Intrauterine exposure to nicotine through maternal vaping disrupts embryonic lung and skeletal development via the Kcnj2 potassium channel
Intrauterine exposure to nicotine through maternal vaping disrupts embryonic lung and skeletal development via the Kcnj2 potassium channel
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DOI：
10.1016/j.ydbio.2023.06.002
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发表时间：
2023-06-30
影响因子：
2.7
通讯作者：
Vladar，Eszter K.
中科院分区：
文献类型：
--
作者：
Ozekin，Yunus H.;Saal，Maxwell L.;Vladar，Eszter K.
怀孕期间吸烟会对婴儿产生不良影响，包括低出生体重、肺发育缺陷和骨骼异常。孕妇越来越多地转向蒸发[使用电子(E)香烟]，认为这是一种被认为比香烟更安全的替代品。然而，尼古丁会干扰胎儿的发育，这表明像吸烟一样，尼古丁蒸发可能对胎儿有害。为了测试母亲蒸发对小鼠胎肺和骨骼发育的影响，怀孕母鼠在整个怀孕期间都暴露在电子烟蒸气中。在胚胎期(E)18.5天，暴露于空气中的小鼠产仔数减少，部分胚胎表现出生长受限现象。收集胎肺进行组织学和全转录组测序。在母体中，尼古丁蒸发胚胎表现出与远端肺发育受损一致的组织学和转录变化。胚胎肺基因表达的变化模拟了香烟烟雾暴露的成年小鼠肺中观察到的转录变化，表明发育缺陷可能是由于直接接触尼古丁造成的。分析了胎儿骨骼的头面部和长骨长度。尼古丁直接结合并抑制Kcnj2钾通道，Kcnj2钾通道对骨骼发育很重要。在蒸发胚胎中，上颌骨、腭骨、肱骨和股骨的长度都缩短了，Kcnj2基因的一个副本的丢失进一步加剧了这种情况。暴露在尼古丁蒸气中的Kcnj2KO/+胚胎的出生体重也显著低于未暴露的任何一种基因型的动物。Kcnj2突变体在暴露于尼古丁蒸气的情况下和不接触蒸气的情况下都有严重的肺缺陷，这表明钾通道可能广泛参与介导尼古丁蒸发的有害发育影响。这些数据表明，宫内尼古丁暴露可能通过抑制Kcnj2而扰乱胎儿肺和骨骼的发育。
Smoking cigarettes during pregnancy is associated with adverse effects on infants including low birth weight, defective lung development, and skeletal abnormalities. Pregnant women are increasingly turning to vaping [use of electronic (e)-cigarettes] as a perceived safer alternative to cigarettes. However, nicotine disrupts fetal development, suggesting that like cigarette smoking, nicotine vaping may be detrimental to the fetus. To test the impact of maternal vaping on fetal lung and skeletal development in mice, pregnant dams were exposed to e-cigarette vapor throughout gestation. At embryonic day (E)18.5, vape exposed litter sizes were reduced, and some embryos exhibited growth restriction compared to air exposed controls. Fetal lungs were collected for histology and whole transcriptome sequencing. Maternally nicotine vaped embryos exhibited histological and transcriptional changes consistent with impaired distal lung development. Embryonic lung gene expression changes mimicked transcriptional changes observed in adult mouse lungs exposed to cigarette smoke, suggesting that the developmental defects may be due to direct nicotine exposure. Fetal skeletons were analyzed for craniofacial and long bone lengths. Nicotine directly binds and inhibits the Kcnj2 potassium channel which is important for bone development. The length of the maxilla, palatal shelves, humerus, and femur were reduced in vaped embryos, which was further exacerbated by loss of one copy of theKcnj2gene. Nicotine vapor exposedKcnj2KO/+embryos also had significantly lower birth weights than unexposed animals of either genotype.Kcnj2mutants had severely defective lungs with and without vape exposure, suggesting that potassium channels may be broadly involved in mediating the detrimental developmental effects of nicotine vaping. These data indicate that intrauterine nicotine exposure disrupts fetal lung and skeletal development likely through inhibition of Kcnj2.