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

XPA-deficient mice have a complete deficiency in nucleotide excision repair , and as such they display a cancer predisposition after exposure to severa l carcinogens. Besides being sensitive to genotoxic agents applied to the s kin, they are also susceptible to human carcinogens given orally, like benz o[a]pyrene (B[a]P). To study the role of the tumor suppressor gene p53 in D NA repair, gene mutation, and tumor induction, we crossed XPA-deficient mic e with p53 knockout mice and lacZ (pUR288) gene marker mice. When treated o rally (by gavage) with B[a]P, the XPA(-/-)/p53(+/-) double transgenic mice developed tumors much earlier and with higher frequency compared to their s ingle transgenic counterparts. The major tumor type found in all genotypes was generalized lymphoma mainly residing in the spleen; several were observ ed in p53(+/-) and XPA(-/-)/p53(+/-) mice. Next, we determined lacZ mutatio n frequencies in several (non)target tissues. It appeared that in the splee n (the major tumor target tissue) of XPA(-/-) and XPA(-/-)/p53(+/-) mice th e lacZ mutation frequency was significantly elevated (80-100 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), whi ch was independent of the genotype. The results obtained with the DNA-repai r deficient XPA mice indicate that a significantly increased lacZ mutation Frequency in a particular organ/tissue is an early marker for tumor develop ment 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 t arget tissue of XPA(-/-)/p53(+/-) or p53(+/-) mice com pared to that of XPA (-/-) and WT mice, respectively. (C) 1999 Wiley-Liss, Inc.