PHARMACOGENETIC DETERMINANTS OF FETAL SOMATIC MUTATION

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Maternal lifestyle factors such as cigarette smoking and alcohol consumption are known to be the most prevalent sources of in utero exposure to toxic substances and clearly impact the health of newborn children. Our goal is to address the fundamental question concerning the extent to which genetic background modulates the impact of environmental exposures on levels of DNA damage. Interindividual and interethnic differences in xenobiotic metabolism are considered to be major contributors to variations observed in disease susceptibility. This proposal will evaluate the hypothesis that environmental and genetic determinants of enzyme activities which bioactivate and detoxify xenobiotics are important factors in modulating transplacental DNA damage. This proposal is directly linked to the ongoing NICHD funded grant 5 R01 HD33016 entitled "Lifestyle Factors Affecting Fetal Somatic Mutation", P.I. W. L. Bigbee. This parent study is investing substantial resources in the acquisition of clinical and epidemiological characterization of 1,500 women and newborns across a wide sociodemographic spectrum and is applying several molecular biomarkers of exposure and effect. These biomarkers include determination of 4- aminobiphenyl hemoglobin adducts levels and mutation frequency levels at two independent loci (glycophorin A and hypoxanthine phosphoribosyl transferase). For these same subjects, we propose to apply genotyping assays to both maternal and newborn blood samples focusing on the polymorphic enzymes involved in the metabolism of chemicals found in cigarette smoke, specifically CYP1A1, CYP2E1, GSTM1, GSTT1, NAT1*, and NAT2*. Screening by RT-PCR for the level of mRNA expression of CYP1A1, CYP1B1 and CYP2E1 in peripheral blood mononuclear cells will also be performed as biomarkers of enzyme phenotypic activity and exposure to tobacco smoke. The integration of pharmacogenetic information from this genotype and phenotype data with sociodemographic information for individually measured environmental risk factors and the measured exposure/effect biomarkers, will enable the study of the specific associations between the expression of the metabolizing enzyme genes and the presence of specific allelic variants, to the induction of genetic damage in newborns. Preliminary data from maternal samples acquired to date support this hypothesis and blood samples continue to be banked to ensure the availability of complete information for each subject. This proposed investigation, in the context of the ongoing funded study, therefore represents a very powerful and cost-effective strategy to investigate the relative contributions of genetic risk factors and maternal environmental interactions to newborn susceptibility to DNA damage.