Dermal Carcinogenicity in Transgenic Mice: Effect of Vehicle on Responsiveness of Hemizygous Tg.AC Mice to Phorbol 12-Myristate 13-Acetate (TPA)

Abstract

The Tg.AC mouse is being evaluated for use in short-term carcinogenicity bioassays. Because the dermal test protocol necessitates dissolving test agents we determined the effects of several solvents on responsivenes s of hemizygous mice to dermal applications of the classical skin tumor promoter, phorbol 12-myristate 13-acetate (TPA). Mice of both sexes received dermal applications of either acetone (negative control) or TPA in various vehicles [acetone, 100% methanol, 70% and 100% ethanol, DMSO and mixtures of acetone and ethanol (1:1), acetone and DMSO (4:1 and 1:1), and acetone and olive oil (4:1)]. Negative control animals did not exhibit papillomas. When administered in acetone, ethanolic or methanolic vehicles TPA caused prompt and robust papillomatous responses. TPA was also tumorigenic in all nonalcoholic vehicles, except the acetone-olive oil mixture. Papilloma responses were generally delayed when TPA was applied in the nonalcoholic solvents but the distinction between TPA-dosed and negative control groups was unequivocal. These results show that choice of vehicle may affect the quantitative and qualitative nature of the response of Tg.AC mice to TPA, but 8 of 9 vehicles proved satisfactory for delivery of TPA.

Keywords

Acetone carcinogenicity bioassay short-term carcinogenesi s models dermal papilloma dimethyl sulfoxide ethanol methanol TPA vehicles transgenic mice.

References

Blanchard KT , Ball DJ , Holden HE , Furst SM , Stoltz JH , Stoll RE (1998). Dermal Carcinogenicity in transgenic mice: Relative responsiveness of male and female hemizygous and homozygous Tg.AC mice to 12-otetradecanoylphorbol 13-acetate (TPA) and benzene. Toxicol Pathol 26: 541—547.

Hansen LA , Tennant RW (1994). Follicular origin of epidermal papillomas in v-Ha-ras transgenic TG.AC mouse skin. Proc Natl Acad Sci USA 91: 7822—7826.

Harvey M. , McArthur MJ , Montgomery CAJ , Bradley A. , Donehower LA (1993). Genetic background alters the spectrum of tumors that develop in p53-deficient mice. FASEB J 7: 938—943.

Harvey M. , McArthur MJ , Montgomery CAJ , Butel JS , Bradley A. , Donehower LA (1993). Spontaneous and carcinogen-induced tumorigenesis in p53-deficient mice. Nature Genet 5: 225—229.

Leder A. , Kuo A. , Cardiff RD , Sinn E. , Leder P. (1990). v-Ha-ras transgene abrogates the initiation step in mouse skin tumorigenesis: Effects of phorbol esters and retinoic acid. Proc Natl Acad Sci USA 87: 9178— 9182.

Robinson D. (1998). The International Life Sciences Institute's role in the evaluation of alternative methodologies for the assessment of carcinogenic risk. Toxicol Pathol 26: 474—475.

Slaga TJ , Fischer SM (1983). Strain differences and solvent effects in mouse skin carcinogenesis experiments using carcinogens, tumor initiators and promoters . Prog Exp Tumor Res 26: 85—109.

Spalding JW , French JE , Tice RR , Furedi-Machacek M. , Haseman JK , Tennant RW (1999). Development of a transgenic mouse model for carcinogenesis bioassays: Evaluation of chemically induced skin tumors in Tg.AC mice. Toxicol Sci 49: 241—254.

Spalding JW , Momma J. , Elwell MR , Tennant RW (1993). Chemical induced skin carcinogenesi s in a transgenic mouse line (Tg.AC) Carrying a v-Ha-ras transgene. Carcinogenesis 14: 1335—1341.

10.

Stoll RE (1998). Cancer hazard identification: Toward simplification and interpretability. Toxicol Pathol 26: 582—583.

11.

Tennant RW , French JE , Spalding JW (1995). Identifying chemical carcinogens and assessing potential risk in short-term bioassays using transgenic mouse models. Environ Health Perspect 103: 942—950.

12.

Tennant RW , Spalding J. , French JE (1996). Evaluation of transgenic mouse bioassays for identifying carcinogens and noncarcinogens. Mutat Res 365: 119—127.

13.

Tennant RW , Stasiewicz S. , Mennear J. , French JE , Spalding JW (1999). Genetically altered mouse models for identifying carcinogens. In: The Use of Short- and Medium-Term Tests for Carcinogens and Data on Genetic Effects in Carcinogenic Hazard Evaluation , McGregor DB , Rice JM , Venitts , (eds). IARC Scientific Publications No 146, International Agency for Research on Cancer , Lyon.

14.

Thompson KL , Rosenzweig BA , Sistare FD (1998). An evaluation of the hemizygous transgenic Tg.AC mouse for carcinogenicity testing of pharmaceuticals. II. A genotypic marker that predicts tumorigenic responsiveness. Toxicol Pathol 26: 548—555.