Authors
Shaw, GM., Nelson, V., Iovannisci, D., Finnell, R., Lammer, EJ.

Title
Maternal occupational exposures and biotransformation genotypes as risk factors for selected congenital anomalies

Journal
American Journal of Epidemiology, 157: 475-484. 2003.

Summary
Biotransformation is a two phase enzymatic process by which foreign compounds are broken down and eliminated from the body. Genes that encode for enzymes involved in this process normally undergo random sequence variations and certain variations may accumulate in a population due to selective pressures. If the frequency of a specific sequence variation reaches 1% or more it is called a polymorphism. If the sequence variation frequency reaches 10%, it is considered common. Polymorphisms may have no effect or they may be considered functional if they result in altered catalytic function, stability, and/or level of expression of the resulting protein. Some evidence has suggested that individuals with certain types of polymorphisms may be differentially susceptible to environmental toxicants. Shaw et al. examined the risk of a variety of birth defects in infants whose mothers were occupationally exposed to chemicals during a critical developmental window. In addition, genotyping for polymorphisms of phase II xenobiotic metabolizing enzymes were analyzed for their association with specific chemical exposures and orofacial clefts.

This study consisted of 1034 cases of infants and fetal deaths (>20 weeks gestation) between 1987-1988 diagnosed with the following birth defects: conotruncal heart defects, limb deficiencies, orofacial clefts [isolated cleft palate (CP), cleft lip or cleft palate (CLP)]. The medical records were reviewed and confirmed by a clinical geneticist. The control group was randomly selected from all infants born alive in the same geographic area and time period. Genotyping for polymorphisms of phase II xenobiotic metabolizing enzymes (GSTM1, GSTT1, NAT1, NAT2) was performed on infant cases with isolated cleft palate and cleft lip with or without cleft palate, as well as 300 randomly selected control infants. In addition, telephone interviews were conducted with the mothers of all infants to obtain demographic and occupational history during a critical exposure window, 1 month prior to and 3 months after conception. Task specific information was collected from which chemical exposures were derived. An industrial hygienist further classified women as "likely", "maybe", or "not" exposed. The interviews were conducted with a relatively high response rate (over 80% cases and 76% controls) however, on average the interviews were conducted nearly 4 years after the delivery date.

An array of 74 chemical exposures were examined for their association with heart, limb and orofacial clefts including pesticides, polycyclic aromatic hydrocarbons, plastics, propellants, pyrolysis/combustion products, and housekeeping cleaners. Overall the results did not reveal any associations with chemical exposures during the month prior to pregnancy and the first trimester of pregnancy and birth defects.

The analysis of isolated CLP or isolated CP which considered both maternal chemical exposures and infant susceptible genotypes showed some elevated by imprecise finding. An increase in isolated CP were observed for GSTM1 homozygous variant genotype and propellants (OR=3.4, 95% CI=1.0-12.0), GSTM1 and hydrocarbons (OR=4.6, 95% CI=1.0-19.0), and NAT2 slow acetylator genotype and propellants (OR=4.0, 95% CI-1.1-13.5).

Although the results of this study are quite inconclusive it does address the important question of gene-environment interactions. Studies have demonstrated that the fetus is able to express biotransformation enzymes early in development. If the fetus contains an enzyme variant that produces slower clearance of a potentially toxic compound, it may increase the length of fetal exposure. However, during gestation the fetus is exposed to all the nutrients and xenobiotics that are in the mother's circulatory system via the placenta. Therefore, it would also have been informative to observe maternal enzyme levels. Some limitations to this study include the possibility of recall bias given its design and the lag time between the delivery data and the questionnaire. Women who had a child with a birth defect may have differentially recalled work exposures prior to and during pregnancy. As well, the study used an indirect method to obtain women's exposures, which was also dependent on the accuracy of the industrial hygienist review.