EFFECTS OF GENDER AND SPECIES ON SPECTRA OF MUTATION INDUCED BY 2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE IN THE LACI TRANSGENE

Feeding of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) to F 344 rats induces colon tumors specifically in male rats. Mutant freque ncies and mutational spectra of the lacI transgene were studied in mal e and female Big Blue(R) transgenic rats after feeding 400 ppm of PhIP in the diet for 60 days. Mutant frequencies in the colon mucosa were increased 20-25 times compared with those of the control rats, being 6 61.4 +/- 33.3 x 10(-6) and 718.2 +/- 16.9 x 10(-6) in males and female s, respectively. No significant differences in types and distribution of the mutations were detected between males and females. One-base del etions were the most frequent mutation, including the characteristic g uanine deletion at 5'-GGGA-3' which is also seen in the Ape gene of ra t colon cancers induced by PhIP. Comparison of the lad mutations in th e rat colon with those previously identified in the mouse colon showed that the rate of G to T transversions was significantly higher in the mouse. This is the first report stating that there exist differences in the mutation specificity on the same gene, among mammalian species. However, the characteristic guanine deletion was recovered in both th e mouse and the rat. These findings do not offer a mechanistic explana tion of the gender specificity of PhIP-induced colon cancer in rats, t hough the universality of the guanine deletion suggests that this alte ration may prove a useful indicator of human exposure. (C) 1997 Elsevi er Science B.V.