Related Experiment Video
Updated: Aug 8, 2026
Rapid Analysis of Chromosome Aberrations in Mouse B Lymphocytes by PNA-FISH
Published on: August 19, 2014
Xpa and Xpa/p53+/- knockout mice: overview of available data
C F van Kreijl1, P A McAnulty, R B Beems
1RIVM, Laboratory of Health Effects Research, Bilthoven, The Netherlands. cf.van.kreyl@rivm.nl
Abstract:
DNA repair deficient Xpa-/- and Xpa-/-/p53+/- knock-out mice in a C57BL/6 genetic background, referred to as respectively the XPA and XPA/p53 model, were investigated in the international collaborative research program coordinated by International Life Sciences Institute (ILSI)/Health and Environmental Science Institute. From the selected list of 21 ILSI compounds, 13 were tested in the XPA model, and 10 in the XPA/p53 model. With one exception, all studies had a duration of 9 months (39 weeks). The observed spontaneous tumor incidence for the XPA model after 9 months was comparable to that of wild-type mice (total 6%). For the XPA/p53 model, this was somewhat higher (9%/13% for males/females). The 3 positive control compounds used, B[a]P, p-cresidine, and 2-AAF, gave positive and consistent tumor responses in both the XPA and XPA/p53 model, but no or lower responses in wild-type mice. From the 13 ILSI compounds tested, the single genotoxic carcinogen (phenacetin) was negative in both the XPA and XPA/p53 model. Positive tumor responses were observed for 4 compounds, the immunosuppressant cyclosporin A, the hormone carcinogens DES and estradiol, and the peroxisome proliferator WY-14,643. Negative results were obtained with 5 other nongenotoxic rodent carcinogens, and 2 noncarcinogens tested. As expected, both DNA repair deficient models respond to genotoxic carcinogens. Combined with previous results, 6 out of 7 (86%) of the genotoxic human and/or rodent carcinogens tested are positive in the XPA model. The positive results obtained with the 4 mentioned nongenotoxic ILSI compounds may point to other carcinogenic mechanisms involved, or may raise some doubts about their true nongenotoxic nature. In general. the XPA/p53 model appears to be more sensitive to carcinogens than the XPA model.
Insights
DNA repair deficient mouse models (XPA and XPA/p53) were tested with 21 International Life Sciences Institute (ILSI) compounds. Both models effectively identified genotoxic carcinogens, with the XPA/p53 model showing increased sensitivity.
Area of Science:
- Toxicology and Carcinogenesis
- Genetics and Molecular Biology
- Biomedical Research
Background:
- DNA repair deficiency is a critical factor in carcinogenesis.
- The XPA-/- (XPA) and XPA-/-/p53+/- (XPA/p53) mouse models were developed on a C57BL/6 background.
- These models were utilized in an international collaborative research program coordinated by ILSI/HESI.
Purpose of the Study:
- To evaluate the carcinogenic potential of 21 International Life Sciences Institute (ILSI) compounds using DNA repair deficient mouse models.
- To assess the sensitivity and reliability of the XPA and XPA/p53 models in detecting genotoxic and non-genotoxic carcinogens.
- To investigate potential alternative carcinogenic mechanisms for compounds classified as non-genotoxic.
Main Methods:
- Thirteen compounds were tested in the XPA model and 10 in the XPA/p53 model over a 9-month period.
- Spontaneous tumor incidence was compared between knockout models and wild-type mice.
- Known carcinogens (B[a]P, p-cresidine, 2-AAF) and various ILSI compounds were administered to assess tumor response.
Main Results:
- Both XPA and XPA/p53 models showed positive and consistent tumor responses to known genotoxic carcinogens.
- The XPA/p53 model demonstrated higher sensitivity to carcinogens compared to the XPA model.
- Four compounds initially classified as non-genotoxic (cyclosporin A, DES, estradiol, WY-14,643) induced positive tumor responses, suggesting potential genotoxicity or alternative mechanisms.
Conclusions:
- DNA repair deficient mouse models, particularly the XPA/p53 model, are sensitive and valuable tools for carcinogen identification.
- The models confirm the genotoxic nature of known carcinogens and highlight potential issues with current classifications of some non-genotoxic compounds.
- Further investigation is warranted for compounds showing positive tumor responses despite being classified as non-genotoxic.
