| Marked Liver Tumorigenesis by Helicobacter hepaticus Requires Perinatal Exposure Bhalchandra A. Diwan,1 Marek Sipowicz,2 Daniel Logsdon,3 Peter Gorelick,3 Miriam R. Anver,4 Kazimierz S. Kasprzak,2 and Lucy M. Anderson2 1Basic Research Program, SAIC-Frederick, Inc., Frederick, Maryland, USA; 2Laboratory of Comparative Carcinogenesis, National Cancer Institute–Frederick, National Institutes of Health, Department of Health and Human Services, Frederick, Maryland, USA; 3Laboratory Animal Sciences Program, and 4Pathology Histotechnology Laboratory, SAIC-Frederick, Inc., Frederick, Maryland, USA Abstract
Background: Although severe hepatitis and liver tumors occur in a high percentage of A/J male mice naturally infected with Helicobacter hepaticus, these effects have not been observed after injection of adult mice with the bacteria. Objectives: We tested the hypothesis that perinatal exposure to the bacteria is required for liver tumorigenesis. Methods: A/J female mice were infected by intragastric (ig) or intraperitoneal (ip) treatment with 1.5  108H. hepaticus before pregnancy. We examined offspring at progressive time intervals, including some kept until natural death in old age. A/J, BALB/c, and C57BL/6 weanling male mice were similarly treated ig with the bacteria and observed for up to 2 years. Results: After ip bacterial infection of A/J females, 41% of their male offspring developed hepatitis and 33% had hepatocellular tumors, including 18% with hepatocellular carcinoma. Treatment by the ig route resulted in a similar incidence of hepatitis in offspring (35%) but fewer total liver tumors (8%) and carcinomas (4%) . By contrast, ig instillation of H. hepaticus in weanling A/J, C57BL/6, or BALB/c mice resulted in low incidence of hepatitis (0–20%) and few liver tumors, despite presence of bacteria confirmed in feces. Conclusions: Results indicate that a high incidence of liver tumors in mice infected with H. hepaticus requires perinatal exposure. Contributing perinatal factors could include known high sensitivity of neonatal liver to tumor initiation, and/or modulation of immune response to the bacterium or its toxins. Mechanisms of human perinatal sensitivity to such phenomena can be studied with this model. Key words: adult exposure, Helicobacter hepaticus, hepatocellular tumors, infection and cancer, perinatal exposure. Environ Health Perspect 116:1352–1356 (2008) . doi:10.1289/ehp.11493 available via http://dx.doi.org/ [Online 13 June 2008]
Address correspondence to L.M. Anderson, NCI at Frederick, Building 538, Room 205B, Ft. Detrick, Frederick, MD 21702 USA. Telephone: (301) 846-5600. Fax: (301) 846-5946. E-mail: andersol@mail.ncifcrf.gov We thank J. Ward for pathology consultations. This work was supported in part by the Intramural Research Program of the National Cancer Institute (NCI) , National Institutes of Health, and with federal funds from the NCI under contract NO1-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement of the U.S. government. The authors declare they have no competing financial interests. Received 19 March 2008 ; accepted 12 June 2008.
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