Vitamin C Prevents Offspring DNA Methylation Changes Associated with Maternal Smoking in Pregnancy
Vitamin C Prevents Offspring DNA Methylation Changes Associated with Maternal Smoking in Pregnancy
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DOI：
10.1164/rccm.201610-2141oc
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发表时间：
2017-09-15
影响因子：
24.7
通讯作者：
Spindel, Eliot R.
中科院分区：
文献类型：
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作者：
Shorey-Kendrick, Lyndsey E.;McEvoy, Cindy T.;Spindel, Eliot R.
理由：母亲在怀孕期间吸烟的婴儿表现出终生肺功能下降。在分娩时的胎盘和脐带血、胎儿肺、口腔上皮和儿童时期的血液中都发现了与怀孕期间母亲吸烟相关的DNA甲基化变化。我们在一项随机临床试验（ClinicalTrials.gov identifier, NCT00632476）中证明，孕妇吸烟者补充维生素C可以减轻母亲吸烟对后代肺功能的影响，并降低1岁时喘息的发生率。目的：确定补充维生素C是否会减少母亲吸烟对后代甲基化的影响，以及特定CpGs的甲基化是否也与呼吸结局有关。方法：对NCT00632476试验期间收集的一部分胎盘、脐带血样本和口腔样本进行靶向亚硫酸氢盐测序，然后使用亚硫酸氢盐扩增子测序对选定的脐带血差异甲基化区域进行独立验证。测量结果和主要结果：大多数（69.03%）在安慰剂组和非吸烟者组之间甲基化差异至少10%的CpGs在维生素C治疗后恢复（至少50%）到非吸烟者的水平。相当大比例的恢复CpGs与表型结果相关，低甲基化CpGs的富集程度更高。结论：我们确定了一种通过补充维生素C在多个位点上实现DNA甲基化正常化的模式。这种模式在组织和时间上的一致性表明对后代DNA甲基化有系统和持续的影响。需要进一步的工作来确定DNA甲基化的全基因组变化如何介导或反映母亲吸烟对肺功能的持续影响。
Rationale: Infants whose mothers smoked during pregnancy demonstrate lifelong decreases in pulmonary function. DNA methylation changes associated with maternal smoking during pregnancy have been described in placenta and cord blood at delivery, in fetal lung, and in buccal epithelium and blood during childhood. We demonstrated in a randomized clinical trial (ClinicalTrials.gov identifier, NCT00632476) that vitamin C supplementation to pregnant smokers can lessen the impact of maternal smoking on offspring pulmonary function and decrease the incidence of wheeze at 1 year of age.Objectives: To determine whether vitamin C supplementation reduces changes in offspring methylation in response to maternal smoking and whether methylation at specific CpGs is also associated with respiratory outcomes.Methods: Targeted bisulfite sequencing was performed with a subset of placentas, cord blood samples, and buccal samples collected during the NCT00632476 trial followed by independent validation of selected cord blood differentially methylated regions, using bisulfite amplicon sequencing.Measurements and Main Results: The majority (69.03%) of CpGs with at least 10% methylation difference between placebo and nonsmoker groups were restored (by at least 50%) toward nonsmoker levels with vitamin C treatment. A significant proportion of restored CpGs were associated with phenotypic outcome with greater enrichment among hypomethylated CpGs.Conclusions: We identified a pattern of normalization in DNA methylation by vitamin C supplementation across multiple loci. The consistency of this pattern across tissues and time suggests a systemic and persistent effect on offspring DNA methylation. Further work is necessary to determine how genome-wide changes in DNA methylation may mediate or reflect persistent effects of maternal smoking on lung function.