Mutagenicity of gamma-radiation, mitomycin C, and etoposide in the Hprt and Tk genes of Tk(+/-) mice.
The recently developed Tk(+/-) mouse detects in vivo somatic cell mutation in the endogenous, autosomal Tk gene. To evaluate the sensitivity of this model, we have treated Tk(+/-) mice with three agents that induce DNA damage by different mechanisms, and determined spleen lymphocyte mutant frequencies (MFs) in the autosomal Tk gene and in the X-linked Hprt gene. gamma-Radiation, which produces single- and double-strand breaks by nonspecific oxidative stress, efficiently increased Hprt MF, but not Tk MF. Mitomycin C, which produces bulky DNA monoadducts and crosslinks, was mutagenic in both the Hprt and Tk genes, but the response was greater in the Tk gene. An inhibitor of the ligase function of DNA topoisomerase II, etoposide, did not increase Hprt MF, and induced a small, but nonsignificant increase in Tk MF. Combined with previous data, the results indicate that the two genes are differentially sensitive to many agents, and that the Tk gene is more sensitive than the Hprt gene to some, but not all types of DNA damage.
Dobrovolsky
Vasily N
VN
Division of Genetic and Reproductive Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079, USA.
Shaddock
Joseph G
JG
Heflich
Robert H
RH
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D002478:Cells, Cultured; D004247:DNA / Q000187:drug effects* / Q000528:radiation effects*; D004261:DNA Replication / Q000187:drug effects; D005047:Etoposide / Q000633:toxicity*; D005260:Female; D005720:Gamma Rays; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics* / Q000528:radiation effects*; D019656:Loss of Heterozygosity / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016685:Mitomycin / Q000633:toxicity*; D009152:Mutagenicity Tests; D013937:Thymidine Kinase / Q000235:genetics* / Q000528:radiation effects*
D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D016685:Mitomycin; D005047:Etoposide; D004247:DNA; D007041:Hypoxanthine Phosphoribosyltransferase; D013937:Thymidine Kinase