Twenty six-week exposure to 2 amino-3 methylimidazo [4,5-ƒ]quinoline (IQ) does not significantly increase the incidence of tumours in HMGCR/mts1 tg579 transgenic mice

Abstract

HMGCR/mts1 tg579 transgenic mice were designed to direct the expression of metastasis-promoting mts1  (S100A4) gene to all the tissues. In order to test the usefulness of this mouse model for carcinogenicity  tests shorter than that recommended by OECD guideline nr. 451, HMGCR/mts1 tg579 transgenic and  C57BL/6ByA (wild type) mice (15 males and 15 females of each genotype per group) received either a  control diet for 53 weeks or a control diet plus 0.03% 2-amino-3 methylimidazo[4,5-ƒ]quinoline  (IQ) for 26 weeks and a control diet for the remaining 27 weeks. IQ is a food mutagen with a carcinogenic  effect in non-human primates and rodents. IQ is a liver carcinogen and also causes lung tumours and  tumours of the forestomach in mice. Body weight gain and feed intake were decreased (p<0.05) during IQ  feeding in IQ-dosed mice of both genotypes and sexes. The daily dose of IQ, as calculated based on the  feed intake, was 43 and 46 mg/kg bw in HMGCR/mts1 tg579 transgenic males and females, and 43 and  45 mg/kg bw in C57BL/6ByA males and females. The survival rates of HMGCR/mts1 tg579 transgenic  mice were 100% for males and 93% for females in the control group, and 93% for both sexes in the IQtreated  group. The survival rates of C57BL/6ByA mice of both sexes were 100% in the control group and  93% in the IQ-treated group. Non-neoplastic lesions were found in all groups, except for HMGCR/mts1  tg579 transgenic control males, primary in the liver and were of various type but of single incidence with  not statistically significant difference between controls and IQ-treated groups of both genotypes and sexes.  Pre-neoplastic lesions were observed preferentially in the liver in IQ-treated HMGCR/mts1 tg579 transgenic  animals of both sexes. The total number of animals with tumours was: in HMGCR/mts1 tg579 transgenic  mice: males - 0/15 and 3/15, females - 2/14 and 1/15 and in C57BL/6ByA: males - 0/15 and 1/15,  females - 1/15 and 4/15, in control and IQ-treated animals, respectively. The primary tumours recorded in  HMGCR/mts1 tg579 transgenic mice were: one pleomorphic malignant lymphoma and one histiosarcoma  in the female control group, one liver hemangiosarcoma, one colon adenocarcinoma, and one malignant  lymphoma/lympholytic in IQ-treated males, and one colon adenoma in IQ-treated females. The primary  tumours recorded in C57BL/6ByA mice were: one histiocytic sarcoma in control females, one colon adenoma  in IQ-treated males, one colon adenocarcinoma, one pleomorphic malignant lymphoma, one malignant  lymphoma/lymphocytic, one thymic lymphoma, and one histiocytic sarcoma in IQ-treated females.  In conclusion, IQ feeding did not statistically significantly increase the incidence of tumours in  HMGCR/mts1 tg579 transgenic and C57BL/6ByA mice in this limited bioassay. The results in HMGCR/mts1  tg579 transgenic mice obtained under current experimental conditions suggest that 53 weeks may be not a  sufficient time span to demonstrate a carcinogenic potential of a test compound in this mouse model.