The continuing long term goals of this project are to: 1) evaluate the validity of interspecies (rat to human) extrapolation of carcinogenicity data using a mammary gland model, and 2) address the hypothesis that environmental xenobiotics are involved in the etiology of human breast cancer. In the first series of aims, the observation that in vitro rat mammary epithelial cells activate DMBA to mutagenic forms much more efficiently than B(a)P, while identically cultured human mammary cells activate B(a)P more effectively than DMBA, will be followed up. Two potential mechanisms that may explain these speciesspecific results will be explored. Late stages of Phase I metabolism of PAHs may yield different isomeric forms of secondary metabolites in human and rat mammary cells, or alternatively, differences in Phase II metabolism (conjugation) could result in speciesspecific detoxification patterns for Phase I metabolites. Direct mammary mutagenesis systems will also be used to further document the species differences. The second series of aims is to examine the ability to extrapolate these in vitro mammary cell species- and carcinogenspecific findings to the in vivo mammary gland. DNAcarcinogen adduct profiles in rat mammary cells in vivo and in vitro will be generated. The relative roles of systemic vs local mammary carcinogen metabolism in the generation of mammary adducts as well as the biological significance of these adducts will be explored. The final set of aims will address the hypothesis that the DNA of in situ human breast cells contains xenobiotic adducts. DNA adducts formed in human mammary cells in situ will be assayed using an enhanced sensitivity 32Ppost-labeling methodology. In addition, tissue from each individual studied for adducts will also be assayed for levels of various xenobiotics in their breast fat. Interindividual, differences in carcinogen metabolism and DNA adduction by human mammary cells from different individuals will be investigated. Potential mechanisms for the generation of DNA adducts in the breast as well as their biological significance will be explored. This project will address both the general question of the validity of interspecies extrapolation in evaluation of the carcingencity of chemicals, and also the role of environmental xenobiotics such as B(a)P in the etiology of human breast cancer, a major lethal human cancer.
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