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Identifying DNA Mutations in Purified Hematopoietic Stem/Progenitor Cells
Published on: February 24, 2014
Transgenic and knockout mice for DNA repair functions in carcinogenesis and mutagenesis
Susan W P Wijnhoven1, Harry van Steeg
1National Institute of Public Health and Environment, RIVM/TOX pb12, P.O. Box 1, 3720 BA Bilthoven, The Netherlands. susan.wijnhoven@rivm.nl
Abstract:
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.
Insights
Genetically modified mice with DNA repair defects, like nucleotide excision repair (NER) and mismatch repair (MMR), offer efficient alternatives to traditional cancer assays. These models use marker genes to detect mutagenicity, aiding in early tumor indication.
Area of Science:
- Genetics and Molecular Biology
- Toxicology and Carcinogenesis
- Animal Models in Research
Background:
- Genetically modified mouse models with defects in DNA repair pathways, particularly nucleotide excision repair (NER) and mismatch repair (MMR), are valuable tools for studying carcinogenesis and mutagenesis.
- Utilizing mutant mice offers advantages over wild-type mice, including reduced costs, fewer animals, improved predictive value for carcinogens, and shorter study durations.
- Current short-term carcinogenicity assays still necessitate substantial animal numbers and extensive pathological analysis, highlighting the need for more efficient alternatives.
Purpose of the Study:
- To review the development and application of DNA repair-deficient mouse models as replacements for long-term cancer assays.
- To discuss the utility of enhanced gene mutant frequencies as early indicators of tumorigenesis.
- To explore the potential of specific mouse models, such as the Xpa/p53 mutant, for broader carcinogen detection.
Main Methods:
- Review of existing literature on DNA repair-deficient mouse models.
- Analysis of the application of marker genes in transgenic mice for detecting mutagenicity.
- Discussion of the sensitivity and response range of various DNA repair-deficient models.
Main Results:
- DNA repair-deficient mouse models, especially those with defects in NER and MMR, show promise in replacing traditional cancer assays.
- Enhanced gene mutant frequencies can serve as early indicators of tumor development.
- Existing models may not detect non-genotoxic carcinogens, indicating a need for more universally responsive models.
Conclusions:
- DNA repair-deficient mouse models offer a more efficient approach to studying carcinogenesis and mutagenesis.
- The Xpa/p53 mutant mouse model is a promising candidate for broad carcinogen detection due to its potential for wide sensitivity.
- Further development of highly sensitive and universally responding mouse models is crucial for comprehensive carcinogen assessment.
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