E-Cigarette Vaping during Pregnancy and Lactation, Germ Cell Epigenetic Memory, and Transgenerational Asthma

怀孕和哺乳期电子烟、生殖细胞表观遗传记忆和跨代哮喘

• 批准号: 10428619
• 负责人: Patrick Allard
• 金额: $ 66.68万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10428619
• 关键词: Accounting; Address; Adult; Allergens; Allergic; Animal Model; Asthma; Cell Survival; Cell model; Cells; Characteristics; Chemicals; Chronic Disease; Data; Data Set; Development; Electronic cigarette; Ensure; Epigenetic Process; Exposure to; Family Smoking Prevention and Tobacco Control Act; Fetal Development; Fetus; Fibroblasts; Flavoring; Generations; Genome; Germ Cells; Guidelines; Health; Heritability; Human; In Vitro; Inhalation; Inhalation Exposure; Inherited; Intervention; Investigation; Knowledge; Lactation; Lead; Link; Lung; Mediating; Modeling; Molecular; Mothers; Mus; Nicotine; Pathway interactions; Perception; Perinatal; Perinatal Exposure; Phenotype; Policies; Policy Maker; Pregnancy; Pregnant Women; Public Policy; RNA Interference; Reporting; Reproducibility; Resistance; Risk; Safety; Smoking; Structure of primordial sex cell; Testing; Woman; Work; Yang; Youth; age group; airway hyperresponsiveness; asthmatic; base; e-cigarette aerosols; electronic cigarette use; epigenetic memory; epigenome; genomic locus; high risk; in vivo; innovation; interdisciplinary approach; lung health; molecular phenotype; mouse model; nicotine exposure; nicotine inhalation; nicotine vapor; novel; offspring; parental influence; phenotypic biomarker; population based; pregnant; reproductive; response; tobacco regulation; tool; transgenerational epigenetic inheritance; transmission process; vaping

Perinatal exposure to smoking and parenteral nicotine has been linked to a high risk of asthma, not just in the exposed offspring, but also transgenerationally in progeny who never encounter any form of nicotine at least as far as the F3 generation. Use of electronic-cigarettes (e-cigs) by pregnant women has been increasing, largely the result of the perception that vaping is relatively safe. This perception is suspected to be erroneous, but few objective studies have evaluated the adverse health effects of vaping. Our investigation will address the effects of vaping and flavorings used in vaping on development of asthma in progeny of mice exposed to e-cigs during pregnancy. We also ask whether this risk is transgenerationally inherited, and how heritability might occur. Germ cells are the only cells that are passed from one generation to the next, and have been shown to be exquisitely sensitive to environmental insults. Based on these considerations and on our preliminary data, we hypothesize that exposure to vaping disrupts the epigenetic machinery in germ cells, causing alterations of epigenetic marks across the genome that leads to a transgenerationally heritable asthma phenotype. Using established models, we will test this hypothesis in vivo in mice by determining whether e-cigs increase risk of asthma in: 1) offspring of pregnant F0 mothers and 2) offspring of F1 and F2 mothers who were naïve to e-cig or nicotine exposure. We will test whether vaporized nicotine (AIM 1A) and flavorings (AIM 1B) have independent effects on transgenerational asthma risk, whether these risks are additive and whether they are exacerbated on allergen sensitization (AIM 1C). Nicotine-induced asthma is associated with a marked alteration of lung fibroblast phenotype, and we hypothesize that these alterations are reversible once the epigenome is restored towards normal. Hence, in AIM 2, we will assess the effects of nicotine and e-cig flavorings on viability (AIM 2A) and epigenetic memory (AIM 2B) of germ cells. Using multi-dimensional -omics tools (the Mergeomics platform) developed by our Co-I Xia Yang (UCLA), we will analyze data generated on molecular pathways across different data sets to determine how germ cell epigenetics are impacted by e-cigs with or without flavorings (AIM 2C). Finally, studies proposed in AIM 2D will attempt to reverse epigenetic changes in fibroblasts isolated from F3 progeny produced by e-cigs using RNAi. Dependent variables will include expression of molecular phenotypic markers that are the hallmarks of the asthmatic phenotype, and functional characteristics of fibroblasts isolated from F3 progeny, compared with appropriate controls. We anticipate that studies in Aim 2 will show reproducible alteration of the phenotype of lung fibroblasts that have differentiated from germ cells in mice that have either: 1) been directly exposed to e-cigs; or 2) never been exposed to nicotine in any form, but inherited the effects of ancestral exposure to e-cigs. These studies will importantly advance our mechanistic knowledge of how vaping might lead to persistent, transgenerationally-inherited risk of asthma in offspring. Further, our studies will help inform regulatory policies concerning exposure to e-cig nicotine and flavorings from vaping.

围产期暴露于吸烟和胃肠外尼古丁与哮喘的高风险有关，不仅仅是在 暴露的后代，但也在后代谁从来没有遇到任何形式的尼古丁，至少 在F3代。孕妇使用电子烟（e-cigs）的人数一直在增加， 这是因为人们认为电子烟相对安全。这种看法被怀疑是错误的，但很少有 客观的研究已经评估了电子烟对健康的不利影响。我们的调查会解决 电子烟和电子烟中使用的调味剂对暴露于电子烟的小鼠后代哮喘的发展 怀孕我们还想知道这种风险是否是跨代遗传的，以及遗传性如何发生。胚芽 细胞是唯一能从一代传到下一代的细胞，并且已经被证明是精致的。 对环境污染敏感。基于这些考虑和我们的初步数据，我们假设 暴露于vaping会破坏生殖细胞中的表观遗传机制，导致表观遗传标记的改变， 导致了一种可转代遗传的哮喘表型。使用已建立的模型， 我们将在小鼠体内测试这一假设，通过确定电子烟是否会增加以下后代患哮喘的风险： 怀孕的F0母亲和2）未接触过电子烟或尼古丁的F1和F2母亲的后代。我们 将测试蒸发的尼古丁（AIM 1A）和调味剂（AIM 1B）是否对 跨代哮喘风险，这些风险是否是累加的，是否因过敏原而加剧 致敏（AIM 1C）。尼古丁诱导的哮喘与肺成纤维细胞的显著改变有关 表型，我们假设这些改变是可逆的，一旦表观基因组恢复到 正常因此，在AIM 2中，我们将评估尼古丁和电子烟调味剂对生存力的影响（AIM 2A）， 表观遗传记忆（AIM 2B）。使用多维组学工具（Mergeomics平台） 由我们的Co-I Xia Yang（UCLA）开发，我们将分析不同分子途径产生的数据， 数据集，以确定生殖细胞表观遗传学如何受到有或没有调味剂的电子烟的影响（AIM 2C）。 最后，AIM 2D中提出的研究将试图逆转从F3分离的成纤维细胞中的表观遗传变化 使用RNAi通过电子烟产生的后代。因变量将包括分子表型的表达 作为哮喘表型标志的标记物，以及分离的成纤维细胞的功能特征 从F3后代，与适当的控制相比。我们预计目标2中的研究将显示可重复性 在具有以下任一项的小鼠中，从生殖细胞分化的肺成纤维细胞的表型改变： 1)直接接触电子烟;或2）从未接触过任何形式的尼古丁，但遗传了 祖祖辈辈接触电子烟这些研究将重要地推进我们对电子烟如何 可能会导致后代患哮喘的持续性转代遗传风险。此外，我们的研究将有助于 告知有关暴露于电子烟尼古丁和电子烟调味剂的监管政策。