Abstract 2721: Induction of aberrant crypt foci in the colon of mice exposed to tobacco carcinogen 2-amino-9H-pyrido[2,3-b]indole

Abstract

Abstract Epidemiological studies indicate that tobacco smoking is a risk factor for colon cancer. However, the etiological agents in tobacco smoke remain uncertain. Heterocyclic aromatic amines (HAAs) that are produced during high-temperature cooking of the proteinaceous food are associated with the elevated risk of colon cancer. Tobacco smoking also produces HAAs, the most abundant one being 2-amino-9H-pyrido[2,3-b]indole (AαC). The carcinogenic potency of AαC is unknown in humans, but AαC forms DNA adducts in multiple organs, including liver and colon, as well as being carcinogenic in rodents. In this study, AαC-induced colon cancer risk was assessed by determining DNA adducts and putative colonic precancerous lesions, aberrant crypt foci (ACF) and dysplastic ACF. For comparison, the HAA, 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), a liver and colon carcinogen in mice, and azoxymethane (AOM), a potent colon carcinogen in rodents, were also administered. AαC (400 ppm) or MeIQ (300 ppm) were fed in a high-fat diet to A/J mice (n = 12 per group) for 4 weeks. AOM was injected intraperitoneally to another 12 mice at 5 mg/kg body weight weekly for 6 weeks. At the end of carcinogen treatment, liver and colon were harvested from 4 mice from each group for DNA adduct measurement. dG-C8-AαC, dG-C8-MeIQ, and O6-methyl-dG DNA adducts were measured by liquid chromatography/mass spectrometry. The remaining 8 mice from each group were then fed a carcinogen-free diet for additional 8 weeks, and then colons harvested. Colonic total and dysplastic ACF were counted by light microscopy after appropriate staining. AαC feeding induced the greatest number of DNA adducts in liver, followed by AOM and MeIQ. AOM administration and AαC feeding induced similar numbers of DNA adducts in the colon, both of which were significantly greater than MeIQ. However, AOM administration induced a significantly greater number of total and dysplastic ACF in the colons than did feeding either AαC or MeIQ, which had similar numbers of ACF and dysplastic ACF. The high levels of AαC DNA adducts and induced dysplastic ACF in this animal model, provide biological plausibility for a causal role for AαC in tobacco-induced colorectal carcinogenesis. However, DNA adduct numbers induced by these three carcinogens was not proportional to the colonic ACF or dysplastic ACF number, suggesting that different types of DNA adducts differ in their ability to promote colonic precancerous lesions. Citation Format: Sangyub Kim, Jingshu Guo, Sabrina P. Trudo, Daniel D. Gallaher, Robert J. Turesky. Induction of aberrant crypt foci in the colon of mice exposed to tobacco carcinogen 2-amino-9H-pyrido[2,3-b]indole. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2721. doi:10.1158/1538-7445.AM2015-2721