Can epigenetics explain the negative effects of smoking during pregnancy?

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If you smoke, and find out you are pregnant, the first piece of advice you will get is to kick the habit, at least temporarily. Smoking during pregnancy is widely known to have negative impacts on the developing fetus, including birth defects, low birth weight and can increase the risk of sudden infant death syndrome. But the exact mechanism to explain how exposure to cigarette smoke during pregnancy causes these negative effects on the fetus has remained elusive.

With a new study publish March 31, researchers moved closer to understanding why children of mothers who smoke during pregnancy have a higher frequency of health problems during birth and into adulthood. The answer, according to a study published in the American Journal of Human Genetics, may lie in epigenetic changes—inheritable chemical marks on the DNA that can be altered by external factors such as environmental exposure, these changes don’t affect the sequence of the gene but instead affects the way a gene behaves.

In general, proving causative links between diseases and specific environmental exposures is a difficult task as there are several confounding factors that may affect the results of any study. We are exposed to a myriad of chemicals every minute of our lives and what we are exposed to is profoundly affected by factors such as socioeconomic status, geographical location and others.  In order to try to minimize the effects of such confounding facts, the authors performed a meta analysis—an analysis of the data generated by multiple previous studies—thereby increasing the number of subjects they looked at to more than 6,500 women. The data collected included epigenetic changes in the DNA of both the mother and the newborn fetus analyzed through blood sampling.

What the researchers found provided new insight into how smoking could affect the unborn fetus. The researchers looked at one important epigenetic mark called DNA methylation. When DNA becomes methylated a small molecule is physically added to a gene which serves to repress its function—think of it as a block for the cell’s machinery to accessing the gene to turn it on. When methylation marks were analyzed, the scientists found that over 6,000 of these marks at different regions in the DNA were different in children of mothers who smoked when compared to those whose mothers were classified as non-smokers.

Pink “balls” are methyl groups

Pink “balls” depict methylation

Several of these changes were seen both in the mother and the fetus, suggesting that they could be the result of an environmental exposure and that had been inherited by the fetus. “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,” said co-senior author Stephanie London, an epidemiologist and physician at the National Institute of Environmental Health Sciences (NIEHS), in a statement issued to the press. “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.”

Independent experts not involved with the study contacted by the Genetic Expert News Service, a GLP sister site, broadly agreed with the conclusions of the study, while also pointing out some caveats to be considered in the process.

The power of this new study, which represents significant progress in this field, lies in the integration of data from thirteen separate studies (a ‘meta-analysis’), greatly increasing the number of samples studied. Michael Cowley, an assistant professor at North Carolina State University said:

[A] challenge of such meta-analyses is ensuring reproducibility between the laboratories collecting and analyzing the data. This new study uses multiple, robust approaches to reduce errors and standardize techniques, and thus we can be confident about their findings.

Whether these [epigenetic] effects actually contribute to increased disease risk cannot be determined from this study, but this demonstration that smoking-associated epigenetic changes have functional relevance is important. Future work will be required to demonstrate causative links between smoking-associated epigenetic changes and offspring disease, but this study provides a reliable foundation on which to build.

Christopher Gregg, an assistant professor of Genetics at the University of Utah said:

…the methodology in this study is not novel, but the size of the study and the striking impact of maternal smoking on DNA methylation in offspring underlies the importance and high impact of the work. The clinical relevance of these findings is that they provide insights into how maternal smoking impacts the fetus and provide initial insights into the mechanisms.

It is well established that pregnant women should not smoke, but these new results reveal that smoking during pregnancy leaves a lasting mark on the genome that persists into childhood, and identifies the sites and genes in the genome that are especially susceptible to these effects.

While indicating that the conclusions of the study provides a “much stronger link between smoking in mothers and epigenetic changes,” Peng Jin, a professor of Human Genetics at Emory University pointed out that technical limitations of the methods used may preclude a more complete understanding of the number and nature of epigenetic changes observed by the authors.

The strength of the study as pointed out by several of the experts, lies in the numbers but it isn’t definitive evidence of epigenetics being the link between smoking and health problems in children, and it is unlikely that it will be the only biological mechanism involved. However, the results provide an as-yet unexplored direction in which researchers can investigate further and understand more clearly how smoking can affect the unborn child.

Arvind Suresh is a former laboratory scientist turned science communicator. He is a Science Media Liaison at the Genetic Expert News Service. Follow him @suresh_arvind.