Oral clefts, smoking &amp; variation toxin biotransformation
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Smoking during pregnancy has been identified as a risk factor for orofacial clefts (cleft lip or cleft palate) in several studies, but not in others. Recently, we completed a large research study of parental smoking during pregnancy and risk for birth defects, supported by two TRDRP grants. California infants who participated were born during 1987-1989 and had either an oro-facial cleft or one of three other selected major birth defects (spina bifida, a heart malformation, or absence of all, or some part, of a limb). We found that about 24% of pregnant California women smoke during pregnancy--this makes smoking one of the most common environmental exposures during pregnancy, so that even small risks may have major implications because so many pregnancies would be at risk. The 24% percent figure is comparable to the frequency of smoking during pregnancy reported from other parts of the U.S. We found that if mothers smoked during early pregnancy, they doubled their risk of delivering an infant with a cleft malformation. The more cigarettes that were smoked per day, the higher risk that the baby would be born with a cleft. The highest risks associated with parental smoking, however, occurred among those infants who inherited an uncommon form of an embryonic facial growth factor, transforming growth factor-a (TGFa). Only about 5% of the general population has this particular uncommon form of TGFa. Other researchers had noticed that a higher percentage (~15%) of children who had a cleft had inherited this form of TGFa. Our results suggest that the reason why this uncommon form of TFGa is seen more frequently among infants with clefts is because the combination of having a mother who smokes during pregnancy, and the baby having the uncommon form of TGFa, makes the chance that the baby develops a cleft much higher.
 
 
 
 
 
 The purpose of the proposed research is to look for other genetic factors that may influence a fetus’ susceptibility to risk of a smoking-induced cleft. We propose to study the influence of genetic variation of six different enzymes that detoxify chemicals in tobacco smoke on the risk for orofacial clefts when mothers smoke during pregnancy. Our hypothesis is that if a fetus inherits an unusual form of an enzyme that detoxifies chemicals unusually slowly, he/she may be at higher risk to develop a birth defect because smoke-related toxins will remain in its blood and tissues longer, and at a higher concentration than in a fetus who inherits the normal form of the enzyme.
 
 
 
 
 
 Each enzyme that we plan to assess has several genetic forms, and for each enzyme, at least one of these genetic forms has been associated with higher risks for smoking-induced cancers compared to people who smoke and who have the common forms of the enzymes. The proposed research program makes use of smoking data and DNA samples from our completed, TRDRP-supported research on orofacial clefts, and support is sought only for adding analyses for the six genes that encode the detoxifying enzymes. The proposed research represents a unique opportunity to investigate the interplay between parental tobacco smoking during pregnancy and fetal variation of several enzymes that detoxify chemicals in tobacco smoke, and how this interaction determines the risk that the fetus will develop an orofacial cleft malformation.