Inorganic arsenics have been linked epidemiologically to the induction of human skin and lung cancer by the International Agency for Research on Cancer (IARC); however, evidence in experimental animals with respect to their carcinogenicity has not yet been established. 1) DMA is a main metabolite of inorganic arsenics via methanearsonic acid (MMA) in mammals.2) This methylation pathway has historically been considered to be a detoxification process for the acute toxicity of inorganic arsenics.3) However, our previous studies have demonstrated that the oral administration of DMA to mice induces lung-specific DNA damage 4) and also exhibits promotion and progression effects on lung-and skintumorigenesis.5-7) Multi-organ tumorigenesis due to the oral administration of DMA to rats has been also reported; DMA administration enhanced the incidence of tumors in liver, kidney, thyroid and urinary bladder induced by certain tumor initiators. [8][9][10] Moreover, in a study reported to the US Environmental Protection Agency (EPA), in which male and female rats and mice were fed DMA for 2 years, a carcinogenic response was found as evidenced by increases in urinary bladder tumors and fibrosarcomas.11) On the other hand, some reports estimated that in vivo 12,13) and in vitro 14) exposure of arsenics produced a reactive oxygen species (ROS). Among the ROS, we have estimated the production of dimethylarsenic peroxy radicals in the metabolic processing of DMA,15) and that further, the radicals would be responsible for DNA damage and the promotion of lung-and skin-tumorigenesis in mice. [4][5][6][7] Collectively, these tumorigenic studies suggest that not DMA itself, but rather its metabolite(s), may promote of multi-organ tumorigenesis in rodents.
16)With regard to skin tumorigenesis by dimethylarsenics, recent reports 17,18) showed that by using K6/ODC transgenic mice that were overexpressed ornithine decarboxylase (ODC) in hair follicle keratinocytes, the application of DMA with or without dimethylbenz(a)anthracene (DMBA) enhanced the formation of papillomas in mice skin in a dose-dependent manner. However, these animal experiments would be limited due to the disadvantage of predominantly forming papillomas because squamous cell carcinoma (SCC) induced by arsenics occurs quite frequently after the formation of keratoses.19) Thus, it is necessary to develop experimental models of skin tumorigenesis with the formation of keratoses, similar to the human skin carcinogenesis by arsenics. On the other hand, Wang et al. 20,21) reported an animal model in which keratoacanthomas and SCCs are formed by irradiation with UVB, a skin-tumor promoter, in 7,12-dimethylbenz(a)-anthracene (DMBA)-treated mice.In the present study, we revealed that the oral administration of DMA has promotion and progression action in a skintumorigenesis model 20,21) of keratoacanthomas formation due to treatment with DMBA as an initiator and UVB as a promoter. We found that the administration of DMA by an oral route promoted not only the formation of papillo...
