Women who smoke during pregnancy and carry a fetus whose DNA lacks both copies of a gene involved in detoxifying cigarette smoke substantially increase their infants’ chances of being born with a cleft lip and/or palate, according to a study published in the January 2007 issue of American Journal of Human Genetics.
Researchers at the University of Iowa, Iowa City, and University of Southern Denmark, Odense, found that pregnant women who smoked and carried fetuses that lacked the GSTT1 enzyme were much more likely to give birth to an infant with a cleft. They noted that the gene is highly expressed in developing craniofacial structures.
In their investigation, the researchers first assembled a list of 16 genes of interest, each of which encodes proteins that plug into various pathways in the body involved in detoxifying dangerous chemicals.
"We picked genes that previous evidence shows either are directly involved in cigarette smoke toxicity or are major players in general toxicity management in people," said Kaare Christensen, MD, PhD, DMSc, a scientist at the University of Southern Denmark and a lead author on the report.
Dr. Christensen and colleagues then analyzed 5,000 DNA samples from their existing database of children with clefts, their parents and siblings.
They also relied on the Craniofacial and Oral Gene Expression Network, an online database of genes expressed throughout the various stages of development. Because cleft lip and/or palate develops during the first five to 12 weeks of the embryo’s/fetus’ development, the researchers had to be sure that the genes of interest are expressed during this period and are switched on in fetal craniofacial structures.
The scientists determined that the mother provides the toxic environmental exposure, which then can be greatly amplified by the genetics of the fetus to produce the cleft. This marks the first time a gene-environment interaction in clefting has been documented at a molecular level.
The data also point the way for future studies to define the specific molecular chain of events that lead to the cleft, which is vital information for understanding and eventually, it is hoped, preventing the process.
The researchers took particular note of the GSTT gene and its contribution to clefting. This gene encodes one of the body’s approximately 20 different glutathione S-transferase enzymes, which collectively play roles in common detoxification processes.
"It may be that the lip and palate can form normally without GSTT1," said Jeff Murray, MD, a scientist at the University of Iowa and the study’s senior author. "But if the chemicals in cigarette smoke challenge the normal development of these structures, fetuses that lack the gene are at a distinct disadvantage."
This study was supported by the National Institute of Dental and Craniofacial Research, National Institutes of Health.
