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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES004813-04
Application #
3252957
Study Section
Safety and Occupational Health Study Section (SOH)
Project Start
1987-10-01
Project End
1991-08-31
Budget Start
1989-09-01
Budget End
1990-08-31
Support Year
4
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Utah State University
Department
Type
Graduate Schools
DUNS #
City
Logan
State
UT
Country
United States
Zip Code
84322
Coulombe Jr, Roger A (2003) Pyrrolizidine alkaloids in foods. Adv Food Nutr Res 45:61-99
Van Vleet, Terry R; Mace, Katherine; Coulombe Jr, Roger A (2002) Comparative aflatoxin B(1) activation and cytotoxicity in human bronchial cells expressing cytochromes P450 1A2 and 3A4. Cancer Res 62:105-12
Van Vleet, Terry R; Klein, Patrick J; Coulombe Jr, Roger A (2002) Metabolism and cytotoxicity of aflatoxin b1 in cytochrome p-450-expressing human lung cells. J Toxicol Environ Health A 65:853-67
Van Vleet, T R; Klein, P J; Coulombe Jr, R A (2001) Metabolism of aflatoxin B1 by normal human bronchial epithelial cells. J Toxicol Environ Health A 63:525-40
Kelly, J D; Eaton, D L; Guengerich, F P et al. (1997) Aflatoxin B1 activation in human lung. Toxicol Appl Pharmacol 144:88-95
Ball, R W; Huie, J M; Coulombe Jr, R A (1995) Comparative activation of aflatoxin B1 by mammalian pulmonary tissues. Toxicol Lett 75:119-25
Coulombe Jr, R A (1993) Biological action of mycotoxins. J Dairy Sci 76:880-91
Ball, R W; Coulombe Jr, R A (1991) Comparative biotransformation of aflatoxin B1 in mammalian airway epithelium. Carcinogenesis 12:305-10
Coulombe, R A; Huie, J M; Ball, R W et al. (1991) Pharmacokinetics of intratracheally administered aflatoxin B1. Toxicol Appl Pharmacol 109:196-206
Wilson, D W; Ball, R W; Coulombe Jr, R A (1990) Comparative action of aflatoxin B1 in mammalian airway epithelium. Cancer Res 50:2493-8

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