Vitamin C to Decrease Effects of Smoking during Pregnancy on Offspring Airway Function, Airway Size, and Epigenetic Correlates: VCSIP cohort follow-up through 10 Years of Age

维生素 C 可减少怀孕期间吸烟对后代气道功能、气道大小和表观遗传相关性的影响：VCSIP 队列随访至 10 岁

• 批准号: 10658356
• 负责人: Cynthia T McEvoy
• 金额: $ 172.76万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658356
• 关键词: 10 year old; 5 year old; 6 year old; Adoption; Adult; Adverse effects; Affect; Age; American; Antismoking; Area; Ascorbic Acid; Asthma; Blinded; Blood; Blood specimen; Child; Child Health; Childhood; Clinical; Clinical Investigator; DNA Maintenance; DNA Methylation; Data; Development; Diameter; Dose; Early Intervention; Epigenetic Process; Exposure to; Fetal Lung; Genes; Growth and Development function; Hair; Health Care Costs; High Resolution Computed Tomography; Impairment; Infant; Intervention; Length; Life; Longitudinal Studies; Lung diseases; Maternal Exposure; Measurement; Measures; Mediating; Mediation; Molecular; Mothers; National Heart, Lung, and Blood Institute; Nicotine; Outcome; Participant; Pathway interactions; Placebos; Pregnancy; Randomized; Randomized, Controlled Trials; Research Personnel; Risk; Risk Factors; Scanning; Smoke; Smoking; Supplementation; Swab; Testing; Time; Toxic Environmental Substances; Trees; Wheezing; Woman; cohort; epigenome; follow-up; improved; in utero; injured airway; longitudinal analysis; lung development; maternal cigarette smoking; offspring; postnatal; prenatal; prenatal cigarette smoking; prenatal intervention; prevent; primary outcome; pulmonary function; respiratory; respiratory health; respiratory morbidity; smoking during pregnancy

Project Summary/Abstract Maternal smoking during pregnancy leads to impaired fetal lung development, decreased airway function (forced expiratory flows), and an increased risk for wheeze/asthma in the offspring. It is an important determinant of lifelong lower airway function and greater respiratory morbidity. In our randomized controlled trial (“Vitamin C to Decrease Effects of Smoking in Pregnancy on Infant Lung Function” [VCSIP]), we demonstrated that vitamin C supplementation versus placebo to pregnant smokers resulted in better airway function in the offspring at 3 and 12 months, and at 5 years of age. These differences in airway function between the offspring of the randomized groups also increased with age. We also demonstrated a significant decrease in the occurrence of wheeze at 4 to 6 years of age. There was no difference in prenatal or postnatal smoke exposure between the randomized groups. All clinical participants and investigators remain blinded to treatment allocations. Mediation analysis indicates the effect of vitamin C on wheeze is primarily due to its effect on airway function. Interventions early in life are important as longitudinal studies demonstrate that airway function trajectories are established early, and children in the lower airway function percentiles tend to have persistently lower airway function into adulthood and are likely at increased risk for adult pulmonary disease. Our studies are the first and only studies to show that an in-utero intervention targeted for a known environmental toxin can produce a persistent increase in airway function early in life. This finding is highly relevant to the aims of the NHLBI. The aims of this proposal are to continue to study the offspring from the unique VCSIP study to determine whether prenatal supplementation with vitamin C to pregnant smokers produces an improved trajectory of airway function and lower respiratory morbidity through 10 years of age (specific aim 1). In specific aims 2 and 3 we will examine the structural and molecular mechanisms by which vitamin C may be acting to modify the effects of maternal smoking during pregnancy on lung development. In specific aim 2, we will use low dose high-resolution computed tomography (HRCT) scans done at 10 years of age to determine if increased airway size underlies the improved airway function. In specific aim 3, evaluating DNA methylation changes in serial buccal and blood samples, we will identify critical genes and pathways most affected by maternal smoking during pregnancy and modified by vitamin C supplementation, as well as their association with respiratory outcomes of airway function, respiratory morbidity, and airway size. The children will be studied with yearly airway function tests, buccal swabs, hair for nicotine levels, blood at ages 7 and 10, and a low dose HRCT scan at 10 years of age. This follow-up will determine whether the vitamin C supplementation in pregnant smokers improves airway function and respiratory morbidity into mid-childhood, determine if the mechanism for the improved airway function is increased airway size, and explore the epigenetic changes that may underlie these beneficial effects of vitamin C supplementation for pregnant smokers.

项目概要/摘要 孕妇在怀孕期间吸烟会导致胎儿肺部发育受损、气道功能下降 （用力呼气流量），以及后代喘息/哮喘的风险增加，这是一个重要的决定因素。 在我们的随机对照试验中（“维生素 C”），会影响终生下呼吸道功能和更高的呼吸道疾病发病率。 为了减少怀孕期间吸烟对婴儿肺功能的影响”[VCSIP]），我们证明了维生素 与安慰剂相比，怀孕吸烟者补充维生素 C 可改善其后代 3 岁时的气道功能 12 个月和 5 岁时，后代之间气道功能存在差异。 我们还证明，随机分组的发生率随着年龄的增长而显着减少。 4 至 6 岁时喘息的发生率在产前或产后烟雾暴露方面没有差异。 随机分组。所有临床参与者和研究人员对治疗分配均不知情。 分析表明维生素 C 对喘息的影响主要是由于其对气道功能的影响。 生命早期很重要，因为纵向研究表明气道功能轨迹已经建立 早期，处于下气道功能百分位数的儿童往往会持续处于低气道功能状态 我们的研究是第一个也是唯一一个。 研究表明，针对已知环境毒素的宫内干预可以产生 这一发现与 NHLBI 的目标高度相关。 该提案的目的是继续研究独特的 VCSIP 研究的后代，以确定 怀孕吸烟者产前补充维生素 C 是否可以改善气道轨迹 功能和降低 10 岁以下呼吸道疾病发病率（具体目标 1）。在具体目标 2 和 3 中，我们将。 检查维生素 C 可能发挥作用以改变其作用的结构和分子机制 母亲怀孕期间吸烟对肺部发育的影响 在具体目标 2 中，我们将使用低剂量高分辨率。 10 岁时进行计算机断层扫描 (HRCT) 扫描，以确定气道尺寸是否增大 在具体目标 3 中，评估连续口腔和血液中的 DNA 甲基化变化。 样本，我们将确定受孕期吸烟影响最大的关键基因和途径，以及 通过补充维生素 C 进行修改，以及它们与气道功能的呼吸结果的关系， 将通过每年的气道功能测试、口腔检查来研究儿童的呼吸道发病率和气道大小。 拭子、头发中的尼古丁含量、7 岁和 10 岁时的血液以及 10 岁时的低剂量 HRCT 扫描。 随访将确定怀孕吸烟者补充维生素C是否改善气道功能 和儿童中期的呼吸道疾病发病率，确定改善气道功能的机制是否是 增加气道尺寸，并探索可能是维生素这些有益作用背后的表观遗传变化 怀孕吸烟者补充C。