© 1994 by Oxford University Press
Journal of the National Cancer Institute, Vol. 86, No. 16, 1222-1227,
August 17, 1994
© 1994 Oxford University Press
Chronic Active Hepatitis and Associated Liver Tumors in Mice Caused by a Presistent Bacterial Infection With a Novel Helicobacter Species
*Affiliations of authors: Office of Laboratory Animal Science, National Cancer Institute Federick and Bethesda, Md
Massachusetts Institute of Technology Cambridge, Mass
Laboratory of Comparative Carcinogenesis, Division of Cancer Research and Development Center (NCI- FCRDC) Frederick, Md
Program Resources. Inc./DynCorp, NCI-FCRDC Frederick, Md
Mycoplasma Section, Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious diseases Frederick
Harlan Sprague-Dawley, Inc., NCI-FCRDC
Laboratory of Viral Carcinogenesis, Division of Cancer Etiology, NCI-FCRDC
Frosyth Dental Center Boston Mass
Correspondence to: J. M. Ward, D. V. M., Ph.D., NCI-FCRDC, Fairview 201, Frederick MD 21702-1201.
Background: In the autumn of 1992, a novel form of chronic, active hepatitis of unknown etiology was discovered in mice at the national Cancer Institute-Frederick Cancer Research and Development Center (NCI-FCRDC), Frederick, Md. A high incidence of Hepatocellular tumors occured in affected animals. The disease entity was orginally identified in A/JCr mice that were untreated controls in a long-term toxicologic study. Purpose: Our original purpose was to determine the orgin and etiology of the chronic hepatitis and to quantify its association with hepatocellular tumors in mice of low liver tumor incidence strains. After a helical microorganism was discovered in hepatic parenchyma of diseased mice, we undertook charcterization of the organism and investigation of its relationship to the disease process. Methods: Hepatic histopathology of many strains of mice and rats, as well as guinea pigs and Syrian hamsters, in our research and animal production facilities was reviewed. Steiner's modification of the Warthin-Starry stain and transmission electron microscopy were used to indentify bacteria in the liver. We transmitted the hepatitis with liver suspensions from affected mice and by inoculation with bacterial cultures. Bacteria were cultivated on blood agar plates maintained under anaerobic or microaerophilic conditions and characterized morphologically, biochemically, and by 16S rRNA sequence. Results: We report here the isolation of a new species of Helicobacter (provisionally designated helicobacter hepaticus sp. nov.) that selectively and persistently colonizes the hepatic bile canaliculi of mice (and possibly the intrahepatic biliary system and large bowel), causing a morphologically distinctive pattern of chronic, active hepatitis and associated with a high incidence of hepatocellular neoplasms in infected animals. Conclusions: The novel Helicpbacter is a likely candidate for the etiology of hepatocellular tumors in our mice.The Helicobacter associated chronic active hepatitis represents a new model to study mechanisms of carcinogenesis by genus of bacteria.implications: Adenocarcinoma of the stomach, the second most prevalent of all human malignancies worldwide, is associated with infection at an early age with helicobacter pylori. Infection leads to several distinctive forms of gastritis, including chronic atrophic gastritis, which is a precursor of adenocarcinoma. H. hepaticus infection in mice constitutes the only other parllel association between a persistent bacterial infection and tumor development known to exist naturally. Study of the H. Hepaticus syndrome of chronic activehepatitis and liver tumors in mice may yield insights into the role of H. pylori in human stomach cancer and gastric lymphoma [J. NatL Cancer Inst 86: 1222–1227, 1994]
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R. L. Melnick, R. C. Sills, C. J. Portier, J. H. Roycroft, B. J. Chou, S. L. Grumbein, and R. A. Miller Multiple organ carcinogenicity of inhaled chloroprene (2-chloro-1,3-butadiene) in F344/N rats and B6C3F1 mice and comparison of dose–response with 1,3-butadiene in mice Carcinogenesis, May 1, 1999; 20(5): 867 - 878. [Abstract] [Full Text] [PDF]
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J. G. Fox, J. A. MacGregor, Z. Shen, X. Li, R. Lewis, and C. A. Dangler Comparison of Methods of Identifying Helicobacter hepaticus in B6C3F1 Mice Used in a Carcinogenesis Bioassay J. Clin. Microbiol., May 1, 1998; 36(5): 1382 - 1387. [Abstract] [Full Text]
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J. K. Haseman, J. R. Hailey, and R. W. Morris Spontaneous Neoplasm Incidences in Fischer 344 Rats and B6C3F1 Mice in Two-Year Carcinogenicity Studies: A National Toxicology Program Update Toxicol Pathol, May 1, 1998; 26(3): 428 - 441. [Abstract] [PDF]
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D. G. Baker Natural Pathogens of Laboratory Mice, Rats, and Rabbits and Their Effects on Research Clin. Microbiol. Rev., April 1, 1998; 11(2): 231 - 266. [Abstract] [Full Text] [PDF]
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A. Nyska, R. R. Maronpot, S. R. Eldridge, J. K. Haseman, and J. R. Hailey Alteration in Cell Kinetics in Control B6C3F1 Mice Infected with Helicobacter hepaticus Toxicol Pathol, November 1, 1997; 25(6): 591 - 596. [Abstract] [PDF]
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B. A. Diwan, J. M. Ward, D. Ramljak, and L. M. Anderson Promotion by Helicobacter hepaticus-Induced Hepatitis of Hepatic Tumors Initiated by N-Nitrosodimethylamine in Male A/JCr Mice Toxicol Pathol, November 1, 1997; 25(6): 597 - 605. [Abstract] [PDF]
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D. E. Malarkey, T.-V. Ton, J. R. Hailey, and T. R. Devereux A PCR-RFLP Method for the Detection of Helicobacter hepaticus in Frozen or Fixed Liver from B6C3F1 Mice Toxicol Pathol, November 1, 1997; 25(6): 606 - 612. [Abstract] [PDF]
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R. R. Maronpot Laboratory Animal Pathology--Emphasis on an Area of Relevance to the Toxicologic Pathologist Toxicol Pathol, July 1, 1996; 24(4): 506 - 506. [PDF]
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J. M. Ward, M.-A. Shibata, and D. E. Devor Emerging Issues in Mouse Liver Carcinogenesis Toxicol Pathol, January 1, 1996; 24(1): 129 - 137. [Abstract] [PDF]
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