The primary objective of this project is to validate and apply a genotoxicity assay for measuring in vivo. Somatic cell mutations in humans. The assay, which was developed during the last six years, will detect loss of gene expression (""""""""null"""""""" mutations) and also conversion of gene expression (mitotic recombination) at the locus coding for the erythrocyte cell surface sialoglycoprotein glycophorin A (GPA). It can be performed on small samples of peripheral blood and results in a measurement of the frequency of hemizygous or homozygous variant red blood cells, which are hypothesized to be the progeny of mutant erythroid precursor cells and reflect the exposure of the bone marrow to mutagenic events. Thus it appears to be a biodosimeter of exposure that should be useful in the conduct of epidemiologic studies. The assay also gives distinctive results for individuals that are heritably susceptible to high cancer incidence (Bloom's Syndrome and Ataxia Telangiectasia). Therefore, it appears to be a maker for susceptibility to mutagenic damage that might well be related to cancer risk, another important maker for epidemiologic studies. The experimental design is to perform this immunolabeling flow cytometric analysis on three different cohorts of individuals exposed to chemical mutagens; 1). cancer patients being treated with chemotherapy that includes known stem cell mutagens, 2) cigarette smokers, and 3) identical twins that have lived under different environmental conditions. Results from these exposed populations will be compared to results on matched control cohorts and/or to assays obtained on the same individuals prior to exposure. Thus, a validation of the relation between exposure to particular mutagenic chemicals and response of this new genotoxicity assay should be established and allow its more general use in epidemiologic studies.
