Transgenic and knockout mice for DNA repair functions in carcinogenesis and mutagenesis.
Genetically modified mouse models with defects in DNA repair pathways, especially in nucleotide excision repair (NER) and mismatch repair (MMR), are powerful tools to study processes like carcinogenesis and mutagenesis. The use of mutant mice in these studies has many advantages over using normal wild type mice with respect to costs, number of animals, predictive value towards carcinogenic compounds and the duration of study. Short-term carcinogenicity assays still require considerable number of animals and extensive pathological analyses. Therefore, alternatives demanding less animals and shorter exposure times would be desirable. In this respect, one approach could be the use of transgenic mice harbouring marker genes, that can easily detect mutagenic features of carcinogenic compounds, especially when such models are in a DNA repair deficient background. Here, we review the progress made in the development and use of DNA repair deficient mouse models as replacements for long-term cancer assays and discuss the applicability of enhanced gene mutant frequencies as early indicators of tumourigenesis. Although promising models exist, there is still a need for more universally responding and highly sensitive mouse models, since it is likely that non-genotoxic carcinogens will go undetected in a DNA repair deficient mouse. One attractive candidate mouse model, having a presumptive broad detective range, is the Xpa/p53 mutant mouse model, which will be discussed in more detail.
Wijnhoven
Susan W P
SW
National Institute of Public Health and Environment, RIVM/TOX pb12, P.O. Box 1, 3720 BA Bilthoven, The Netherlands. susan.wijnhoven@rivm.nl
van Steeg
Harry
H
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D004260:DNA Repair / Q000502:physiology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout / Q000502:physiology*; D008822:Mice, Transgenic / Q000502:physiology*; D009153:Mutagens / Q000633:toxicity*; D009369:Neoplasms / Q000235:genetics; D018570:Risk Assessment
D002273:Carcinogens; D009153:Mutagens