Long-term infection with Helicobacter felis and inactivation of the tumour suppressor gene p53 cumulatively enhance the gastric mutation frequency in Big Blue transgenic mice

Abstract

The aims of this study were to determine whether colonization with Helicobacter felis resulted in the accumulation of mutations within murine gastric tissue and whether the degree of genetic damage was increased by p53 deficiency. Female C57BL/6 mice carrying either the lambda/lacI transgene (Big Blue transgenic mice) or the lambda/lacI transgene and deficient in one allele of the p53 tumour suppressor gene (TSG-p53/Big Blue) were inoculated with H felis. Seven months after inoculation, mutations in the target lacI gene were assessed using the Big Blue transgenic mutagenesis assay system in these animals and in controls. There was an approximately two-fold increase in lacI mutations in gastric mucosa harvested from mice infected with H felis and also from non-infected mice heterozygous for the p53 allele relative to wild-type mice. The mutation frequency in mice infected with H felis and deficient in one allele of p53 was increased approximately three-fold. Active gastric inflammation was significantly greater in H felis-infected p53 hemizygous mice compared with H felis p53 wild-type mice. Gastric epithelial proliferation was similarly increased with infection in both of these latter groups of mice. In infected mice, there was a significant correlation between the mutation frequency and the degree of active gastric inflammation. These data suggest a synergistic action between infection with H felis and p53 deficiency in the accumulation of mutations within gastric tissue. Active neutrophil infiltration in gastric Helicobacter infection may contribute to the increased levels of mutation observed.