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DNA DAMAGE INDUCED BY METHYLATED TRIVALENT ARSENICALS: ROLE OF REACTIVE OXYGEN SPECIES
Impact/Purpose:
To explore the role of ROS and biomethylation of arsenic in arsenics genotoxicity and carcinogenicity. ROS formed from biomethylated forms of inorganic arsenicals can damage DNA and can exert multiple effects in the carcinogenesis pathways including cellular toxicity, tumor promotion, and progression through varied effects on signal transduction resulting in altered growth promoting, growth inhibitory, and apoptotic pathways. These results might help to explain the multiple effects of arsenic.
Description:
Exposure to arsenic is worldwide due to both natural and man-made processes. Arsenic-associated human diseases include lung, liver, bladder and skin cancer, cardiovascular and vascular disorders, neurological disorders, skin diseases, and liver disorders. Premalignant skin lesions such as Bowens disease also have been associated with arsenic exposure. Inorganic arsenic can exist in drinking water in two major forms: arsenite and arsenate. In mammals, inorganic arsenic can be biomethylated to monomethylarsonous acid (MMAIII), dimethylarsinous acid (DMAIII), and dimethylarsinic acid (DMAV). Levels of many of these organometallic forms of arsenic have been found in the urine of humans exposed to arsenic in their drinking water. Although biomethylation of inorganic arsenic was thought initially to be a detoxification process, this notion has been questioned because the methylated trivalent arsenic metabolites MMAIII and DMAIII have been shown to be toxic to mammalian liver, skin, urinary bladder, and lung cells in culture. Recently the Environmental Carcinogenesis Division reported that the trivalent methylated forms of arsenic, MMAIII and DMAIII, were genotoxic to mammalian and non-mammalian DNA inducing DNA damage. The goals of these studies are to ascertain the mode of genotoxic action of the biomethylated forms of arsenic, MMAIII and DMAIII. We will examine the role of reactive oxygen species (ROS) in the processes of DNA damage induced by the arsenicals. Our approach will be to employ ROS inhibitors and examine their modulation of arsenical-induced DNA damage. We will also use the spectroscopic technique, electron spin resonance (ESR) to identify the ROS forms being generated. Finally, we will determine the amounts of DMAV, the oxidized form of DMAIII to determine oxygen consumption.