Epigenetic Link Identified Between Maternal Smoking During Pregnancy and Offspring Obesity

Maternal smoking during pregnancy is known to increase the risk of obesity in offspring later in life, but the mechanisms underpinning that relationship haven’t been clear. A study headed by researchers at the University of Kentucky has now identified a potential cellular mechanism that may represent the missing link. The scientists found that babies born to mothers who smoked while pregnant have increased tissue levels of a protein called chemerin, which is produced by fat cells and appears to play a role in energy storage. The findings suggest that smoking during pregnancy could trigger changes to fetal gene regulation that are involved in fat cell development and, potentially, obesity.

“It has been consistently shown that mothers who smoke during pregnancy confer increased risk of obesity to their baby, but the mechanisms responsible for this increased risk are not well understood,” said research lead Kevin Pearson PhD. “These data mark a first step towards defining those mechanisms with an eye toward potential interventions in the longer term.”

The team reports its findings in Experimental Physiology, in a paper titled, “ Smoking during pregnancy increases chemerin expression in neonatal tissue.”

Nearly 35% of all adults in the U.S. and about 20% of children aged 6-19 years are obese, the authors wrote. Estimates suggest that obesity-related healthcare costs amount to $200 billion annually. “Thus, understanding how to prevent and treat obesity and obesity-related diseases is crucial in stalling or reversing this epidemic.”

Although multiple factors are involved in the development of obesity and associated metabolic disorders, the in utero environment during pregnancy could also contribute, the researchers continued. As they point out, “It has been consistently shown that tobacco smoke exposure during fetal development increases the risk of pediatric and adult offspring obesity and adult offspring type 2 diabetes.” Despite this, 15-18% of pregnant women in the U.S. will smoke throughout their pregnancies and during nursing.

What isn’t well understood is how maternal smoking during pregnancy and offspring obesity are linked. One potential player, they suggested, is a protein called chemerin, an inflammatory adipokine that has been implicated in the differentiation of fat cells (adipocytes). Increased levels of chemerin have been found in the blood of obese people, and also in the lung fluid of mice exposed to cigarette smoke. While it wasn’t yet known whether elevated chemerin expression represents a feature of human smokers or offspring born to smoking mothers, “These attributes make chemerin a reasonable biomarker that could be associated with in utero smoke exposure and may explain why babies born to mothers who smoke during pregnancy are at an increased risk of developing obesity later in life.” The researchers further pointed out that a better understanding of those mechanisms that are changed in offspring exposed to tobacco smoke in utero may offer up potential targets for drug therapy.

Pearson and colleagues analyzed DNA and RNA levels in foreskin tissue from infants born to 65 new mothers, split between two cohorts. Forty six mothers were included in cohort 1 (2012-2013) and another 19 were included in cohort 2 (2015-2016). All of the infants were full term and had undergone routine circumcision. About half of the mothers reported smoking during pregnancy.

The results from both cohorts confirmed that infant weight and length were significantly lower among babies exposed to cigarette smoke in utero. Whole foreskin tissue from infants born to smoking mothers also showed elevated chemerin gene expression, and there was evidence that this increase may be at least in part due to epigenetic regulation. “we saw a decrease in chemerin DNA methylation at the CpG3 site in whole tissues of newborns born to mothers who smoked during pregnancy,” they wrote Cell culture experiments showed that chemerin mRNA expression was also elevated in primary dermal fibroblasts cultured from the foreskins of infants born to smoking mothers, when compared with cells taken from babies born to non-smoking mothers.

“We demonstrated that chemerin mRNA expression was increased in dermal foreskin tissue and primary dermal fibroblasts, and that DNA methylation of chemerin was decreased in dermal foreskin tissue of human neonates exposed in utero to cigarette smoke,” the authors stated. “The present data support a potential mechanism whereby children or adults exposed in utero to cigarette smoke could demonstrate greater rates of obesity later in life … Other teams have also shown that although newborns exposed in utero to cigarette smoke tend to be smaller, they have greater rates of obesity later in life. This recurrent finding indicates “altered developmental programming,” Pearson et al noted.

The authors acknowledge that their study had a number of limitations, and only involved male newborns. Due to limited tissue availability the researchers were also only able to evaluate DNA methylation and chemerin mRNA expression, rather than protein expression directly. This, they pointed out, should be evaluated by further studies. Nevertheless, the team concluded, “we demonstrate that chemerin expression is altered in neonatal issue and primary fibroblasts from newborns of mothers who smoked during pregnancy.” The scientists also maintain that the changes observed in response to in utero smoke exposure are likely regulated by epigenetics. “Our data provide a potentially novel mechanism behind increased later-life obesity risk in babies born to mothers who smoke during pregnancy.”

Pearson and colleagues aim to carry out further studies to see whether their findings can be replicated in female offspring, potentially using cells from umbilical cord as the test tissue. They also hope to study the effects of smoke exposure during pregnancy in engineered mice lacking either chemerin or its receptor.