Congenital heart disease is a major cause of mortality and morbidity. Exposure to halogenated hydrocarbons, specifically trichloroethylene (TRI), during pregnancy has been associated with congenital heart disease in animal models and retrospective epidemiology studies. Multiple studies support trichloracetic acid (TCA), a TRI metabolite, as the metabolite, as the more proximate teratogen. Overall hypothesis is that commonly observed levels of trichlorinated hydrocarbon exposure during human pregnancy are associated with an increase for offspring congenital heart disease and that genetic and phenotypic differences in the key enzymes responsible for the formation of TCA are associated with differences in offspring susceptibility.
The specific aims are to 1) prospectively determine the risk of congenital heart disease from commonly observed levels of maternal exposure to trichlorinated hydrocarbons during pregnancy and 2) determine the differences in the offspring risk for congenital heart disease from maternal intersubject variation in the enzymes catalyzing the disposition of TRI among mother-infant pairs with documented trichlorinated hydrocarbon exposure during pregnancy. To complete these aims, we will determine the presence of congenital heart disease by performing echocardiography on infants selected using a stratified recruitment strategy based on 1) maternal urinary trihalogenated hydrocarbon concentrations measured during pregnancy using a sensitive GCMS assay 2) maternal CYP2E1 genotype for a polymorphism associated with increased CYP2E1 activity in the presence of inducers and 3) maternal ADH2 genotype, a polymorphism which impacts the metabolism of other small molecular weight hydrocarbons. In addition, because multiple environmental factors alter CYP2E1 metabolic ability, some by post-transcriptional mechanisms, we will evaluate maternal white blood cell microsomal immunoreactive CYP2E1 during pregnancy as an important biomaker of increased offspring risk. Because the genotypes of interest are more common in the African-American population and because TRI emissions are documented in the Milwaukee area, an urban Milwaukee, African-American population will be studied. Maternal exposure to volatile organic solvents and ethanol will be measured and induced as potential confounders. Ultimately, the data generated in this proposal, will leaf to a better understanding of the genetic and environmental mechanisms determining susceptibility for congenital heart disease and provide the knowledge necessary for future public health prevention/intervention strategies.
| Yauck, Jennifer S; Malloy, Marsha E; Blair, Kathleen et al. (2004) Proximity of residence to trichloroethylene-emitting sites and increased risk of offspring congenital heart defects among older women. Birth Defects Res A Clin Mol Teratol 70:808-14 |
