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: 9355720
• 负责人: Cynthia T McEvoy
• 金额: $ 112.64万
• 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/9355720
• 关键词: 1 year old; 15 year old; 3 year old; Address; Adverse effects; Affect; Age; American; Antismoking; Ascorbic Acid; Asthma; Birth; Blood; Caring; Cells; ChIP-seq; 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; Intervention Studies; Learning; Link; Low income; Lung; Measures; Methylation; Morbidity - disease rate; Mothers; Nicotine Dependence; Outcome; Patients; 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; follow-up; genetic analysis; improved; in utero; infancy; insight; lung development; maternal cigarette smoking; nicotine use in pregnancy; non-smoker; offspring; pregnancy prevention; pregnant; prenatal; prevent; prospective; protective effect; pulmonary function; randomized trial; respiratory; respiratory health; smoking cessation

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.

项目摘要 尽管有强烈的反吸烟努力，但至少有12％的美国妇女在 怀孕，每年出生的450,000多名烟熏婴儿。孕产妇在期间吸烟 怀孕对肺发育的不利影响，肺功能下降和 增加哮喘的风险。在JAMA发表的随机对照试验（RCT）中，我们提供了 证据表明孕产妇维生素C补充（怀孕期间每天500毫克）可以降低 怀孕期间的孕产妇在后代肺功能和随后的轮胎发生率上。 该回声应用的目的是结合两个研究的RCT的产前队列的后代 补充维生素C对孕妇吸烟者的影响对后代呼吸系统结果和 确定在怀孕期间补充母体维生素C的创新疗法是否导致 后代肺功能测试（PFTS）和呼吸健康的改进长期改善。开始 了解产前维生素C可能阻止后代健康变化的机制 吸烟者，我们检查了基因特异性DNA甲基化，从斑点，脐带血和颊 从前瞻性遵循的孕妇安慰剂后代收集的拭子（2-5岁） 治疗的吸烟者，维生素C处理的吸烟者或非吸烟者。与维生素C对 减少孕产妇吸烟对辅助维生素C的后代PFT和Wheeleze的影响 防止大多数由母子吸烟引起的DNA甲基化的重大变化 斑点和脐带血。令人惊讶的是，这种预防DNA甲基化改变仍然是证据2-5 多年后，在后代颊拭子中。该初步数据表明维生素的基础机制 C预防孕产妇吸烟对后代肺部健康的某些影响涉及 预防母子吸烟引起的表观遗传变化。该应用程序具有4个特定目标：1， 从2种补充维生素C的RCT到怀孕的吸烟者组成的后代组合组合； 2，确定母体维生素C对孕妇吸烟者的受保护作用是否对 后代肺部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受保护的影响的基础 维生素C的影响；和4，收集核心数据，以与整体回声研究相互作用。呼吸道 健康将通过纵向半年度，经过验证的呼吸史和年度PFT进行评估 在3岁。颊拭子将每年收集，并在6年，9年和12年的时间内进行血液，以提供DNA 遗传分析。 DNA甲基化的变化将通过甲基化芯片和硫酸氢盐测序测量。 这项研究将解决怀孕期间的吸烟如何影响呼吸结局，提供机理和 治疗见解，并提供主题和数据回声以解决其他关键结果。