Journal Article

Integration of <i>In Vivo</i> Genotoxicity and Short-term Carcinogenicity Assays Using F344 <i>gpt</i> Delta Transgenic Rats: <i>In Vivo</i> Mutagenicity of 2,4-Diaminotoluene and 2,6-Diaminotoluene Structural Isomers

Naomi Toyoda-Hokaiwado, Tomoki Inoue, Kenichi Masumura, Hiroyuki Hayashi, Yuji Kawamura, Yasushi Kurata, Makiko Takamune, Masami Yamada, Hisakazu Sanada, Takashi Umemura, Akiyoshi Nishikawa and Takehiko Nohmi

in Toxicological Sciences

Volume 114, issue 1, pages 71-78
Published in print March 2010 | ISSN: 1096-6080
Published online December 2009 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfp306

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An important trend in current toxicology is the replacement, reduction, and refinement of the use of experimental animals (the 3R principle). We propose a model in which in vivo genotoxicity and short-term carcinogenicity assays are integrated with F344 gpt delta transgenic rats. Using this model, the genotoxicity of chemicals can be identified in target organs using a shuttle vector λ EG10 that carries reporter genes for mutations; short-term carcinogenicity is determined by the formation of glutathione S-transferase placenta form (GST-P) foci in the liver. To begin validating this system, we examined the genotoxicity and hepatotoxicity of structural isomers of 2,4-diaminotoluene (2,4-DAT) and 2,6-diaminotoluene (2,6-DAT). Although both compounds are genotoxic in the Ames/Salmonella assay, only 2,4-DAT induces tumors in rat livers. Male F344 gpt delta rats were fed diet containing 2,4-DAT at doses of 125, 250, or 500 ppm for 13 weeks or 2,6-DAT at a dose of 500 ppm for the same period. The mutation frequencies of base substitutions, mainly at G:C base pairs, were significantly increased in the livers of 2,4-DAT–treated rats at all three doses. In contrast, virtually no induction of genotoxicity was identified in the kidneys of 2,4-DAT–treated rats or in the livers of 2,6-DAT–treated rats. GST-P–positive foci were detected in the livers of rats treated with 2,4-DAT at a dose of 500 ppm but not in those treated with 2,6-DAT. Integrated genotoxicity and short-term carcinogenicity assays may be useful for early identifying genotoxic and nongenotoxic carcinogens in a reduced number of experimental animals.

Keywords: gpt delta transgenic rat; diaminotoluenes; genotoxicity; carcinogenicity; 3R principle

Journal Article.  4977 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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