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父母尼古丁与哮喘的高风险有关，而不仅仅是在 暴露的后代，但也在进展中转变，他们至少从未遇到过任何形式的尼古丁 直到F3一代。孕妇使用电子烟（电子烟）一直在增加，在很大程度上 人们认为烟是相对安全的结果。怀疑这种看法是错误的，但很少 客观研究评估了烟的不利影响。我们的投资将解决效果 在暴露于电子烟的小鼠中，用于开发哮喘的烟雾和调味料 怀孕。我们还询问这种风险是否是转变的遗传，以及如何发生遗传力。胚芽 单元是唯一从一代传递到下一代的单元格，并且已被证明是准确的 对环境侮辱敏感。基于这些考虑因素和我们的初步数据，我们假设 暴露于烟雾的情况会破坏生殖细胞中的表观遗传机制，从而导致表观遗传标记的改变 跨基因组导致一种转化可遗传的哮喘表型。使用既定模型， 我们将通过确定电子烟是否会增加哮喘的风险：1）后代来检验小鼠体内的假设。 怀孕的F0母亲和2）幼稚的E-cig或尼古丁暴露的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）对 转基因哮喘风险，这些风险是添加剂以及它们是否在过敏原上加剧 灵敏度（AIM 1C）。尼古丁诱导的哮喘与肺成纤维细胞的明显改变有关 表型，我们假设一旦表观基因组恢复到 普通的。因此，在AIM 2中，我们将评估尼古丁和电子烟调味剂对生存能力的影响（AIM 2A）和 生殖细胞的表观遗传记忆（AIM 2B）。使用多维 - 组工具（合并平台） 由我们的Co-i Xia Yang（UCLA）开发，我们将分析在不同的分子途径上产生的数据 数据集以确定生殖细胞表观遗传学如何受到带有或没有调味剂的电子烟的影响（AIM 2C）。 最后，在AIM 2D中提出的研究将尝试逆转从F3分离的成纤维细胞的表观遗传变化 使用RNAi由电子烟产生的后代。因变量将包括分子表型的表达 标记是哮喘表型的标志，以及成纤维细胞的功能特征 与适当的对照相比，来自F3后代。我们预计AIM 2中的研究将显示可再现的 与具有分化的肺成纤维细胞的表型改变了具有： 1）直接暴露于电子烟中；或2）从未以任何形式暴露于尼古丁，而是继承了 祖先暴露于电子烟。这些研究将重要的是我们对如何烟的机械知识提高了 可能导致后代哮喘的持久，变革性的风险。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烟气调味料的监管政策。