Evaluation of initiation activity of dimethylarsinic acid: Initiation potential of rat hepatocarcinogenesis

Abstract

There is a dearth of data on the initiation activity of dimethylarsinic acid (DMA (V)), a major metabolite of the ubiquitous environmental and occupational carcinogen and toxicant, arsenic (As). The initiation activity of DMA (V) was investigated on rat hepatocarcinogenesis with liver being a major target organ for As-induced carcinogenicity. A total of 50 rats at 10 weeks old were randomly divided in a nine-week medium-term bioassay into four groups. Groups 1 and 2 received 200 ppm of DMA (V) in drinking water for four weeks while groups 3 and 4 drank only tap water until the sixth week when groups 1 and 3 were given 0.01% 2-acetylaminofluorene (2-AAF) in their diet for two weeks in the promotion stage. All animals were subjected to two-third partial hepatectomy (PH) at the seventh week. Quantitative analysis of glutathione S-transferase placental form (GST-P) positive foci in liver, a pre-neoplastic marker of rat hepatocarcinogenesis, demonstrated higher numbers in group 1 (DMA (V) + 2-AAF) than 3 (2-AAF alone) at foci consisting of two–four cells and 15 or a greater number of cells. The numbers of GST-P positive foci consisting of five–nine cells were significantly higher in group 1 than 3. Foci consisting of 10–14 cells were also higher but not significantly different. The GST-P positive foci were apparently similar in groups 2 and 4. Expression of total GST-P positive foci was significantly higher in group 1 compared to 2, 3 or 4. The proliferating cell nuclear antigen (PCNA) test performed to clarify the apparent trend of GST-P data revealed significantly higher PCNA index in group 1. Data indicate weak initiation potential of DMA (V) and for the first time appear to provide evidence for initiation activity in DMA (V)-induced hepatocarcinogenesis in rats.

Keywords:

• arsenic
• biomethylation
• dimethylarsinic acid (V)
• hepatocarcino-genesis
• initiation activity
• toxicity

Acknowledgments

The authors deeply appreciate the technical assistance of Kaori Touma and other technical staff for miscellaneous assistance. This investigation was supported by a grant by the Iijima Foundation, Japan for research on cancer risk assessment.