Effects of nicotine salt-rich JUUL aerosols on the mouse developing lung

电子尼古丁输送设备（ENDS），包括电子香烟（e-cigs）和juul型设备，于2007年进入美国市场。从吸电子烟到现在的“JUULing”，电子烟行业正在迅速发展，以满足用户的娱乐和戒烟需求。在美国，超过10%的女性在怀孕期间吸烟，最近的调查显示，孕妇吸电子烟的比例与孕妇吸烟的比例相似。然而，吸入ENDS气溶胶对母亲和胎儿健康的影响在很大程度上是未知的。我们最近发现，在子宫内暴露于第三代电子烟气溶胶的小鼠在出生时体长和体重更小。肺结构的改变和Wnt信号通路的下调也被观察到，这表明子宫内电子烟暴露延迟了肺发育。然而，关于子宫内暴露于含有50 mg/ml尼古丁盐和苯甲酸的JUUL气溶胶影响肺部发育的表观遗传学和分子机制的信息不足。在这项提议中，我们打算研究母胎相互作用的潜在机制，导致子宫内暴露于JUUL气溶胶的后代肺部发育受阻。总体而言，本提案旨在1)确定影响妊娠结局的母体“JUULing”引起的母胎免疫毒理学反应的改变；2)评估1天、4周龄和8周龄小鼠在子宫内暴露JUUL气溶胶诱导的肺毒性，以评估出生时、出生后肺泡形成后和暴露于屋尘螨过敏原后对肺发育的影响。

Electronic nicotine delivery devices (ENDS), including electronic-cigarettes (e-cigs) and JUUL-type devices, were introduced to the US market in 2007. From e-cig vaping and now to 'JUULing', the ENDS landscape is evolving quickly to satisfy users' recreational and smoking aid cessation needs. In the US, more than 10% of women smoke during their pregnancy and recent surveys show that rates of maternal vaping is similar to those of maternal smoking. However, the effects of inhaling ENDS aerosol on the health of both mothers and fetuses are largely unknown. We recently showed that mice exposed in utero to third-generation e-cig aerosols had smaller body length and weight at birth. Altered lung structure and down-regulated Wnt signaling pathway were also observed, suggesting that in utero e-cig exposures delayed lung development. Yet, there is insufficient information regarding the epigenetic and molecular mechanisms by which in utero JUUL aerosol exposures, containing 50 mg/ml of nicotine salt and benzoic acid, affect lung development. In this proposal, we intend to investigate the mechanisms underlying the maternal-fetal interactions, leading to impeded lung development in the in utero JUUL aerosolexposed offspring. Overall, this proposal aims at 1) identifying the altered maternal-fetal immunotoxicological responses caused by maternal 'JUULing' that are affecting the pregnancy outcomes; and 2) evaluating the pulmonary toxicity induced by in utero JUUL aerosol exposures in mice at 1 day, plus at 4 and 8 weeks of age, to assess the effects on lung development at birth, after post-natal alveolarization, and following exposures to housedust mite allergens. This study will provide scientific evidence for future regulations on JUUL products for pregnant women and developmentally vulnerable populations. This will also help better inform the healthcare providers and the 10% of women who use ENDS during pregnancy.