Analysis of gastric mutations frequency induced by Helicobacter pylori during long term chronic infection in mice.

E.Touati, V.Michel, J.M.Thiberge, M.Huerre, N.Wuscher, and A.Labigne.

Institut Pasteur, 28 rue du Dr Roux, Paris, France

There is now considerable evidence that infection with Helicobacter pylori is an important etiological factor in the development of gastric carcinoma. Bacterial and host factors as well as diet and environmental conditions are likely to play an important role in gastric carcinogenesis. The main goals of this study were: i) to evaluate the mutagenic effects possibly induced at the gastric level, during chronic infection by Helicobacter pylori in mice; ii) to identify host, bacterial or environmental factors which could mediate the genesis of precancerous lesions in this model. Big Blue transgenic mice carrying the lambda/lacI transgene that allows the detection of mutations in any organ, were used. Six week-old specific-pathogen free C57Bl/6 Big Blue mice were inoculated intragastrically with a suspension of H. pylori, strain SS1 (n=7), or H. felis, strain CS1 (n=7), prior to sacrifice at 6 and 12 months post-inoculation. Control groups of mice (n=6) were given peptone trypsin broth alone. Gastric tissue samples were divided in two segments (each containing antrum and body mucosa), and were used to determine the gastric mutant frequency and for immunohistochemical studies. At six months post-infection, stomachs exhibited a severe gastritis in 100% of H.felis-infected mice and a moderate gastritis in only 25% of the H.pylori-infected mice. However, analysis of the mutant frequency showed an increase of a 4.5-fold and a 1.7-fold in H.pylori and H.felis-infected mice respectively, as compared to the non-infected groups. Sequencing of the mutations induced in the DNA extracted from the gastric mucosa of the infected mice showed the presence of a high rate of transversions (AT->CG and GC->TA) which are known to be associated with oxidative damages. Thus, results obtained following 6 months of chronic infection already evidence a genotoxic effect of H.pylori on the gastric mucosa in this mouse model.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Carcinogenesis.

This presentation received an honorable mention in our poster contest and was recognized with the Symposium Presidents' Award for Scientific Excellence.