Development and validation of a new transgenic hairless albino mouse as a mutational model for potential assessment of photocarcinogenicity.
Short-term phototoxicity testing is useful in selecting test agents for the longer and more expensive photocarcinogenesis safety tests; however, no validated short-term tests have been proven reliable in predicting the outcome of a photocarcinogenesis safety test. A transgenic, hairless, albino (THA) mouse model was developed that carries the gpt and red/gam [Spi(-)] genes from the gpt delta mouse background and the phenotypes from the SKH-1 mouse background to use as a short-term test in lieu of photocarcinogenesis safety tests. Validation of the THA mouse model was confirmed by exposing groups of male mice to sub-erythemal doses of ultraviolet B (UVB) irradiation for three consecutive days emitted from calibrated overhead, Kodacel-filtered fluorescent lamps and measuring the mutant frequencies (MFs) in the gpt and red/gam (Spi(-)) genes and types of mutations in the gpt gene. The doses or irradiation were monitored with broad-spectrum dosimeters that were calibrated to a NIST-traceable standard and cumulative CIE-weighted doses were 20.55 and 41.0mJ/cm(2) (effective). Mice were sacrificed 14 days after the final UVB exposure and MFs in both the gpt and red/gam genes were evaluated in the epidermis. The exposure of mice to UVB induced significant ten- to twelve-fold increases in the gpt MF and three- to five-fold increases in the Spi(-) MF over their respective background MF, 26±3×10(-6) and 9±1×10(-6). The gpt mutation spectra were significantly different between that of the UVB-irradiated and that of non-irradiated mice although the mutation spectra of both groups were dominated by C→T transitions (84% and 66%). In mice exposed to UVB, the C→T transitions occurred almost exclusively at dipyrimidine sites (92%), whereas in non-irradiated control mice, the C→T transitions occurred at CpG sites (86%). These results suggest that the newly developed THA mice are a useful and reliable model for testing UVB-induced mutagenicity in skin tissue. The application of this model for short-term prediction of solar-induced skin carcinogenicity is presently under investigation.
National Center for Toxicological Research, Division of Genetic and Molecular Toxicology, USFDA, Jefferson, AR, United States. Electronic address: Mugimane.manjanatha@fda.hhs.gov.
Mugimane G
MG
Manjanatha
National Center for Toxicological Research, Division of Genetic and Molecular Toxicology, USFDA, Jefferson, AR, United States.
Sharon D
SD
Shelton
National Center for Toxicological Research, Division of Genetic and Molecular Toxicology, USFDA, Jefferson, AR, United States.
Ying
Y
Chen
Department of Experimental and Systems Pharmacology, Washington State University College of Pharmacy, Spokane, WA, United States.
Shobhan
S
Gaddameedhi
National Center for Toxicological Research, Office of Scientific Coordination, USFDA, Jefferson, AR, United States.
Paul C
PC
Howard
National Center for Toxicological Research, Division of Biochemical Toxicology, USFDA, Jefferson, AR, United States.
Mary D
MD
Boudreau
D000818:Animals; D004307:Dose-Response Relationship, Radiation; D004817:Epidermis / Q000378:metabolism / Q000528:radiation effects*; D029968:Escherichia coli Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic / Q000235:genetics*; D023421:Models, Animal; D009152:Mutagenicity Tests; D059645:Mutation Rate; D010430:Pentosyltransferases / Q000235:genetics* / Q000378:metabolism; D014466:Ultraviolet Rays
D029968:Escherichia coli Proteins; D010430:Pentosyltransferases; C071962:Gpt protein, E coli
Mutant frequency; Mutation frequency; Spi(−) selection assay; Transgenic Hairless albino mouse; gpt-Delta mouse