Metallothionein (I/II) suppresses genotoxicity caused by dimethylarsinic acid.
Arsenic is an environmental chemical of considerable concern due to its association with an increased risk of human cancer. Dimethylarsinic acid (DMAA) is one of the major methylated metabolites of ingested arsenicals in most mammals. To better clarify the role of metallothionein (MT) in modifying DMAA genotoxicity, MT-I/II null mice, and the corresponding wild-type mice, were exposed to DMAA (0, 188, 375 or 750 mg/kg body weight) via a single oral dose. Twenty-four hours after the DMAA injection, there was increased formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in serum and urine and a higher number of DNA strand breaks in peripheral blood cells. These increased levels were concomitant with increasing dose concentrations of DMAA in both strains of mice and they were significantly higher in MT-I/II null mice than in wild-type mice. Furthermore, the induction of apoptotic cells in the urinary bladder epithelium of MT-I/II null mice was significantly higher than in dose-matched wild-type mice exposed to DMAA. On the other hand, in both liver and in the alveolar and bronchial areas of the lung, the extent of DMAA-induced apoptosis was not different between wild-type and MT-I/II null mice and was increased in both strains. In addition, the concentration of hepatic MT in wild-type mice increased in a DMAA dose-dependent manner but was undetectable in MT-I/II null mice and could not subsequently be induced by DMAA. In conclusion, DMAA exposure causes oxidative stress, DNA damage and specific induction of apoptosis in target organs of arsenic carcinogenesis, which may be attributable to the mechanism(s) of arsenic-induced carcinogenesis in rodents. MT exhibited some protective roles during DNA damage presumably by acting as an antioxidant.
Jia
Guang
G
Health Effects Research Team, National Institute for Environmental Studies, Ibaraki 305-8506, Japan.
Sone
Hideko
H
Nishimura
Noriko
N
Satoh
Masahiko
M
Tohyama
Chiharu
C
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D017209:Apoptosis; D001773:Blood Cells / Q000187:drug effects / Q000473:pathology; D002101:Cacodylic Acid / Q000037:antagonists & inhibitors / Q000633:toxicity*; D002274:Carcinogens, Environmental / Q000633:toxicity*; D020552:Comet Assay; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000097:blood / Q000652:urine; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism; D051547:Heme Oxygenase-1; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008565:Membrane Proteins; D008668:Metallothionein / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism; D001743:Urinary Bladder / Q000187:drug effects / Q000473:pathology
D002274:Carcinogens, Environmental; D008565:Membrane Proteins; D013879:Thioredoxins; D000080242:8-Hydroxy-2'-Deoxyguanosine; D008668:Metallothionein; D002101:Cacodylic Acid; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D003849:Deoxyguanosine