Maternal vitamin C supplementation to decrease effects of smoking during pregnancy on infant lung function and health:Follow-up of 2 randomized trials and association with changes in DNA methylation

母亲补充维生素 C 可减少怀孕期间吸烟对婴儿肺功能和健康的影响：两项随机试验的随访以及与 DNA 甲基化变化的关联

• 批准号: 9262768
• 负责人: Cynthia T McEvoy
• 金额: $ 124.3万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-21 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9262768
• 关键词: 1 year old; 15 year old; 3 year old; Address; Adverse effects; Advertising; Affect; Age; American; Antismoking; Ascorbic Acid; Asthma; Birth; Blood; Caring; Cells; Cheek structure; Child; Child health care; Childhood; Clinical; DNA; DNA Methylation; Data; Data Element; Development; Education; Elements; Environmental Exposure; Epigenetic Process; Expenditure; Failure; Genes; Genotype; Health; Healthcare; Incidence; Infant; Innovative Therapy; Intervention; Learning; Life; Link; Low income; Lung; Measures; Methylation; Morbidity - disease rate; Mothers; Nicotine Dependence; Outcome; Patients; Personal Satisfaction; Phase; Placebos; Placenta; Pregnancy; Pregnancy in Adolescence; Pregnant Women; Prevention; Publishing; Pulmonary function tests; Randomized; Randomized Clinical Trials; Randomized Controlled Trials; Recording of previous events; Recurrence; Research; Respiratory physiology; Risk; Smoke; Smoker; Smoking; Supplementation; Swab; Therapeutic; Tobacco smoke; Umbilical Cord Blood; Wheezing; Woman; bisulfite sequencing; cohort; cost; early adolescence; fetal tobacco exposure; follow-up; genetic analysis; improved; in utero; infancy; insight; lung development; maternal cigarette smoking; non-smoker; offspring; pregnancy prevention; pregnant; prenatal; prevent; protective effect; pulmonary function; randomized trial; respiratory; respiratory health; smoking cessation; statistics

Project Summary Despite strong anti-smoking efforts, at least 12% of American women cannot quit smoking when pregnant, resulting in more than 450,000 smoke-exposed infants born yearly. Maternal smoking during pregnancy adversely affects lung development as seen by lifelong decreases in pulmonary function and increased risk of asthma. In a randomized controlled trial (RCT), published in JAMA, we have provided evidence that maternal vitamin C supplementation (500 mg daily during pregnancy) can decrease the effects of maternal smoking during pregnancy on offspring lung function and the subsequent incidence of wheeze. The purpose of this ECHO application is to combine the offspring from the prenatal cohorts of two RCTs studying the effects of vitamin C supplementation to pregnant smokers on offspring respiratory outcomes and to determine if the innovative therapy of maternal vitamin C supplementation during pregnancy leads to prolonged improvements on offspring’s pulmonary function tests (PFTs) and respiratory health. To begin to understand mechanisms by which prenatal vitamin C may be preventing changes in the health of offspring of smokers, we examined gene specific DNA methylation from a subset of placentas, cord bloods and buccal swabs (ages 2-5) collected from subjects who were the offspring of prospectively-followed pregnant placebo- treated smokers, vitamin C-treated smokers, or non-smokers. In parallel with the effects of vitamin C on the reduction of the effects of maternal smoking on offspring PFTs and wheeze, the supplementary vitamin C prevented the majority of significant changes in DNA methylation induced by maternal smoking in both placentas and cord blood. Strikingly, this prevention of alterations in DNA methylation was still evident 2-5 years later in offspring buccal swabs. This preliminary data suggests that the mechanism underlying vitamin C’s prevention of some of the effects of maternal smoking on offspring pulmonary health involves the prevention of epigenetic changes induced by maternal smoking. Thus this application has 4 specific aims: 1, to create the combined cohort of offspring from the 2 RCTs of vitamin C supplementation to pregnant smokers; 2, to determine if the protective effects of maternal vitamin C supplementation to pregnant smokers on offspring pulmonary health extend to early adolescence; 3, to begin to characterize the epigenetic mechanisms that appear to underlie the effects of smoking during pregnancy on offspring lung health and on the protective effects of vitamin C; and 4, to gather core data for and interact with the overall ECHO study. Respiratory health will be assessed by longitudinal semi-annual, validated respiratory histories and yearly PFTs beginning at 3 years of age. Buccal swabs will be collected yearly and blood at 6, 9 and 12 years to provide DNA for genetic analysis. DNA methylation changes will be measured by methylation chips and bisulfite sequencing. This study will address how smoking during pregnancy affects respiratory outcomes, provide mechanistic and therapeutic insights, and provide subjects and data to ECHO to address other key outcomes.

项目概要 尽管反吸烟的努力很大，但至少 12% 的美国女性在吸烟时无法戒烟。 怀孕期间，每年导致超过 450,000 名婴儿在母亲吸烟期间出生。 怀孕对肺发育产生不利影响，表现为肺功能终生下降， 在《美国医学会杂志》（JAMA）上发表的一项随机对照试验（RCT）中，我们提供了增加哮喘风险的方法。 有证据表明，母亲补充维生素 C（怀孕期间每天 500 毫克）可以降低以下影响： 母亲在怀孕期间吸烟对后代肺功能和随后喘息发生率的影响。 该 ECHO 应用程序的目的是将两个 RCT 研究的产前队列的后代结合起来 怀孕吸烟者补充维生素 C 对后代呼吸系统结果的影响 确定孕期补充维生素 C 的创新疗法是否会导致 后代肺功能测试（PFT）和呼吸系统健康的长期改善。 了解产前维生素 C 可能预防后代健康变化的机制 吸烟者，我们检查了来自胎盘、脐带血和口腔子集的基因特异性 DNA 甲基化 从预期怀孕安慰剂的后代受试者中收集的拭子（2-5岁） 接受治疗的吸烟者、接受维生素 C 治疗的吸烟者或非吸烟者 与维生素 C 的作用平行。 减少母亲吸烟对后代 PFT 和喘息的影响，补充维生素 C 阻止了母亲吸烟引起的 DNA 甲基化的大部分显着变化 令人惊讶的是，这种对 DNA 甲基化改变的预防仍然很明显 2-5。 数年后，在后代口腔拭子中，这一初步数据表明维生素的作用机制。 C 预防母亲吸烟对后代肺部健康的一些影响包括 预防母亲吸烟引起的表观遗传变化因此该应用有 4 个具体目标：1、 创建针对怀孕吸烟者补充维生素 C 的 2 项随机对照试验的后代组合队列； 2、确定孕妇补充维生素C是否对怀孕吸烟者的保护作用 肺后代健康延伸至青春期早期；3、开始表征表观遗传机制 这似乎是怀孕期间吸烟对后代肺部健康和保护性影响的基础 维生素 C 的影响；4，收集整个 ECHO 研究的核心数据并与之互动。 将通过每半年一次的纵向、经过验证的呼吸史和每年开始的 PFT 来评估健康状况 每年采集 3 岁时的口腔拭子，并在 6、9 和 12 岁时采集血液以提供 DNA。 遗传分析将通过甲基化芯片和亚硫酸氢盐测序来测量DNA甲基化变化。 这项研究将探讨怀孕期间吸烟如何影响呼吸系统结果，提供机制和 见解，并向 ECHO 提供受试者和治疗数据以解决其他关键结果。