Maternal smoking during pregnancy and DNA methylation disruption in toddlers

Background: Cigarette smoking has been linked to significant and long-term epigenetic alterations (Joubert et al, 2016; Fa et al, 2016). Smoking-related changes in DNA methylation have been detected in somatic tissues of... [ view full abstract ]

Background: Cigarette smoking has been linked to significant and long-term epigenetic alterations (Joubert et al, 2016; Fa et al, 2016). Smoking-related changes in DNA methylation have been detected in somatic tissues of smokers and former smokers, in the placenta of smoking mothers and in fetal and neonatal tissues. These alterations in methylation patterns can lead to destabilization of genome activity in differentiated embryonic tissues causing irreversible disturbances in the development programme. This study aims to investigate the long-term epigenetic effects of fetal and tobacco smoke exposure in early childhood. Here we present the preliminary results based on a small cohort study. 

Methods: Genome-wide DNA methylation profiling was performed using Illumina Infinium HumanMethylation450 array that targets over 450,000 CpG sites. DNA methylation of blood samples from 56 children were analyzed: 28 children with a history of maternal smoking during pregnancy (M_age = 21 ± 9 months) and 28 children of non-smoking mothers (M_age = 23 ± 10 months).

Results: Due to small sample size, no significant intergroup differences in DNA methylation were found after multiple testing correction. However, approximately 10% (~48K of 450K) of CpG sites showed a nominally significant (p < .05) methylation difference between the comparison groups; a decrease in global methylation in the toddlers with a history of maternal smoking was observed. Children with a history of exposure were reliably distinguished from controls based on methylation profiles of the top 527 CpGs (p_nominal < 10^-3). In accordance with the genome annotation, these CpGs were related to 400 genes. Pathway enrichment analysis showed that these differentially methylated genes were predominantly involved in the control of the development and differentiation of cells, including neurons. In addition, changes in the methylation level of several genes controlling muscarinic and nicotinic acetylcholine signaling pathways were found, that, in turn, can be attributed to direct impacts of maternal smoking on the regulation of specific biological pathways in children’s genomes.

Conclusions: Maternal smoking during pregnancy can cause significant and long-term epigenetic changes in newborns. These changes are of a twofold nature—gene-specific and global methylation alterations; they include both the changes related to the direct genomic response to tobacco smoke components and the genome-wide methylation changes that may affect cascade regulation of child development.

With support of Russian Foundation for Basic Research (N17-06-00667).

References:

Joubert B.R., Felix J.F., Yousefi P., Bakulski K.M., Just A.C., Breton C., Reese S.E., Markunas C.A., Richmond R.C., Xu C.J., Küpers L.K., et a. DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis. Am J Hum Genet. 2016. 98(4): 680-696.

Fa S., Larsen T.V., Bilde K., Daugaard T.F., Ernst E.H., Olesen R.H., Mamsen L.S., Ernst E., Larsen A., Nielsen A.L. Assessment of global DNA methylation in the first trimester fetal tissues exposed to maternal cigarette smoking. Clin Epigenetics. 2016. 8: 128.