In vivo genotoxicity evaluation of dimethylarsinic acid in MutaMouse.
Dimethylarsinic acid (DMA) induces DNA damage in the lung by formation of various peroxyl radical species. The present study was conducted to evaluate whether arsenite or its metabolite, DMA, could initiate carcinogenesis via mutagenic DNA lesions in vivo that can be attributed to oxidative damage. A transgenic mouse model, MutaMouse, was used in this study and mutations in the lacZ transgene and in the endogenous cII gene were assessed. When DMA was intraperitoneally injected into MutaMice at a dose of 10.6 mg/kg per day for 5 consecutive days, it caused only a weak increase in the mutant frequency (MF) of the lacZ gene in the lung, which was at most 1.3-fold higher than in the untreated control animals. DMA did not appreciably raise the MF in the bladder or bone marrow. Further analysis of the cII gene in the lung, the organ in which DMA induced the DNA damage, revealed only a marginal increase in the MF. Following DMA administration, no change in the cII mutation spectra was observed, except for a slight increase in the G:C to T:A transversion. Administration of arsenic trioxide (arsenite) at a dose of 7.6 mg/kg per day did not result in any increase in the MF of the lacZ gene in the lung, kidney, bone marrow, or bladder. Micronucleus formation was also evaluated in peripheral blood reticulocytes (RETs). The assay for micronuclei gave marginally positive results with arsenite, but not with DMA. These results suggest that the mutagenicity of DMA and arsenite might be too low to be detected in the MutaMouse.
Noda
Yasuhiro
Y
Department of Biochemical Toxicology, Nihon University College of Pharmacy, 7-7-1 Narashinodai, Funabashi-shi 274-8555, Japan. yasunoda@phar.nagoya-cu.ac.jp
Suzuki
Takayoshi
T
Kohara
Arihiro
A
Hasegawa
Akira
A
Yotsuyanagi
Toshihisa
T
Hayashi
Makoto
M
Sofuni
Toshio
T
Yamanaka
Kenzo
K
Okada
Shoji
S
D000818:Animals; D002101:Cacodylic Acid / Q000633:toxicity*; D004249:DNA Damage; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009153:Mutagens / Q000633:toxicity*; D009154:Mutation
D009153:Mutagens; D002101:Cacodylic Acid