Methylated Trivalent Arsenic Species Are Genotoxic

Abstract

The reactivities of methyloxoarsine (MAs(III)) and iododimethylarsine (DMAs(III)), two methylated trivalent arsenicals, toward supercoiled phiX174 RFI DNA were assessed using a DNA nicking assay. The induction of DNA damage by these compounds in vitro in human peripheral lymphocytes was assessed using a single-cell gel (SCG, "comet") assay. Both methylated trivalent arsenicals were able to nick and/or completely degrade phiX174 DNA in vitro in 2 h incubations at 37 degrees C (pH 7.4) depending on concentration. MAs(III) was effective at nicking phiX174 DNA at 30 mM; however, at 150 microM DMAs(III), nicking could be observed. Exposure of phiX174 DNA to sodium arsenite (iAs(III); from 1 nM up to 300 mM), sodium arsenate (from 1 microM to 1 M), and the pentavalent arsenicals, monomethylarsonic acid (from 1 microM to 3 M) and dimethylarsinic acid (from 0.1 to 300 mM), did not nick or degrade phiX174 DNA under these conditions. In the SCG assay in human lymphocytes, methylated trivalent arsenicals were much more potent than any other arsenicals that were tested. On the basis of the slopes of the concentration-response curve for the tail moment in the SCG assay, MAs(III) and DMAs(III) were 77 and 386 times more potent than iAs(III), respectively. Because methylated trivalent arsenicals were the only arsenic compounds that were observed to damage naked DNA and required no exogenously added enzymatic or chemical activation systems, they are considered here to be direct-acting forms of arsenic that are genotoxic, though they are not, necessarily, the only genotoxic species of arsenic that could exist.

Family correlations of arsenic methylation patterns in children and parents exposed to high concentrations of arsenic in drinking water.

“…Family members who resided in Chiu Chiu had a high prevalence of arsenic-induced skin lesions. It had been thought that methylation reduced the toxicity of arsenic (12), but recent laboratory evidence suggests that methylated trivalent MMA may be more toxic than the inorganic forms (14,26). The low values of InAs/metAs found in family A could indicate that the biotransformation of arsenic through methylation may be associated with increased health effects.…”

Peer Reviewed: Arsenic Speciation

“…However, this notion was based on an earlier, incomplete understanding that did not take into account the intermediate trivalent metabolites, MMA III and DMA III . Recent studies of human cytotoxicity of As III , MMA III , and DMA III (9); acute toxicity in hamsters (10); enzyme inhibition (10 -12); and potent ability to cause DNA damage (13) have shown that MMA III and DMA III are at least as toxic as, if not more so than, inorganic arsenic species. These new findings challenge the conventional wisdom of arsenic toxicity with regard to biomethylation, which may actually be an activation process.…”

“…Some evidence shows that the trivalent arsenic species cause oxidative damage to DNA (13,40). Electron spin resonance with spin trapping has detected free radicals produced in cells incubated with As III (41).…”

“…However, the high levels of arsenic in lobsters pose no known health concern because it is primarily in the form of the innocuous arsenobetaine (5)(6)(7). Arsenobetaine, the predominant species present in most crustaceans, is essentially nontoxic (8), unlike the highly toxic trivalent arsenic species, such as inorganic arsenite, monomethylarsonous acid, and dimethylarsinous acid (9)(10)(11)(12)(13). More than 20 arsenic compounds are present in the natural environment and biological systems (Table 1).…”

CZE for the speciation of arsenic in aqueous soil extracts

“…Methylation is considered as the most important natural transformation path that converts inorganic arsenic into organic arsenic species of lower toxicity such as monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) [1,2]. Recent studies revealed that methylation also leads to the formation of highly toxic trivalent intermediates that are not stable under nonphysiological conditions [3]. Otherwise, several phenylarsenic compounds, namely, 4-hydroxy-3-nitrobenzenearsonic acid (roxarsone), phenylarsonic acid (PAA), p-aminophenylarsonic acid (p-APAA) and o-aminophenylarsonic acid (o-APAA), are of industrial origin and are commonly used as animal-feed additives [4].…”