Aflatoxin Bl (AFBl) is a toxin produced by the mold Aspergillus flavus which is potently carcinogenic in a number of animal tissues. When present in the diet, it is a potent hepatocarcinogen, but some epidemiological studies indicate that AFBl is a risk factor in the development of tracheobronchial tumors in workers exposed to AFBl-laden dusts, such as is common in grain terminals, peanut and cottonseed processing plants, and grain silos, and hence may be a significant occupational carcinogenic hazard. The long-range goal of the proposed research is to determine the carcinogenic potential of this toxin in the respiratory tract of mammalian species, as well as provide important information on the mechanisms of carcinogen action in upper airway epithelium. Important determinants in susceptibility to aflatoxin carcinogenesis include the relative extent of enzyme- mediated activation and detoxification, repair of resultant AFBl- DNA adducts, and the response of the exposed tissues. The characteristics and activity of phase I enzyme systems for AFB1 activation. Production of specific metabolites, formation and relative rates of removal of specific AFBl-DNA adducts will be determined in tracheal explant cultures derived from mammalian species (rabbit, hamster, rat, monkey, and human) with differing cellular morphology of the upper airways which we have shown in previous studies to relate to AFBl susceptibility. In these cultures, the cellular distribution of labeled AFB1 will be determined via autoradiographic analysis, and specific ultrastructural cellular alterations in the respiratory epithelium will be determined using electron microscopy. Little is known of the efficiency of phase II detoxification reactions in mammalian upper airway epithelium. Glutathione, UDP-glucuronic acid and sulfate conjugates of AFB1 formed in culture, as well as glutathione-s-transferase and epoxide hydrase activity will also be characterized. These in vitro mechanism studies will be accompanied by whole- animal studies to examine potential gross, ultrastructural, histochemical, pre- or carcinogenic alterations in tracheobronchial morphology in hamsters exposed to AFBl via the respiratory tract.
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