Carcinogenesis, Vol 18, 2327-2332, Copyright © 1997 by Oxford University Press
A de Vries, ME Dolle, JL Broekhof, JJ Muller, ED Kroese, CF van Kreijl, PJ Capel, J Vijg and H van Steeg
We were interested to study the relationship between DNA lesions, DNA
repair, mutation fixation, and tumour development. Therefore, mice
harbouring lacZ reporter genes and being either wild-type or defective in
the DNA excision repair gene XPA, were treated with the genotoxic
carcinogen 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-N2-dG adducts (the major formed DNA adduct
by benzo[a]pyrene in mice), and lacZ mutation frequencies were measured
both in target (spleen) and non-target (lung and liver) tissues. Both in
wild-type and XPA-deficient mice, benzo[a]pyrene treatment resulted in
increased BPDE-N2-dG adduct levels in all three tissues analysed. In
XPA-deficient mice, BPDE-N2-dG adduct levels still increased up to 13 weeks
of oral benzo[a]pyrene treatment, whereas in DNA repair proficient mice
steady-state levels were reached after 5 weeks of treatment. After 13
weeks, the BPDE-N2-dG adduct levels observed in XPA-/- mice, were 2- to
3-fold higher than the steady state levels observed in XPA+/+ mice in the
same tissues. Mutation frequencies in the lacZ reporter gene were the same
in wild- type and XPA-deficient mice that were treated with the solvent
only. Oral benzo[a]pyrene treatment resulted in an increase in mutation
frequency in the lacZ marker gene in all three tissues, but this increase
was most profound in the spleen. After 13 weeks of treatment, a 7-fold
increase in lacZ mutation frequency was detected in the spleen of wild-type
mice as compared to mutation frequencies in control mice. At the same time
point, a 15-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 cells
after oral treatment with the genotoxic compound benzo[a]pyrene.
Interestingly, as we established in a previously performed carcinogenicity
assay, the same oral treatment with benzo[a]pyrene induced lymphomas
residing in the spleen of XPA- deficient mice.
ARTICLES
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 tumour development
University of Utrecht, Department of Immunology, The Netherlands.
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