Exposure to dimethylarsinic acid, a main metabolite of inorganic arsenics, strongly promotes tumorigenesis initiated by 4-nitroquinoline 1-oxide in the lungs of mice

Abstract

The effect of dimethylarsenics on the pulmonary tumorigenesis initiated by 4-nitroquinoline 1-oxide (4NQO) in mice was examined. The exposure of mice to dimethylarsinic acid (DMAA), a major metabolite of inorganic arsenics in mammals, resulted in not only promotion but also progression of the tumorigenic process in the lungs of mice administered 4NQO. Furthermore, dimethylarsenics influenced the differentiation process in lung tumorigenesis by 4NQO. These results may pave the way for the elucidation of lung carcinogenesis caused by arsenics.

Oral Administration of Dimethylarsinic Acid, a Main Metabolite of Inorganic Arsenic, in Mice Promotes Skin Tumorigenesis Initiated by Dimethylbenz(a)anthracene with or without Ultraviolet B as a Promoter.

“…26,27) We have estimated that the promotion and progression of lung-and skin-tumorigenesis in mice is not directly ascribable to DMA itself, but to the dimethylarsenic peroxy radical [(CH 3 ) 2 AsOO ·] 15) produced during the metabolic processing of DMA. [5][6][7] This is a reactive oxygen species (ROS). There are two reports showing the positive data of 8-hydroxy-2Ј-deoxyguanosine (8-OHdG), known as a product of oxidative damage due to ROS, by arsenic exposure: One demonstrated the enhancement of the amount of 8-OHdG in the liver of rat by DMA exposure, 12) and another provided 8-OHdG positive data in arsenic-related neoplasms and keratoses of humans.…”

“…On the other hand, some reports indicated that DMA exposure in rats increased the activity of ornithine decarboxylase (ODC), a tumor promotion marker, in the liver 9,12) ; conversely, DMA exposure in mice decreased that in the liver and lung, 28) although DMA administration promoted lung-and skin-tumorigenesis. [5][6][7][8][9] These facts suggest that rats are more responsive to dimethylarsenic than mice in terms of tumor promotion.…”

“…[5][6][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.…”

“…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. …”

“…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.…”