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Epigenetic Changes Associated with Prenatal Tobacco Exposure

By Negin Martin
September 2009

Breton, Carrie
First author Carrie Breton is currently an assistant professor in the USC Department of Preventive Medicine and a collaborator in the Children's Environmental Health Science Center at the University of Southern California.( Exit NIEHS
(Photo courtesy of Carrie Breton)

Gilliland, Frank
Gilliland, shown at a 2008 meeting in Chapel Hill, is the principal investigator on three NIEHS grants, which are associated with more than 300 publications. In addition to NIEHS funding, support for this study was provided by the Hastings Foundation and the American Society of Clinical Oncology.
(Photo courtesy of Steve McCaw)

A new NIEHS-funded study published by researchers at the University of Southern California (USC) reports that life-long effects of prenatal exposure to tobacco may be mediated by changes in DNA methylation.

The USC study( Exit NIEHS, soon to be published in the American Journal of Respiratory and Critical Care Medicine and now online, provides some of the first evidence that alterations in the epigenome may be a possible mechanism for life-long and even inherited effects of in utero exposure to tobacco smoke. This is the first study to report changes in DNA-methylation in cells from the oral cavity after prenatal exposure.

"This research could be an important first step into understanding how we may be able to intervene in these developments on an epigenetic level," said first author Carrie Breton, Sc.D. "This research could also lead to new ways for researchers to investigate biological mechanisms that might explain known health effects associated with maternal smoking."

Prenatal exposure to tobacco smoke has been linked to increased incidence of asthma and pulmonary disease in children. However, it is poorly understood why the adverse health effects associated with maternal smoking persist through children's lives and are in some cases transgenerational.

The study's lead investigator, Frank Gilliland, M.D., Ph.D.,( Exit NIEHS is a Professor of Preventive Medicine and the Director of the Division of Environmental Health at the University of Southern California in Los Angeles. Gilliland's research focuses on genetic and dietary factors that contribute to environmentally triggered lung disease and breast cancer. As a principal investigator, he has published a number of epidemiological studies about the effects of radon exposure on progeny and the adverse respiratory effects of air pollution.

Gilliland's team of scientists discovered gene-specific and global alterations in DNA methylation patterns of children who were exposed to tobacco smoke in utero.

The researchers collected buccal cell samples from over 300 kindergartners and first graders to look for global DNA methylation patterns. Buccal cells - pronounced "buckle" - are aero-digestive cells that are constantly regenerated and shed. These cells can be collected by gently scraping the inside of the cheek and can be used for genetic studies. A questionnaire was used to determine the maternal smoking history.

Two DNA repetitive elements, long interspersed nucleotide element 1 (LINE1) and short interspersed nucleotide element (AluYb8), served as surrogate markers for the detection of global methylation. AluYb8 methylation was significantly lowered in exposed children. No significant differences between LINE1 methylation of exposed and unexposed children was evident unless children carried a mutation in their Glutathione S-transferase Mu1 (GSTM1) genes.

GSTM1 is a detoxifying enzyme that protects the body against carcinogens, oxidative stress and environmental toxins. Silencing mutations in GSTM1 increase susceptibility to adverse health effects of smoking. Exposed children with GSTM1 null mutation showed differences in their LINE1 methylation pattern.

The results of this study suggest that maternal smoking during pregnancy and GSTM1 gene variations are contributing factors to epigenetic changes in exposed children.

Epigenetic changes can persist through multiple cell divisions, cell differentiation and even be passed on to progeny. Unlike DNA mutations, epigenetic changes are reversible since the sequence of DNA remains unaltered. Long-term effects of many environmental pollutants including tobacco smoke are suspected to be mediated through epigenetic changes to DNA.

Currently, there are over a billion tobacco users worldwide. Smoking tobacco claims over 5 million lives annually and is the number one preventable cause of death in the world.

Citation: Breton CV, Byun HM, Wenten M, Pan F, Yang A and Gilliland FD.( 2009. Prenatal Tobacco Smoke Exposure Affects Global and Gene-Specific DNA Methylation. Am J Respir Crit Care Med. Epub ahead of print.

(Negin Martin, Ph.D., is a biologist in the NIEHS Laboratory of Neurobiology Viral Vector Core Facility and a 2009 Science Communication Fellow with Environmental Health Sciences. She recently completed a postdoctoral fellowship with the NIEHS Membrane Signaling Group.)

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