Short-term carcinogenicity testing of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) in E(mu)-pim-1 transgenic mice.
The usefulness of transgenic E(mu)-pim-1 mice over-expressing the pim-1 oncogene in lymphoid tissues, as sensitive test organisms was studied in a short-term carcinogenicity study. The mice were fed standard diet Altromin 1314 supplemented either with 0.03% 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) for 7 months or with 0.03% 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) for 6 months. PhIP and IQ are heterocyclic amines formed during cooking of meat and fish and are mutagenic to bacteria and cultured mammalian cells. PhIP is a potent mouse lymphomagen, while IQ is a liver carcinogen and also causes lung tumors and tumors of the forestomach in mice. We found that transgenic E(mu)-pim-1 mice are highly susceptible to PhIP induced lymphomagenesis but do not respond to the IQ treatment. PhIP feeding of E(mu)-pim-1 mice not only increased the total number of T-cell lymphomas but also decreased the latency time compared to either transgenic or wild-type controls. The effect was most pronounced in the treated female E(mu)-pim-1 mice, which showed a higher incidence of PhIP induced T-cell lymphomas than transgenic males and a strongly reduced latency period after PhIP treatment compared to non-transgenic mice. Our results suggest that the transgenic E(mu)-pim-1 mouse may be a useful model for short-term carcinogenicity screening of potential genotoxic carcinogens having the lymphoid system as target tissue. The carcinogen IQ which does not have the lymphoid system as a target was not recognized in this model.
National Food Agency, Institute of Toxicology, Søborg, Denmark.
I K
IK
Sørensen
A
A
Mortensen
E
E
Kristiansen
C
C
van Kreijl
R H
RH
Adamson
S S
SS
Thorgeirsson
D000818:Animals; D015197:Carcinogenicity Tests / Q000379:methods*; D002273:Carcinogens / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004742:Enhancer Elements, Genetic; D005260:Female; D007093:Imidazoles / Q000633:toxicity*; D008214:Lymphocytes / Q000502:physiology; D008223:Lymphoma / Q000139:chemically induced*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051573:Proto-Oncogene Proteins c-pim-1; D011804:Quinolines / Q000633:toxicity*; D012737:Sex Factors; D013997:Time Factors
D002273:Carcinogens; D007093:Imidazoles; D011518:Proto-Oncogene Proteins; D011804:Quinolines; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; C496636:Pim1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1