Pre-neoplastic lesions associated with liver and colon responses to 1,2-dimethylhydrazine in an animal model of colorectal cancer

Background: The high incidence and mortality of colorectal cancer (CRC) combined with the lack of an effective method for early diagnosis and effective treatments make CRC one of the most relevant cancers to be studied. Thus, our work aims to study the spectrum of liver and colon lesions induced in rats by the 1,2-Dimethylhydrazine (DMH). Materials and methods: Twenty-nine male Wistar rats were randomly divided into two control groups (CTRL1 (n=6) and CTRL2 (n=6)) administrated with ethylenediamine tetraacetic acid (EDTA)-saline; and two induced groups (CRC1 (n=8) and CRC2 (n=9)) administrated with DMH (40 mg/kg) for 7 consecutive weeks. The CRC1 and CTRL1 groups, and the CRC2 and CTRL2 groups were sacrificed 11 and 17 weeks after the first administration, respectively. A complete necropsy was performed. Liver and colon samples of all animals were collected, fixed in formalin, and processed for histopathological analysis. The animals' blood and a small portion of the liver were collected to analyze serum markers of inflammation and to validate chemical induction through the comet assay, respectively. Results: Half of the animals belonging to the CRC1 group presented mild to moderate dysplasia foci (n=3) in the colon. The incidence of neoplasia was only 16.7% (n=1) in the CRC2 group. Moreover, one animal from the CRC2 group also exhibited severe dysplasia and two presented mild to moderate dysplasia foci. Inflammatory lesions in colon samples were present in all animals from CRC groups. Although the animals showed local inflammation, there was no evidence of systemic inflammation (normal CRP and IL-6 serum levels). Lymphoid inflammatory aggregates were observed in the liver of all animals. Furthermore, DMH induced other changes, such as hepatocyte megalocytosis and single-cell necrosis. Results from liver comet assay showed a lower genetic damage index in control groups when compared to DMH-exposed groups (p<0.05), i.e. DMH induced DNA damage in rats’ liver. Conclusions: Once animals showed predominantly pre-neoplastic lesions, our data suggest that the disease was at an early stage. In the future, we intend to change the dose of the carcinogen and the time of exposure to observe advanced stages of CRC development. We consider that this model is useful in the study of CRC chemoprevention associated with local inflammation