Mode Of Action For Dma Carcinogenesis In The

Inorganic and organic arsenicals are not DNA reactive chemicals (IARC, 1980; Jacobson-Kram and Montalbano, 1985; U.S. EPA, 1997). Although they have produced positive results in a variety of genotoxicity screens, these involve mechanisms generally associated either with DNA repair, chromosomal aberrations or clastogenicity (IARC, 1980; Jacobson-Kram and Montalbano, 1985). In a few instances, possible mechanisms regarding the cause of these genotoxic alterations have been identified, but for the most part, they have not. It is clear, based on chemical and biochemical data as well as structure-activity relationships, that arsenicals do not and will not react with DNA (IARC, 1980; Jacobson-Kram and Montalbano, 1985; U.S. EPA, 1997). However, arsenicals, particularly As(III) species are well known to interact with protein sulphydryl groups, including some proteins that are known to be involved with DNA repair, microtubule structure and other proteins that are involved with the integrity of DNA and chromosome structure (IARC, 1980; Wang and Rossman, 1996; Rossman, 1998).

In the human, arsenic-induced skin carcinogenesis appears to involve hyperkeratosis associated with epidermal hyperplasia (IARC, 1980; Schwartz, 1997). It is unclear whether this is due to a direct mitogenic effect of inorganic arsenic on the epidermis or if it is due to toxicity and regeneration (Germolec et al., 1998).

Since DMA is not directly DNA reactive, carcinogenesis in the rat bladder secondary to administration of high doses of DMA is likely caused by increased proliferation, either due to increased cell births or decreased cell deaths. There is no evidence that arsenicals have a direct effect on apoptosis or differentiation of the bladder epithelium of the rat. Therefore, it is most likely that the increased cell proliferation is due to an increase in cell births. This could be due to direct mitogenesis or toxicity followed by regeneration.

We demonstrated that DMA at 40 and 100 mg/kg in the diet produced cytotoxicity and increased proliferation of the bladder epithelium; at lower doses this was not observed (Arnold et al., 1999). Similar effects have been seen by Fukushima and colleagues utilizing DMA in the drinking water at comparable overall doses (Wanibuchi et al., 1996). The hyperplasia that is produced is reversible upon discontinuation of DMA administration (Arnold et al., 1999). We demonstrated that the cytotoxicity was not due to the formation

Fig. 1. Cellular cytotoxicity of the bladder epithelium 6 h after feeding of 100 mg/kg DMA to a female rat (bar = 10 ^m).

of urinary solids in the rat following DMA administration, either precipitate, microcrystal-luria, or calculus formation (Arnold et al., 1999). There was some evidence that increased urinary calcium excretion might contribute to the toxicity or proliferation (Arnold et al., 1999). This did not answer whether the cell proliferation occurred first or whether it was toxicity with consequent regeneration.

In recent experiments in our laboratory, we have demonstrated that DMA, administered as 100 mg/kg of the diet, produces a cytotoxic effect on the urothelium within 6 h of administering the compound (Fig. 1), whereas the increase in cell proliferation occurs after three days of administration (Arnold et al., 2000). The increase in labeling index appears to increase through two weeks of administration and then decreases by ten weeks of administration, although it is still well above control levels. These studies clearly demonstrate that DMA administration produces a cytotoxic response in the urothelium with consequent regeneration (Fig. 2), rather than direct mitogenesis. The urinary calcium changes following DMA administration were not seen at the earlier time points when cytotoxicity and regeneration had already occurred. Whether urinary calcium abnormalities contribute to the continued proliferative stimulus to the bladder epithelium is unknown, but it is clear that it is not essential to its induction.

The exact mechanism by which DMA administration produces cytotoxicity on the bladder epithelium is unknown. We have demonstrated that sodium arsenite is cytotoxic to rat urothelium in culture at doses of approximately 0.5 mM (Yamamoto et al., 2000). In the same experiments, sodium arsenate produced cytotoxicity at concentrations of approximately 5 mM whereas DMA and monomethylarsonous acid (MMA) were cytotoxic at concentrations of 0.2 mM and 1 mM, respectively. Wanibuchi et al. (1996) and Yoshida et al. (1997) reported that DMA administered in the drinking water resulted in urinary concentrations of approximately mM levels of arsenite and mM concentrations of DMA. The concentrations of arsenate and MMA were significantly less than 1 mM. Assuming that the toxicity to the urothelium following DMA administration occurs via urinary exposures, the in vitro data and the urinary concentrations following DMA administration to rats suggest

Fig. 2. Extensive cellular necrosis and exfoliation of the female rat urothelium after 7 days of DMA administered as 100 mg/kg in the diet (bar = 0.1 mm).

that toxicity is most Likely due to arsenite, but possibly also due to DMA. It is un√ľkely that arsenate or MMA are responsible, considering their extremely low concentrations in the urine. However, the effects of MMA(III) have not been evaluated either in urine or in urothelial culture systems.

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