Effects of e-cigarette exposure during pregnancy on offspring lung function and disease: Characterization of pulmonary, intergenerational, and epigenetic effects

怀孕期间接触电子烟对后代肺功能和疾病的影响：肺、代际和表观遗传效应的特征

• 批准号: 10167106
• 负责人: KENT Ed PINKERTON
• 金额: $ 48.69万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-14 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10167106
• 关键词: Affect; Age; American; Asthma; Birth; Chemosensitization; Child; Childhood Asthma; Collaborations; DNA Methylation; Dermatophagoides Antigens; Development; Electronic cigarette; Epigenetic Process; Exposure to; Extrinsic asthma; Future; Gases; Gene Expression; Generations; Health; House Dust; Human; Inbred BALB C Mice; Infant; International; Laboratories; Lung; Lung diseases; Measurement; Measures; Mechanics; Mediating; Mitogens; Modeling; Mus; National Institute of Drug Abuse; Nature; Nicotine; Nicotine Dependence; Nicotinic Receptors; Partner in relationship; Perinatal; Placenta; Play; Predisposition; Pregnancy; Pulmonary function tests; Reactive Oxygen Species; Reproducibility; Research; Respiratory physiology; Risk; Role; Smoke; Smoker; Smoking; Standardization; Structure; Testing; Time; Woman; Work; air filter; asthma model; bisulfite sequencing; e-cigarette aerosols; electronic cigarette use; electronic cigarette user; in utero; intergenerational; lung development; maternal cigarette smoking; methacholine; mouse model; neonatal exposure; nicotine exposure; non-smoker; offspring; postnatal; pregnant; prenatal exposure; pulmonary function; respiratory; respiratory health; response; smoking during pregnancy

Abstract Reflecting the highly addictive nature of nicotine, 10-12% of American women smoke during pregnancy. Maternal smoking during pregnancy alters normal lung development to produce lifelong decreases in offspring pulmonary function and increased risk of respiratory diseases. Work from our laboratory and others has shown that almost all the effects of maternal smoking during pregnancy on lung development are mediated by nicotine crossing the placenta to interact with nicotinic receptors in developing lung. This strongly suggests that use of e-cigarettes during pregnancy will have significant detrimental effects on lung development and offspring lung disease; and worse, that nicotine addiction will drive pregnant e-cigarette users to continue use during pregnancy. Further, as well as causing lifelong changes in offspring pulmonary function, in-utero nicotine exposure also appears to alter pulmonary function in subsequent generations, most likely through epigenetic mechanisms. This makes it critically important to characterize the effects of in-utero e-cigarette exposure on offspring lung development and function. Thus, the overall objective of this application is to use a mouse model to characterize the effects of perinatal e-cigarette exposure on offspring pulmonary function and disease and the potential for intergenerational transmittal of the respiratory harms of in-utero e-cigarette exposure. This application represents a collaboration between two outstanding groups, the Pinkerton laboratory which is a world leader in respiratory exposures and the Spindel laboratory, a world leader in the pulmonary effects of in utero nicotine exposure. Our specific aims are as follows: Aim 1. To characterize the direct effect of maternal in-utero e-cigarette exposure on first generation (F1) offspring pulmonary function, respiratory disease and epigenetic changes. This will be done by exposing pregnant BALB/c mice to filtered air, e-cigarettes without nicotine and e-cigarettes with nicotine from gestation day 1 to postnatal day 7 and effects on lung analyzed at 8 weeks of age. In addition, the effects of in-utero exposures on asthma susceptibility will be analyzed using sensitization to house dust mite antigen. Aim 2. To characterize the intergenerational effect of grand-maternal in-utero e-cigarette exposure on second generation (F2) offspring pulmonary function, respiratory disease and epigenetic changes. This will be done as for aim1, but intergenerational effects on the F2 generation will be determined. Aim 3. To characterize the additive, multigenerational effect of both grand-maternal and maternal in-utero e-cigarette exposure on offspring pulmonary function, respiratory disease and epigenetic changes. It is an unfortunate fact that children of smokers are more likely to smoke than children of non- smokers; thus, we will test for the potential of additive harms of multigenerational in-utero e-cigarette exposure. Together these aims will provide a comprehensive analysis of the effects of in-utero e-cigarette exposure on offspring pulmonary function and the potential for multigenerational potentiation of the effects.

抽象的 反映了尼古丁的高度上瘾的性质，有10-12％的美国妇女在怀孕期间吸烟。 怀孕期间的母亲吸烟改变了正常的肺发育以产生终生的后代降低 肺功能和呼吸道疾病的风险增加。我们的实验室和其他人的工作 表明，怀孕期间几乎所有孕产妇吸烟对肺发育的影响都是由 尼古丁穿越胎盘以与发育中的肺中的烟碱受体相互作用。这强烈暗示 怀孕期间电子烟的使用将对肺发育和 后代肺疾病；更糟糕的是，尼古丁成瘾将驱使怀孕的电子烟使用者继续使用 怀孕期间。此外，以及导致后代肺功能的终生变化 尼古丁暴露似乎也改变了随后的几代肺功能，很可能是通过 表观遗传机制。这使得表征Utero e-aigarette的影响至关重要 后代肺发育和功能的暴露。因此，此应用程序的总体目的是使用 鼠标模型以表征围产期电子烟暴露对后代肺功能的影响 疾病和呼吸器内电子烟呼吸损害的代际传播的潜力 接触。该应用程序代表了两个杰出小组之间的合作，Pinkerton 实验室是世界呼吸道暴露和Spindel实验室的世界领导者，这是世界领导者 子宫内尼古丁暴露的肺作用。我们的具体目的如下： 目的1。表征母体内部电子烟对第一代的直接影响 （F1）后代肺功能，呼吸道疾病和表观遗传变化。这将由 将怀孕的BALB/C小鼠暴露于过滤的空气中 妊娠第1天至第7天，以及对8周龄分析的肺部影响。另外， 将使用灵敏度分析哮喘易感性的局限性暴露，以容纳粉尘螨抗原。 目的2。要表征大婚姻内部电子烟的代际效应 第二代（F2）后代肺功能，呼吸道疾病和表观遗传变化。 这将与AIM1一起完成，但是将确定对F2代的代际影响。 目的3。要表征孙子和母体的添加剂，多代效应 对后代肺功能，呼吸道疾病和表观遗传的utero utero电子烟暴露 更改。不幸的事实是，吸烟者的儿童比非非 - 吸烟者；因此，我们将测试多代utero式电子烟的累加危害的潜力。 这些目的共同将全面分析Utero E-Ibigarette暴露对 后代肺功能以及效应多代增强的潜力。