Promoting effects of dimethylarsinic acid on N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary bladder carcinogenesis in rats

Abstract

Arsenicals are epidemiologically significant chemicals in relation to induction of urinary bladder cancer in man. In the present study, we investigated the dose-dependent promotion potential of dimethylarsinic acid (DMA), a major metabolite of inorganic arsenicals in mammals, for rat urinary bladder carcinogenesis. In experiment 1, 6-week-old male F344 rats were treated with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 4 weeks and then given one of several concentrations of DMA in their drinking water (groups 1–6: 0, 2, 10, 25, 50 and 100 p.p.m.) for 32 weeks. The development of preneoplastic lesions and tumors (papillomas and carcinomas) in the urinary bladder was enhanced by treatment with DMA in a dose-dependent manner. A significant increase in multiplicity of tumors (papillomas and carcinomas) was observed even at a low concentration of DMA (10 p.p.m.). On the other hand, no preneoplastic lesions and tumors were observed in the rats treated with DMA alone. In experiment 2, different concentrations of DMA (groups 1–4: 0, 10, 25 and 100 p.p.m.) in drinking water were administered to the rats for 8 weeks without prior initiation by BBN. A significant increase in the 5-bromo-2'-deoxyuridine labeling index and alteration of the surfaces of the urinary bladder epithelial cells, as revealed by scanning electron microscopy, provided evidence of a dose-dependent increase in cell proliferation due to the DMA treatment. These results suggest that DMA has the potential to promote rat urinary bladder carcinogenesis and one of the mechanisms involved is its stimulation of cell proliferation in the urinary bladder epithelium.