Use of DNA repair-deficient XPA transgenic mice in short-term carcinogenicity testing

At present (putative) human carcinogens are identified via epidemiological studies and testing using the chronic 2-yr rodent bioassay. Both methods ha ve severe limitations in that they are slow, insensitive, expensive, and ar e also hampered by many uncertainties. The development of methods to modify specific genes in the mammalian genome has provided promising new tools fo r use in identifying carcinogens and characterizing their (qualitative) ris k. Several transgenic mouse lines are currently under study to test their p ossible use in short-term carcinogenicity testing. One such candidate alter native transgenic model is the XPA knock-out mouse. These mice have an almo st complete deficiency in DNA nucleotide excision repair (NER). Nevertheles s, XPA-deficient mice are viable and have a background of a low incidence o f spontaneous development of cancers. Approximately 15% of the mice develop hepatocellular adenomas (only after 1.5 yr). After treatment with ultravio let-B radiation or 7,12-dimethylbenz(a)anthracene, the XPA-deficient mice d eveloped squamous cell carcinomas and papillomas, respectively, on their sk in. Oral treatment of XPA-deficient mice with benzo[a]pyrene (B[a]P), 2-ace tylaminofluorene (2-AAF), and 2-amino-1-methyl-6-phenylimidazo [4,5-b]-pyri dine (PhIP) resulted in lymphomas (B[a]P), liver and bladder tumors (2-AAF) , and intestinal adenomas plus lymphomas (PhIP). These results look encoura ging, but it should be noted that the compounds and agents tested thus far have all been substrate for nucleotide excision repair. Animal studies with different genotoxic or nongenotoxic compounds, as organized for instance w ithin the framework of the International Life Sciences Institute/Health and Environmental Sciences Institute program, are needed to further evaluate t he suitability of the XPA model for short-term carcinogenicity testing.