Toxicologic Pathology

 

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Toxicologic Pathology, Vol. 35, No. 7, 853-864 (2007)
DOI: 10.1080/01926230701748131

Invited Review

Mouse Skin Models for Carcinogenic Hazard Identification: Utilities and Challenges

Dave Lynch1, Jessica Svoboda1, Sumanth Putta1, Hans E. J. Hofland2, Wendy H. Chern2 and Laura A. Hansen1

1 Creighton University School of Medicine, Omaha, NE
2 Stiefel Laboratories, Inc., Palo Alto, CA

Correspondence: Address correspondence to: Laura A. Hansen, Department of Biomedical Sciences, Creighton University School of Medicine, 2500 California Plaza, Omaha, NE 68178; E-mail:LHansen{at}creighton.edu

This report addresses 1) the predictability of mouse skin models for carcinogenic hazard identification, 2) the association between early changes in the skin and later tumorigenic responses, and 3) the relative sensitivity of three mouse models of skin tumorigenesis; i.e. the genetically-initiated Tg.AC and RasH2 lines and the SENCAR mouse model. All three mouse models responded similarly, with mild inflammation and epidermal hyperplasia, to several weeks of treatment with a topical agent. Based on our previous research experience, we hypothesized that inflammation, irritation, proliferation, and/or hyperplasia in the skin would precede and predict the appearance of tumors in these sensitive mouse skin models. Consistent with our hypothesis, the test agent caused a low but significant tumorigenic response in Tg.AC mice. We propose that inflammation, irritation, and hyperplasia are sensitive predictors of a later tumorigenic response in Tg.AC mice. Further studies are needed, however, to better determine the relative sensitivity of these 3 models to a wider variety of agents.

Key Words: Carcinogen identification • skin tumors • carcinogenesis • biomarkers • proliferation • irritation • inflammation

Abbreviations: API, active pharmaceutical ingredient • DMBA, 7, 12-dimethyl benz[a]anthracene • DNFB, 2, 4-dinitro-1-fluorobenzene • F, forestomach • G, gavage • Ip, intraperitoneal • MNU, N-methyl-N-nitrosourea • NT, not tested or not published record • NTP, National Toxicology Program • SOA, site of application • TCDD, 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin • TPA, 12-O-tetradecanoyl phorbol-13-acetate • UV, ultraviolet irradiation


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