Oral administration of dimethylvinyl chloride increases frequency of forestomach papillomas in Tg.AC mice

This work was initiated to determine the potential for the Tg.AC mouse mode l to identify chemical carcinogens by an oral route of administration. Tg.A C v-Ha-ras transgenic mice were exposed to dimethyvinyl chloride (DMVC; 1-c hloro-2-methylpropene), a structural analog of the human carcinogen vinyl c hloride. In the National Toxicology Program 2-yr bioassay, DMVC induced tum ors in the oral, nasal, and gastric epithelia of rats and mice, initial stu dies were performed in female Tg.AC mice to determine an appropriate oral d ose of DMVC to evaluate the potential for stratified gastric or oral epi th elia of Tg.AC mice to serve as a target tissue for a transgene-dependent in duced tumorigenic response. DMVC was administered to 13- to 14-wk-old Tg.AC mice by gavage at doses of 0, 50, 100, and 200 mg/kg five times a week for 20 wk. The forestomachs of DMVC-treated Tg.AC mice had an increasing numbe r of papillomas, which were associated with an increase in the dose of DMVC . The average numbers of papillomas per mouse per dose were 2.4, 7.6, 14.1, and 12.6 for the 0, 50, 100, and 200-mg/kg dose groups, respectively. The optimum papillomagenic dose of 100 mg/kg DMVC was established and administe red for 5, 10, and 15 wk to investigate the kinetics of papilloma induction in Tg.AC mice. The average numbers of papillomas per animal were 1.8, 8.8, and 19.0 at 5, 10, and 15 wk, respectively. Reverse transcription-polymera se chain reaction assays determined that the v-Ha-ras transgene was transcr iptionally active in all tumor tissues but not in nontumor tissues. In si t u hybridization assays performed in conjunction with bromodeoxyuridine in v ivo labeling localized the transgene-expressing cells of the forestomach pa pillomas to the proliferating cellular component of the tumors, as previous ly seen in skin papillomas of Tg.AC mice. The present results confirm that DMVC is tumorigenic and that oral routes of administration can be used to r apidly elicit a transgene-associated tumor response in the forestomach of T g.AC mice. Published 2000 Wiley-Liss, Inc.(dagger).