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Possible Application of Human c-Ha-ras Proto-Oncogene Transgenic Rats in a Medium-Term Bioassay Model for Carcinogens

¹ Department of Molecular and Environmental Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan
² Department of Molecular Toxicology, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya 467-8601, Japan
³ Experimental Pathology and Chemotherapy Division, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan
⁴ Department of Pathology 2, Kansai Medical University, Osaka 570-8506, Japan

Correspondence: Address correspondence to: Hiroyuki Tsuda, Department of Molecular Toxicology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan; e-mail:htsuda{at}med.nagoya-cu.ac.jp

With the aim of developing a medium-term assay for screening of environmental carcinogens, we exposed mammary carcinogen sensitive human c-Ha-ras proto-oncogene transgenic (Hras128) rats to various carcinogens, including compounds that do not normally induce mammary tumors. Seven-week-old Hras128 rats and wild-type littermates received administrations of 3-methylcholanthrene (3-MC), benzo[a]pyrene (B[a]P), anthracene, pyrene, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), dimethylarsinic acid (DMA), diethylnitrosamine (DEN) or azoxymethane (AOM) and were sacrificed at week 12 (females) (at week 10 for the 3-MC group) or week 20 (males). Female Hras128 rats receiving NNK, DEN, or DMA showed a significant increase in mammary tumor incidence and/or multiplicity compared to the respective values with olive oil or deionized distilled water (DDW) vehicles. In male Hras128 rats, a significant increase in mammary tumors was also observed in groups administered 3-MC, B[a]P, anthracene, IQ, and NNK. Mutations of transgenes were observed in codons 12 and/or 61 in the induced tumors by PCR-RFLP except in the DEN group in female and in the MeIQx group in male Hras128 rats. Thus various carcinogens, not necessarily limited to those normally targeting the breast, were found to induce mammary carcinomas in Hras128 rats, especially in females, pointing to potential use for medium-term screening.

Key Words: Transgenic rat • Hras • mammary tumors • medium-term assay

Abbreviations: MNU, N-methyl-N-nitrosourea • DMBA, dimethyl-benzoanthracene • 3-MC, 3-methylcholanthrene • B[a]P, benzo[a]pyrene • IQ, 2-amino-3-methylimidazo[4, 5- f ]quinoline • MeIQx, 2-amino-3,8-dimethylimidazo[4, 5- f ]quinoxaline • NNK, 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone • DEN, diethylnitrosamine • AOM, azoxymethane • DMA, dimethylarsinic acid • PCR, polymerase chain reaction • RFLP, restriction fragment length polymorphisms

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