This is a new project which means that the summary of work consists mostly of plans although some preliminary findings are included. The capability of exogenous compounds or their metabolites to form adducts with DNA is considered a crucial step in the initiation of carcinogenesis. A goal in this laboratory is to examine human tissue for DNA adducts for the purpose of assessment of exposures of humans to potential genotoxic agents. In a current study, digests of DNA prepared from human lymphocytes incubated with (3H) benzo(a)pyrene revealed adduct formation by both liquid chromatography and 32P-postlabeling analysis. The extent of adduct formation exhibited a wide range among individual donors, which might correlate with the individual capacity to deactivate reactive intermediates. Lymphocytes from smokers appeared to have no greater capacity to form adducts than lymphocytes from nonsmokers. We are currently analyzing lymphocyte DNA from heavy smokers and nonsmokers for the presence (in vivo) of polycyclic aromatic hydrocarbon-related adducts. The 32P-postlabeling method should provide a sensitive means for detection of adducts in human tissues. This study is being extended to include the detection of DNA adducts in human breast tissue. Furthermore dose-response relationships for DNA adducts are being examined in rodent models for hormone dependent mammary and liver cancer to evaluate whether estrogen-DNA adducts are formed and/or estrogens influence DNA adduction of dietary constituents or other hormones. In the mammary studies, the relationship, if any, between DNA adducts and altered growth factor (cell proliferation) pathways is being investigated.
