内皮一氧化氮合酶和低氧诱导因子-1α蛋白水平降低，并且调节DNA甲基化的基因表达增加，并且靶向涉及肺发育的基因的microRNA上调在P21。结论AELE导致肺泡和血管生长受损，尽管在P21时饮食和环境正常，但这种现象一直持续到成年年龄。AELE还可以改变参与肺重构的基因的表达。结果AELE增加了P21和成年小鼠的平均线性截距，并降低了径向肺泡计数和继发性分隔。在P21和成年小鼠中，毛细血管数量也减少了。AELE肺的血管内皮生长因子A（VEGFA），VEGF受体2，内皮一氧化氮合酶和低氧诱导因子-1α蛋白水平降低，并且调节DNA甲基化的基因表达增加，并且靶向涉及肺发育的基因的microRNA上调在P21。结论AELE导致肺泡和血管生长受损，尽管在P21时饮食和环境正常，但这种现象一直持续到成年年龄。AELE还可以改变参与肺重构的基因的表达。