Effect of heterozygous loss of p53 on benzo[a]pyrene-induced mutations and tumors in DNA repair-deficient XPA mice

Conny Th M. Van Oostrom, Miranda Boeve, Jolanda D. Van Den Berg, Annemieke De Vries, Martijn E.T. Dollé, Rudolf B. Beems, Coen F. Van Kreijl, Jan Vijg, Harry Van Steeg

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

XPA-deficient mice have a complete deficiency in nucleotide excision repair, and as such they display a cancer predisposition after exposure to several carcinogens. Besides being sensitive to genotoxic agents applied to the skin, they are also susceptible to human carcinogens given orally, like benzo[a]pyrene (B[a]P). To study the role of the tumor suppressor gene p53 in DNA repair, gene mutation, and tumor induction, we crossed XPA-deficient mice with p53 knockout mice and lacZ (pUR288) gene marker mice. When treated orally (by gavage) with B[a]P, the XPA(-/-)/p53(+/-) double transgenic mice developed tumors much earlier and with higher frequency compared to their single transgenic counterparts. The major tumor type found in all genotypes was generalized lymphoma mainly residing in the spleen; several sarcomas were observed in p53(+/-) and XPA(-/-)/p53(+/-) mice. Next, we determined lacZ mutation frequencies in several (non)target tissues. It appeared that in the spleen (the major tumor target tissue) of XPA(-/-) and XPA(-/-)/p53(+/-) mice the lacZ mutation frequency was significantly elevated (80100 x 10-5), and was two times higher as found in spleens of B[a]P-treated WT and p53(+/-) mice (P = 0.003). In nontumor target tissues like liver and lung, we found a moderate increase in the lacZ gene mutation frequency (30-40 x 10-5), which was independent of the genotype. The results obtained with the DNA-repair deficient XPA mice indicate that a significantly increased lacZ mutation frequency in a particular organ/tissue is an early marker for tumor development at later stages at the same site. However, the synergistic effect of a XPA(-/-)- and a p53(+/-)-deficiency in tumor development is not reflected by an absolute increase in the lacZ mutation frequency in the major tumor target tissue of XPA(-/-)/p53(+/-) or p53(+/-) mice compared to that of XPA(-/-) and WT mice, respectively.

Original languageEnglish (US)
Pages (from-to)124-130
Number of pages7
JournalEnvironmental and Molecular Mutagenesis
Volume34
Issue number2-3
DOIs
StatePublished - Nov 8 1999
Externally publishedYes

Keywords

  • Benzo[a]pyrene
  • Mutagenesis
  • Transgenic mice
  • Tumor induction
  • XPA
  • Xeroderma pigmentosum
  • lacZ
  • p53

ASJC Scopus subject areas

  • Epidemiology
  • Genetics(clinical)
  • Health, Toxicology and Mutagenesis

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  • Cite this

    Van Oostrom, C. T. M., Boeve, M., Van Den Berg, J. D., De Vries, A., Dollé, M. E. T., Beems, R. B., Van Kreijl, C. F., Vijg, J., & Van Steeg, H. (1999). Effect of heterozygous loss of p53 on benzo[a]pyrene-induced mutations and tumors in DNA repair-deficient XPA mice. Environmental and Molecular Mutagenesis, 34(2-3), 124-130. https://doi.org/10.1002/(SICI)1098-2280(1999)34:2/3<124::AID-EM11>3.0.CO;2-F