Abstract
BackgroundCigarette smoking has severe adverse health consequences in adults and in the offspring of mothers who smoke during pregnancy. One of the most widely reported effects of smoking during pregnancy is reduced birth weight which is in turn associated with chronic disease in adulthood. Epigenome-wide association studies have revealed that smokers show a characteristic “smoking methylation pattern”, and recent authors have proposed that DNA methylation mediates the impact of maternal smoking on birth weight. The aims of the present study were to replicate previous reports that methylation mediates the effect of maternal smoking on birth weight, and for the first time to investigate whether the observed mediation effects are sex-specific in order to account for known sex-specific differences in methylation levels.MethodsMethylation levels in the cord blood of 313 newborns were determined using the Illumina HumanMethylation450K Beadchip. A total of 5,527 CpG sites selected on the basis of evidence from the literature were tested. To determine whether the observed association between maternal smoking and birth weight was attributable to methylation, mediation analyses were performed for significant CpG sites. Separate analyses were then performed in males and females.ResultsFollowing quality control, 282 newborns eventually remained in the analysis. A total of 25 mothers had smoked consistently throughout the pregnancy. The birthweigt of newborns whose mothers had smoked throughout pregnancy was reduced by >200g. After correction for multiple testing, 30 CpGs showed differential methylation in the maternal smoking subgroup including top “smoking methylation pattern” genes AHRR, MYO1G, GFI1, CYP1A1, and CNTNAP2. The effect of maternal smoking on birth weight was partly mediated by the methylation of cg25325512 (PIM1); cg25949550 (CNTNAP2); and cg08699196 (ITGB7). Sex-specific analyses revealed a mediating effect for cg25949550 (CNTNAP2) in male newborns.ConclusionThe present data replicate previous findings that methylation can mediate the effect of maternal smoking on birth weight. The analysis of sex-dependent mediation effects suggests that the sex of the newborn may have an influence. Larger studies are warranted to investigate the role of both the identified differentially methylated loci and the sex of the newborn in mediating the association between maternal smoking during pregnancy and birth weight.
Highlights
Cigarette smoking has severe adverse health consequences in adults and in the offspring of mothers who smoke during pregnancy
The analyses focused on high confidence smoking-related sites, and were restricted to CpG sites with: (i) significant association with smoking in a large recent meta-analysis [31]; or (ii) a reported mediating effect in the association between maternal smoking and birth weight [37, 38]
A total of n=5,527 of these CpG sites had previously been reported associated with smoking and were selected for association testing
Summary
Cigarette smoking has severe adverse health consequences in adults and in the offspring of mothers who smoke during pregnancy. One of the most widely reported effects of smoking during pregnancy is reduced birth weight which is in turn associated with chronic disease in adulthood. Low birth weight has in turn been associated with various long-term health problems in adulthood. These include increased vulnerability to stress [7], cognitive deficits [8], and chronic somatic disorders, such as cardiovascular disease [9, 10], and obesity [11]. On the basis of such research, previous authors have proposed that chronic disease in adulthood may be initiated during pregnancy as a result of exposure to adverse intrauterine conditions. According to the theory of “fetal programming”, alterations in fetal nutrition and endocrine status result in developmental adaptations, which cause permanent changes in cellular structure, physiology, and metabolism, thereby predisposing to disease in adult life [14, 15]
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