INDUCTION OF DNA-ADDUCTS AND MUTATIONS IN SPLEEN, LIVER AND LUNG OF XPA-DEFICIENT LACZ TRANSGENIC MICE AFTER ORAL TREATMENT WITH BENZO[A]PYRENE - CORRELATION WITH TUMOR-DEVELOPMENT/

We were interested to study the relationship between DNA lesions, DNA repair, mutation fixation, and tumour development, Therefore, mice har bouring lacZ reporter genes and being either wild-type or defective in the DNA excision repair gene XPA, were treated with the genotoxic car cinogen benzo[a]pyrene at an oral dose of 13 mg/kg b.w. (3 times/week) . At different time points, i.e. 1,5,9 or 13 weeks after start of the oral administration, levels of BPDE-N-2-dG adducts (the major formed D NA adduct by benzo[a]pyrene in mice), and lacZ mutation frequencies we re measured both in target (spleen) and non-target (lung and liver) ti ssues, Both in mild-type and XPA-deficient mice, benzo[a]pyrene treatm ent resulted in increased BPDE-N-2-dG adduct levels in all three tissu es analysed, In XPA-deficient mice, BPDE-N-2-dG adduct levels still in creased up to 13 weeks of oral benzo[a]pyrene treatment, whereas in DN A repair proficient mice steady-state levels were reached after 5 week s of treatment, After 13 weeks, the BPDE-N-2-dG adduct levels observed in XPA(-/-) mice, were 2- to 3-fold higher than the steady state leve ls observed in XPA(+/+) mice in the same tissues, Mutation frequencies in the lacZ reporter gene were the same in wild-type and XPA-deficien t mice that were treated with the solvent only, Oral benzo[a]pyrene tr eatment resulted in an increase in mutation frequency in the lacZ mark er gene in all three tissues, but this increase was most profound in t he spleen, After 13 weeks of treatment, a 7-fold increase in lacZ muta tion frequency was detected in the spleen of wild-type mice as compare d to mutation frequencies in control mice, At the same time point, a 1 5-fold increase in lacZ mutation frequency was observed in the spleen of XPA-deficient mice, The data presented here show, that a defect in NER mainly results in enhanced mutation frequencies in Lymphocytic cel ls after oral treatment with the genotoxic compound benzo[a]pyrene. In terestingly, as we established in a previously performed carcinogenici ty assay, the same oral treatment with benzo[a]pyrene induced lymphoma s residing in the spleen of XPA-deficient mice.