Use of E mu-PIM-1 transgenic mice short-term in vivo carcinogenicity testing: lymphoma induction by benzo[a]pyrene, but not by TPA

E mu-pim-1 transgenic mice are predisposed to develop lymphomas. Due totheir low spontaneous tumour incidence and their increased sensitivitytowards the lymphomagen ethylnitrosourea these mice may present aninteresting model for short-term carcinogenicity testing. Here, we reporton the further exploration of this transgenic mouse model with twoadditional carcinogens known to have, among others, thelymphohaematopoietic system as target, i.e. benzo[a]pyrene (B[a]P) and12-O-tetradecanoylphorbol-13-acetate (TPA). B[a]P, given three times a week(by gavage) for 13 weeks at 4.3, 13 or 39 mg/kg body weight, resulted in adose-related increase in lymphomas up to a 90% incidence in E(mu)-pim-1mice during the observation period of 40 weeks. B[a]P also induced tumoursof the forestomach within this observation period, though at a lowerincidence and apparently equally effective in wildtype and transgenic mice.TPA, on the other hand, was unable to induce lymphomas (or tumours in anyother organ) in either transgenic or wildtype animals within theobservation period of 44 weeks, when applied dermally at the maximumtolerated dose of 3 microg/mouse, twice a week for 35 weeks. Molecularanalysis showed that B[a]P-induced lymphomas in transgenic mice were ofT-cell origin, 80% of which had elevated levels of c-myc expression. Noneof the lymphomas had increased N-myc expression and mutation analysis ofthe ras-gene family revealed a K-ras mutation in only one out of eighttumours investigated. Also, none of the lymphomas showed aberrantexpression of p53 as determined by immunohistochemistry. It is concludedthat the E mu-pim-1 mouse model will not be very suitable for short-termcarcinogenicity testing in general: only genotoxic chemicals that have thelymphohaematopoietic system as target for carcinogenesis in wild- typemice, appear to be efficiently identified.