Mutagenic
carcinogens rapidly induced
tumors in the p53 haploinsufficient mouse. Heterozygous p53-deficient (+/-) mice were exposed to different mutagenic
carcinogens to determine whether p53 loss of heterozygosity (LOH) was
carcinogen-and tissue-dependent. For 26 weeks, C57BL/6 (N4) [corrected] p53-deficient (+/-) male or female mice were exposed to
p-cresidine,
benzene or
phenolphthalein.
Tumors were examined first for loss of the wild-type p53 allele.
p-cresidine induced p53 LOH in three of 13
bladder tumors, whereas hepatocellular
tumors showed p53 LOH in
carcinomas (2/2), but not in
adenomas (0/3).
Benzene induced p53 LOH in 13 of 16
tumors examined. Finally,
phenolphthalein induced p53 LOH in all
tumors analyzed (21/21). Analysis of the
p-cresidine-induced
bladder tumors by cold single-strand conformation polymorphism (SSCP) analysis of exon 4-9 amplicons failed to demonstrate polymorphisms associated with mutations in
tumors that retained the p53 wild-type allele.
p-cresidine induced a dose-related increase in lacI mutations in bladder
DNA. In summary, these data demonstrate that loss of the wild-type allele occurred frequently in thymic
lymphomas and
sarcomas, but less frequently in
carcinomas of the urinary bladder. In the bladder
carcinomas other mechanisms may be operational. These might include (i) other mechanisms of p53 inactivation, (ii) inactivating mutations occurring outside exons 4-9 or (iii) p53 haploinsufficiency creating a condition that favors other critical genetic events which drive bladder
carcinogenesis, as evidenced by the significant decrease in
tumor latency. Understanding the mechanisms of p53 LOH and chemical
carcinogenesis in this genetically altered model could lead to better models for prospective identification and understanding of potential human
carcinogens and the role of the p53 tumor suppressor gene in different pathways of chemical
carcinogenesis.