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METHYLATED ARSENICIII SPECIES ARE POTENTIAL PROXIMATE OR ULTIMATE GENOTOXIC FORMS OF ARSENIC
Citation:
Mass, M J., A H. Tennant, B Roop, B. Kundu, K H. Brock, A. Kligerman, D M. DeMarini, W. R. Cullen, C. Wang, D. Thomas, AND M Styblo. METHYLATED ARSENICIII SPECIES ARE POTENTIAL PROXIMATE OR ULTIMATE GENOTOXIC FORMS OF ARSENIC. Presented at Society of Toxicology, San Francisco, CA, March 18-25, 2001.
Description:
METHYLATED ARSENIC(III) SPECIES ARE POTENTIAL PROXIMATE OR UL TIMA TE GENOTOXIC FORMS OF ARSENIC
Inorganic arsenic (iAs, arsenite and arsenate) has been thought to act as a genotoxicant without reacting directly with DNA; neither iAs nor As(V) methylated metabolites are electrophiles. New techniques have detected methyl- and dimethyl-As(III) in urine from people exposed to arsenic in drinking water. These forms are more cytotoxic and potent as enzyme inhibitors than iAs. In this study, synthetic methyl- and dimethyl-As(III), as methyloxoarsine [As(III)MeO] and iododimethylarsine [As(III)Me 2 I], were assayed in vitro by supercoiled-plaslid unwinding assay that detects nicks and breaks in DNA, a single cell gel (comet) assay in human lymphocytes that detects breaks and alkaline labile sites, the Allies assay in strains TA98, TAIOO, and TA104, a prophage-induction assay that detects SOS repair, and the mouse lymphoma L5l78Y TK +/- assay that detects small and large scale genetic damage. We report that methylated As(III) species are able to interact directly with DNA. They can nick (unwind) DNA, produce double-stranded breaks, and/or induce alkaline labile sites at concentrations much lower than seen with iAs. In the comet assay a 2 hr exposure to As(III) methylated species doubled the tail moment at concentrations 30 to 300-fold less than with iAs. In the mouse lymphoma assay, mutation by As(III)MeO was seen down to 0.5 flM, 30 to 100-fold more potent than arsenite. The methylated As(III) species were not point mutagens in the Allies test but As(III)Me2I induced SOS repair at -5 flM. All assays are consistent with As(III)-rnethylated species that are genotoxic through interaction with DNA. Methylated As(III) species could be proximate or ultimate genotoxic fofll1s of iAs.
This is an abstract of a proposed presentation and does not represent USEPA policy.