Dermal Carcinogenicity in Transgenic Mice: Relative Responsiveness of Male and Female Hemizygous and Homozygous Tg.AC Mice to 12-O-Tetradecanoylphorbol 13-Acetate (TPA) and Benzene

Abstract

Assessment of the carcinogenic potential of chemical agents continues to rely primarily upon the chronic rodent bioassay, a resourceintensive exercise. Recent advances in transgenic technology offer a potential resource conserving approach to carcinogen detection. Incorporation of oncogenes with known roles in the development of neoplasms into the genomes of laboratory rodents may provide new models with the potential of quickly and accurately separating carcinogenic from noncarcinogenic chemicals. The insertion of the v-Ha-ras oncogene into the genome of F V B N mice imparts the qualities of genetically initiated skin in the transgenic mouse line designated as Tg.AC. The skin of either hemizygous (animals carrying the transgene on 1 allele) or homozygous (transgene copies on both alleles) Tg.AC mice promptly responds to the application of nongenotoxic carcinogens, such as the classical tumor promoting phorbol esters, with the development of squamous papillomas. Tumor production generally begins after 8-10 applications of 2.5 pg/ mouse (3 times/wk) of 12-0-tetradecanoylphorbol 13-acetate (TPA). Maximal tumor response is usually in evidence within 20 wk. If this transgenic mouse line is to be useful in the identification of carcinogenic chemicals, experimental protocols must be systematically optimized. Experiments were conducted to compare the relative responsiveness of male and female hemizygous and homozygous Tg.AC mice to the dermal application of TPA and the known human leukemogen, benzene. Results revealed shipment-related variabilities in the relative responsiveness of hemizygous male and female mice to the application of the proliferative agent. Homozygous mice of both sexes were more reliable and uniform in responsiveness to both TPA and benzene. Therefore, our standard protocol for the conduct of bioassays with the Tg.AC mouse line specifies the use of homozygous males and/or females.

Biological, cellular, and molecular characteristics of an inducible transgenic skin tumor model: a review

“…The NR phenotype was originally reported following poor TPA responses in positive control Tg.AC hemizygous mice (Weaver et al, 1998), and may have been an unknown confounding factor in other studies (Blanchard et al, 1998). Subsequent examination of the entire Tg.AC line demonstrated a germline transmission of the deleted palindrome.…”

The role of transgenic mouse models in carcinogen identification.

“…The rasH2 mouse is hemizygous for the human c-Ha-ras transgene under control of its endogenous promoter and enhancer sequences. It was developed by Saitoh et al (1990) in CB6F1 mice to evaluate the association of chemically induced transgene expression and tumor induction (Katsuki et al 1991;Yamamoto et al 1996Yamamoto et al , 1998a +d; +g (Blanchard et al 1998;+g (Yamamoto et al 1998b (Storer et al 2001) ±d; +g (Eastin et al 2001) ±g; +g; (Weisburger 1977) +g (Usui et al 2001;Yamamoto et al 1998b) Melphalan 148-82-3 1 Known +; +; +; +ip +; + +ip (Eastin et al 1998;+g (Eastin et al 1998;±ip (Yamamoto et al 1998b) (Weisburger 1977) Storer et al 2001) 2001) Cyclosporin A 79217-60-0 1 Known NT -; --g; +f; +f (Eastin et al 1998;±f (Eastin et al 1998; ±g (Maronpot et al 2000;Storer et al 2001) 2001) Usui et al 2001;Yamamoto et al 1998a) Diethylstilbestrol 56-53-1 1 Known NT -; NT -sc; +f (Eastin et al 1998;-g (Eastin et al 1998 (Yamamoto et al 1998b) (NCI/NTP 1978a) Abbreviations: -, negative; +, positive; ±, equivocal; d, dermal; f, food; g, gavage; I, inhalation; ip, intraperitoneal; LET, linear energy transfer; NT, not tested or no published record; sc, subcutaneous; wb, whole body. Individual results were found in the cited references or in the IARC (2002) or the NTP databases (NTP 2002).…”

p27 Kip1 (Cdkn1b)-Deficient Mice Are Susceptible to Chemical Carcinogenesis and May Be a Useful Model for Carcinogen Screening

“…p27-deficiency does not accelerate morbidity, tumor multiplicity, or tumor size in Smad3−/− mice (49). Interestingly, unlike those oncogenic mutations with which p27 cooperates, mutations of Smad3 are rare in human cancers (1,43,76).…”