Chronic Helicobacter pylori infections induce gastric mutations in mice.
OBJECTIVE
Helicobacter pylori is an important etiologic factor in the development of gastric cancer. The aim of this study was to analyze the role of H. pylori infections in the induction of mutagenic events in gastric epithelial cells. The effect of a high-salt diet as a genotoxic risk factor was also investigated.


METHODS
Big Blue transgenic male mice (C57Bl/6) were inoculated with H. pylori (strain SS1) or Helicobacter felis (strain CS1) for 6 and 12 months. The frequency and spectrum of mutations at the stomach level were assessed. Inflammatory host response and inducible nitric oxide synthase (iNOS) expression by reverse-transcription polymerase chain reaction and immunohistochemistry analysis were also performed.


RESULTS
After 6 months, the gastric mutant frequency was 4-fold and 1.7-fold higher in mice infected with H. pylori and H. felis, respectively, than in uninfected mice. It was associated with a high frequency of transversions (AT --> CG and GC --> TA) known to result from oxidative damages. The Helicobacter-infected mice exhibited severe gastritis and a high level of iNOS messenger RNA expression. Hyperplasia developed 12 months after inoculation, and both the mutagenic effects and iNOS expression decreased in H. pylori- and H. felis-infected mice. No synergistic effects of a high-salt diet and Helicobacter infection were observed regarding the frequency of gastric mutation.


CONCLUSIONS
A direct gastric mutagenic effect due to H. pylori infection in the Big Blue transgenic mouse model has been shown 6 months after inoculation. This genotoxicity can be attributable to oxidative DNA damage involving the inflammatory host response.
Touati
Eliette
E
Unité de Programmation Moléculaire et de Toxicologie Génétique, Institut Pasteur, Paris, France. etouati@pasteur.fr
Michel
Valérie
V
Thiberge
Jean-Michel
JM
Wuscher
Nicole
N
Huerre
Michel
M
Labigne
Agnès
A
D000818:Animals; D002908:Chronic Disease; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000502:physiology; D016481:Helicobacter Infections / Q000235:genetics*; D016480:Helicobacter pylori; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000187:drug effects / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D017673:Sodium Chloride, Dietary / Q000494:pharmacology; D013047:Specific Pathogen-Free Organisms; D013270:Stomach / Q000166:cytology; D013274:Stomach Neoplasms / Q000235:genetics* / Q000276:immunology / Q000382:microbiology*
D017673:Sodium Chloride, Dietary; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse