Analysis of the gastric mutations induced by chronic Helicobacter pylori infections in a mouse model and influence of high-salt diet.
aUnité de Pathogénie Bactérienne des Muqueuses, bUnité de Recherche et d’Expertise en Histotechnologie et Pathologie; Institut Pasteur, Paris cedex 15, France
AIM: H. pylori is an important etiologic factor in the development of gastric carcinoma. Carcinogenesis processes are likely to result from an accumulation of mutations involving genes that guarantee the stability of the genome. The main goals of this study were i) to analyze the role of H. pylori in the induction of mutagenic events at the gastric epithelial cells level, ii) to identify risk factors that could participate in such a mutagenic effect. Since high- salt diet has been reported to favor the development of gastric tumor, its influence in the present model has been investigated. METHODS: C57BL/6 Big Blue male mice carrying the lambda/lacI transgene that allows the detection of mutations in any organs, were infected intragastrically by H. pylori strain SS1 for 6 and 12 months. The frequency and spectrum of the mutations at the stomach level were assessed. Inflammatory host response, inducible nitric oxide synthase (iNOS) and TNFalpha genes expression, immunohistochemistry analysis for cell proliferation and apoptosis have been investigated. RESULTS: After 6 months of infection, the gastric mutant frequency is increased 4-fold as compared to uninfected mice and is associated with a high level of transversions AT->CG and GC->TA, events known to result from oxidative DNA damages. Infected-stomachs exhibited a severe gastritis correlated with high level of iNOS messenger RNA expression 5-fold increased as compared to non-infected samples. Twelve months post-infection, hyperplasia developed and the TNFalpha gene expression is increased 3-fold by the infection as compared to the control. In this condition, the mutagenic effects and the iNOS mRNA expression declined. Concomitantly, an extension of gastric epithelial cells proliferation and an activation of Caspase-3 have been observed. No synergistic effects of a high-salt diet and H.pylori infection were observed regarding the frequency of gastric mutation. CONCLUSIONS: These results illustrate the ability of H. pylori to damage DNA at the gastric epithelial cells level and strengthened its role in the gastric carcinogenesis process. The H. pylori associated genotoxicity can be attributable to oxidative DNA damage involving the inflammatory host response and it is not exacerbated by high-salt diet.
Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in oral session 897 (Precursor lesions).