Date of Graduation

1996

Document Type

Dissertation/Thesis

Abstract

C57BL/6 female mice were used to analyze the effect on chromosomes of chronic ingestion of a single mutagen. Three known carcinogens were analyzed: 2-amino-1-methyl-6-phenylimidazo (4,5-b) pyridine (PhIP), cyclophosphamide (CP) and urethane (ethyl carbamate, EC). Exposures to PhIP were in powdered rodent chow. The endpoints analyzed were chromosome aberrations as measured by chromosome painting for mouse chromosomes 2 and 8, sister chromatid exchanges (SCEs) and micronucleated erythrocytes (MN NCEs). Analysis of peripheral blood lymphocytes and bone marrow by chromosome painting was done at 4 weeks and 16 weeks; no significant increases in the frequency of aberrations were seen. A significant increase in the frequency of MN NCEs was seen at 16 weeks. A significant increase in the frequency of SCEs in peripheral blood lymphocytes was seen in mice exposed for 25 weeks. The frequencies of MN NCE's and SCE's decreased to within control values after PhIP was removed from the diet for approximately 1 month. These results indicate that chronic ingestion of PhIP does not result in the persistence of chromosome damage measured by chromosome painting, SCEs or MN NCEs. Cylclophosphamide was dissolved in sterile drinking water. Bone marrow was analyzed by chromosome painting at 4 and 8 weeks and peripheral blood lymphocytes were analyzed by chromosome painting at 18 weeks; a statistically significant difference between control and exposed mice was not seen. A significant increase in frequency of MN NCEs was seen at all concentrations of CP starting at 4 weeks. Following removal of CP frequencies decreased to control levels. These results suggest that chronic ingestion of CP does not result in the induction or persistence of chromosome aberrations measured by chromosome painting or micronucleated erythrocytes. Urethane was dissolved in sterile drinking water. Bone marrow was analyzed by chromosome painting at 4 and 8 weeks; a significant increase in the frequency of fragments was seen at both timepoints. Peripheral blood lymphocytes were analyzed by chromosome painting at 18 weeks; a significant increase in aberrations was not seen. A significant increase in MN NCEs was seen at 4, 8 and 12 weeks, which decreased to within control values after EC had been removed from the drinking water for 6 weeks. These results indicate that chronic ingestion of EC is clastogenic and that induced lesions do not persist following removal of EC. PhIP, CP and EC did not induce stable chromosome aberrations detectable under the experimental conditions used here. However all three carcinogens induced a significant increase in the frequency of micronucleated normochromatic erythrocytes. Thus the carcinogens reached the tissues of choice. Also, PhIP induced a significant increase in sister chromatid exchanges further indicating the clastogenic effect of these chemicals. These combined results imply that chronic exposure to chemical carcinogens induces chromosome breakage measurable by traditional assays (sister chromatid exchanges and micronuclei) but not the breakage and reunion necessary to see chromosome damage by painting. (Abstract shortened by UMI.).

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