Abstract |
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 lambda 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.
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Authors | Naomi Toyoda-Hokaiwado, Tomoki Inoue, Kenichi Masumura, Hiroyuki Hayashi, Yuji Kawamura, Yasushi Kurata, Makiko Takamune, Masami Yamada, Hisakazu Sanada, Takashi Umemura, Akiyoshi Nishikawa, Takehiko Nohmi |
Journal | Toxicological sciences : an official journal of the Society of Toxicology
(Toxicol Sci)
Vol. 114
Issue 1
Pg. 71-8
(Mar 2010)
ISSN: 1096-0929 [Electronic] United States |
PMID | 20026473
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Escherichia coli Proteins
- Mutagens
- Phenylenediamines
- Pentosyltransferases
- Gpt protein, E coli
- 2,6-diaminotoluene
- 2,4-diaminotoluene
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Topics |
- Animals
- Carcinogenicity Tests
(methods)
- Escherichia coli Proteins
(genetics)
- Liver
(drug effects)
- Male
- Mutagenicity Tests
(methods)
- Mutagens
(toxicity)
- Pentosyltransferases
(genetics)
- Phenylenediamines
(toxicity)
- Rats
- Rats, Inbred F344
- Rats, Transgenic
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