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Smoking During Pregnancy Affects Infants' DNA Methylation Patterns, Study Finds

NEW YORK (GenomeWeb) – Mothers who smoke during their pregnancy affect the DNA methylation patterns of their babies' genomes, according to a study appearing in the American Journal of Human Genetics today.

The Pregnancy and Childhood Epigenetics Consortium performed a meta-analysis examining the association between maternal smoking during pregnancy and DNA methylation of newborns' DNA. Their study drew on more than 6,600 participants and looked at more than 450,000 CpG sites to identify nearly 3,000 CpG sites that hadn't before been linked to either smoking or methylation in newborns or adults.

A number of the genes corresponding to those CpG sites are associated with diseases like orofacial clefts or asthma, conditions that have been linked to maternal smoking. Other corresponding genes, meanwhile, were associated with cancers that are linked to smoking in adults.

"I find it kind of amazing when we see these epigenetic signals in newborns, from in utero exposure, lighting up the same genes as an adult's own cigarette smoking. There's a lot of overlap," co-senior author Stephanie London, an epidemiologist and physician at the National Institute of Environmental Health Sciences, said in a statement. "This is a blood-borne exposure to smoking — the fetus isn't breathing it, but many of the same things are going to be passing through the placenta."

London and her colleagues pulled together 13 birth cohort studies that had collected data on maternal smoking during pregnancy and that had gauged DNA methylation from newborn blood samples. All the cohorts used the sample platform to gauge methylation status at some 450,000 CpG sites.

Of the 6,685 newborns in the study, 13 percent had been exposed to sustained maternal smoking in utero and a quarter had been exposed to some maternal smoking, including mothers who quit early in their pregnancy and mothers who had an occasional cigarette.

From their meta-analysis, the researchers uncovered 6,073 CpG sites that were differentially methylated in infants exposed to sustained maternal smoking,

In a separate analysis of 3,187 older children with an average age of 6.8 years, the researchers found these CpG sites still exhibited differential methylation, though many showed a weaker effect.

Based on a review of the literature, London and her colleagues noted that nearly half of these sites, corresponding to 2,017 genes, hadn't before been linked to smoking.

The 6,073 differentially methylated CpG sites correspond to genes that are enriched for a number of different biological processes, the researchers reported, including ones involved in anatomical development and cell, tissue, or organ development, proliferation, morphogenesis, differentiation, and growth.

In particular, they uncovered six differentially methylated CpG sites linked to BMP4, a bone morphogenic protein that has been associated with orofacial clefts, as well as six differentially methylated CpG sites associated with BHMT2, another gene that has been linked with orofacial clefts as well as with selenium levels. Selenium, the researchers noted, has been shown to protect against orofacial clefts after exposure to teratogens.

"We already knew that smoking is related to cleft lip and palate, but we don't know why," London said. "Methylation might be somehow involved in the process."

She and her colleagues also noted differentially methylated CpG sites linked to NRP2 and ESR1, both of which have been associated with cancer.

They further examined whether these methylation status changes corresponded with gene expression levels. Using data from the Rotterdam Study, which focused on adults, the researchers were able to match 2,636 of the CpG sites to a gene transcript. Of those, 254 were significantly associated with the expression of a nearby gene in adults. In particular, they noted a striking association with IL32 and with HOXB2, both of which have also been linked to cancer.