Precancerous ACF induction affects their regional distribution forsaking oxidative stress implication in 1,2-dimethylhydrazine-induced colon carcinogenesis model

Colon cancer is thought to develop in a stepwise fashion. In this study, the relationship between aberrant crypt foci (ACF) regional distribution and oxidative stress evolution was studied in a murine model of initial colon carcinogenesis induced by dimethylhydrazine (DMH). Mice were given 2 weekly subcutaneous injections of DMH (20 mg/kg) and killed at the 10th, 12th or 14th week. ACF was scored for number, distribution and crypt multiplicity after methylene-blue coloration and histologically analyzed afterwards. Oxidative stress evaluation was assessed through myeloperoxidase activity (MPO), nitric oxide (NO), l-ornithine and malondialdehyde (MDA) levels as well as antioxidant CAT, SOD and GSH. DMH treatment showed a shift from small to large ACF but also from distal to proximal colon between week 10 and 14 (p < 0.05). This was further illustrated histologically with crypt disruption and mucin depletion. Oxidative stress imbalance was observed in all DMH-treated groups. All markers (MPO, MDA and NO) peaked at week 12 (p < 0.01) and decreased at week 14 (p < 0.05) while l-ornithine decreased through all protocol (p < 0.01). Antioxidants decreased in all points (p < 0.05) but only GSH increased at week 14 (p < 0.05). This work provided insight to response-patterns of oxidative stress between distal and proximal colon, showing for the first time a decreasing implication during the development process and suggesting other inflammatory, immunologic or microbiota implication as factors to be considered during chemotherapy approaches.