Transgenic mouse mutation assays: Potential for confusion of genotoxic an non-genotoxic carcinogenesis: A proposed Solution
✍ Scribed by J. Ashby; U. Leigibel
- Publisher
- John Wiley and Sons
- Year
- 1992
- Tongue
- English
- Weight
- 393 KB
- Volume
- 20
- Category
- Article
- ISSN
- 0893-6692
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✦ Synopsis
The terms genotoxic and non-genotoxic are used increasingly to distinguish rodent carcinogens that are overtly DNA-reactive and mutagenic from those that appear to induce cancer by other mechanisms. There are, however, no universally agreed definitions of these terms . Initial discussions centred on whether a genotoxic agent was one that bound covalently to DNA, or whether the term should also include agents that produce mutagenic changes by affecting metaphase spindles or, for example, topoisomerase enzymes (see . recently emphasised the fact that cells undergoing division are more prone to the mutagenic action of a genotoxin, and thus, that tissue toxicity may play an important role in rodent carcinogenesis. Further, has suggested that the process of cell division itself might lead to the production of new mutations or the expression of endogenous (spontaneous) mutations in certain rodent tissues. These added dimensions increase the need for agreement on the meaning of the term genotoxic.
The advent of transgenic mouse mutation assays based on the lacI/lacZ genes brings with it the implicit advantage of being able to determine mutation incidences following protracted dosing, as happens during a carcinogenicity bioassay. This will theoretically allow the integration of primary genotoxic effects with secondary influences such as selective tissue toxicity. These assays also appear initially to offer a possible means of solving the problems posed by the definition of the terms genotoxic and non-genotoxic. Thus, some chemicals (genotoxins) may damage DNA after a single administration leading to the immediate induction of viable mutations in daughter cells. In contrast, some other chemicals (nongenotoxins) might produce no mutations under these conditions of test, but might, upon multiple dosing, produce tissue changes leading to the secondary induction of mutations. Such changes could include mitogenesis, peroxisome proliferation, etc. The simple prospect therefore exists that a genotoxic carcinogen will produce mutations in transgenic mice after a single administration, while putative non-genotoxic carcinogens may only produce mutations when repeated dosing has produced appropriate tissue changes that themselves produce mutations. This prospect has the attraction that the terms genotoxic