Impact on birth weight of maternal smoking throughout pregnancy mediated by DNA methylation

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.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-4652-7) contains supplementary material, which is available to authorized users.

Maternal Birth Weight and BMI Mediate the Transgenerational Effect of Grandmaternal BMI on Grandchild’s Birth Weight

“…It is possible that the influences of grandmaternal BMI and smoking on epigenetic changes can persist into later life of the mothers and then be transferred to the third generation. A few studies have investigated the mediating role of DNA methylation and have found that differential DNA methylations mediated the association between maternal smoking during pregnancy and birth outcomes, including lower BW , small for gestational age , and preterm birth . Further studies are needed to corroborate the epigenetic mechanism across two generations and explore how it may play a role in transgenerational effects.…”

Variable DNA methylation in neonates mediates the association between prenatal smoking and birth weight

“…B 374: 20180120 detectable in neonatal blood, and that variable DNA methylation is associated with an established outcome of maternal smoking [45,46] we next asked whether methylomic variation might mediate the relationship between maternal smoking in pregnancy and lower birth weight. Previous attempts to explore this using data from cord blood have been relatively inconsistent [14,15], supporting a mediation role for DNA methylation at non-overlapping DNA methylation sites. We repeated our EWAS of maternal smoking, excluding birth weight as a covariate, and identified an extended set of 143 DMPs (electronic supplementary material, table S7) which contained 105 (95.5%) of the 110 DMPs we identified in the analysis adjusting for birth weight.…”

“…There is also interest in the role that DNA methylation may play as mediator through which environmental exposures can influence long-term health outcomes. For example, there is evidence that the causal relationship between maternal smoking during pregnancy and low birth weight is mediated through differences in DNA methylation at specific loci across the genome [14,15]. While noteworthy, these analyses have been based on moderate samples sizes, have generally not replicated the same loci, and may have overestimated mediation effects because of invalid assumptions and misclassification of the exposure [16].…”

Chained Risk Assessment for Life-Long Disease Burden of Early Exposures–Demonstration of Concept Using Prenatal Maternal Smoking

“…Exposure to maternal smoking leads to epigenetic changes in the exposed fetus [16][17][18][19], indicating persistent changes in susceptibility to environmental exposures [5]. Emerging evidence is suggesting DNA methylation as a mechanism for the effect of maternal smoking on birth weight [20]. Furthermore, maternal smoking during early pregnancy is causing disproportionate growth restriction, demonstrating differences in susceptibility of organ systems for adverse effects [15].…”