Babies born to mothers who smoke during pregnancy show modifications in their DNA that mirror those seen in adult smokers, according to findings from a meta-analysis of DNA methylation studies.
The analysis is the first from the international Pregnancy and Childhood Epigenetics (PACE) consortium, which is studying the impact of in utero and early-life exposures on newborn epigenome by analyzing birth cohorts from the U.S. and Europe using a single DNA methylation platform.
Researchers identified more than 6,000 DNA modifications in babies born to moms who smoked during pregnancy. About half of these modifications corresponded to specific genes, including some linked to lip and cleft palate and asthma. Maternal smoking during pregnancy has been previously implicated as a risk factor for these conditions.
Other identified genes are linked to cancers associated with adult smoking, including lung, colorectal, and liver, researcher Bonnie Joubert, PhD, of the National Institute of Environmental Health Sciences, and colleagues, wrote in the American Journal of Human Genetics, published online March 31.
In an interview with MedPage Today, Joubert said the study is the largest ever to explore the impact of maternal smoking on DNA expression in newborns. Smaller studies have also shown links between in utero exposure to cigarette toxins and DNA methylation.
"These findings re-enforce the known evidence that smoking during pregnancy is harmful to offspring, and it provides additional data on the underlying pathways that could be involved in this," she said.
Maternal smoking during pregnancy has been linked to an increased risk for specific developmental, birth-related disorders, including lip and cleft palate, low-birth weight, reduced pulmonary function, sudden infant death syndrome (SIDS), and asthma.
"Our findings might implicate epigenetic mechanisms in the etiology of these exposure-disease relationships," the researchers wrote.
The analysis included 13 birth cohort studies from the United States and Europe, with a total of 6,685 mother-newborn pairs. In 13% of cases there was sustained (daily) exposure to maternal smoking during pregnancy, and in 25% there was some exposure from mothers who were occasional smokers or who quit smoking early in pregnancy. The rest of the newborns (62%) were born to mothers who did not smoke.
Five of the cohort studies included in the analysis included older children (n=3,187, average age=6.8 years), and 8% of these children were exposed to sustained maternal smoking in utero.
Joubert and colleagues explored the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) using a commercial methylation assay (Illumina 450K BeadChip).
Among the main findings:
- 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation.
- Several of the identified genes were related to diseases previously linked to maternal smoking, including bone morphogenetic protein 4 (BMP4), which is related to lip and cleft palate; and estrogen receptor 1 (ESR1), which is closely linked to breast and hepatocellular cancers and asthma.
- Several differentially methylated CpGs were associated with gene expression, and the researchers observed enrichment in pathways and processes critical to development.
- In the subanalysis of older children, 100% of CpGs showed nominal or greater levels of significance, which the researchers concluded were far more than would be expected by chance (P< 2.2 x 10-16).
Data with repeat measures in the same children were limited, so the researchers were not able to analyze changes in methylation over time.
"Our findings suggest that [in utero] exposure to maternal smoking has lasting effects, but it would certainly be helpful to actually follow children from birth to confirm this," Joubert said.
The researchers concluded that their findings "could provide new insights into the mechanisms involved in the detrimental health outcomes that arise from [maternal smoking] in utero exposure."
"This inaugural paper from the PACE consortium represents a major effort to combine data from many studies in a large-scale meta-analysis of epigenome-wide association studies of maternal smoking in relation to methylation in newborns," they wrote.
Funding for the international PACE consortium is provided by the National Institute of Environmental Health Sciences and others.
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