title: Detection of genotoxic and non-genotoxic carcinogens in Xpc(-/-)p53(+/-) mice.
abstract: An accurate assessment of the carcinogenic potential of chemicals and pharmaceutical drugs is essential to protect humans and the environment. Therefore, substances are extensively tested before they are marketed to the public. Currently, the rodent two-year bioassay is still routinely used to assess the carcinogenic potential of substances. However, over time it has become clear that this assay yields false positive results and also has several economic and ethical drawbacks including the use of large numbers of animals, the long duration, and the high cost. The need for a suitable alternative assay is therefore high. Previously, we have proposed the Xpa*p53 mouse model as a very suitable alternative to the two-year bioassay. We now show that the Xpc*p53 mouse model preserves all the beneficial traits of the Xpa*p53 model for sub-chronic carcinogen identification and can identify both genotoxic and non-genotoxic carcinogens. Moreover, Xpc*p53 mice appear to be more responsive than Xpa*p53 mice towards several genotoxic and non-genotoxic carcinogens. Furthermore, Xpc*p53 mice are far less sensitive than Xpa*p53 mice for the toxic activity of DNA damaging agents and as such clearly respond in a similar way as wild type mice do. These advantageous traits of the Xpc*p53 model make it a better alternative for in vivo carcinogen testing than Xpa*p53. This pilot study suggests that Xpc*p53 mice are suited for routine sub-chronic testing of both genotoxic and non-genotoxic carcinogens and as such represent a suitable alternative to possibly replace the murine life time cancer bioassay.
authors.affiliation: Laboratory for Health Protection Research, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
authors.forename: Joost P M
authors.initials: JP
authors.lastname: Melis
authors.forename: Ewoud N
authors.initials: EN
authors.lastname: Speksnijder
authors.forename: Raoul V
authors.initials: RV
authors.lastname: Kuiper
authors.forename: Daniela C F
authors.initials: DC
authors.lastname: Salvatori
authors.forename: Mirjam M
authors.initials: MM
authors.lastname: Schaap
authors.forename: Saskia
authors.initials: S
authors.lastname: Maas
authors.forename: Joke
authors.initials: J
authors.lastname: Robinson
authors.forename: Aart
authors.initials: A
authors.lastname: Verhoef
authors.forename: Jan
authors.initials: J
authors.lastname: van Benthem
authors.forename: Mirjam
authors.initials: M
authors.lastname: Luijten
authors.forename: Harry
authors.initials: H
authors.lastname: van Steeg
mesh_terms: D000818:Animals; D015197:Carcinogenicity Tests / Q000379:methods; D002273:Carcinogens / Q000633:toxicity*; D004249:DNA Damage / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009152:Mutagenicity Tests / Q000379:methods; D009153:Mutagens / Q000633:toxicity*; D010865:Pilot Projects; D051760:Xeroderma Pigmentosum Group A Protein / Q000235:genetics*
chemical_list: D002273:Carcinogens; D004268:DNA-Binding Proteins; D009153:Mutagens; D051760:Xeroderma Pigmentosum Group A Protein; C497315:Xpa protein, mouse; C501002:Xpc protein, mouse