Age-dependent induction of aberrant crypt foci in rat colon by 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine and azoxymethane.

Abstract

Pups and adult rats received seven oral exposures (three time weekly) of the food mutagen PhIP (50 mg/kg), or two subcutaneous exposures (once weekly) of the experimental carcinogen azoxymethane (3.75 mg/kg). Aberrant crypt foci (ACF) were scored 8 weeks after the first exposure. In addition, lactating dams with suckling pups were orally exposed to 50 mg/kg of PhIP, three times weekly for three weeks. Direct PhIP exposure of pups induced 2.2 times more ACF than similar exposure of adult rats (2.0+/-0.0 versus 0.9+/-0.8, P<0.05). The growth of ACF, expressed as crypt multiplicity AC/ACF, was 3.5 times larger in neonatally exposed rats than in rats exposed in adulthood (8.0+/-7.3 versus 2.3+/-1.6, P<0.05). PhIP exposure via breast milk induced ACF in 3 of 25 animals. However, the difference versus controls, which had no ACF, did not reach statistical significance. Contrary to PhIP, azoxymethane induced more ACF in adult rats than in pups (2.8+/-1.9 versus 4.8+/-1.7, P<0.05). Similarly to PhIP however, azoxymethane induced 3.2 times larger ACF (AC/ACF) in pups than in adult rats (11.9+/-8.4 versus 3.7+/-1.9, P<0.001). Whereas no PhIP-induced ACF (0/15) were observed in the lymphoid follicles, approximately 60% of the azoxymethane-induced ACF (32/56) were located in these structures. This difference was statistically significant (P<0.001). The density of azoxymethane-induced ACF was 80 times larger in the lymphoid follicles than in the surrounding mucosa (P<0.01). Based on the assumption that the formation of ACF with high multiplicity is predicative for the tumour development we conclude that neonatal rats are more susceptible to PhIP and azoxymethane than adult rats.