Arsenic is a toxic and carcinogenic element with widespread environmental contamination and human exposure. Currently, elemental arsenic levels are used as a monitor of arsenic exposure. There is, however, increasing evidence that arsenic speciation both within the environment and enzymatic speciation upon consumption may profoundly affect the toxic and genotoxic parameters of arsenicals. The hypothesis to be tested is that the reaction between arsenite and the energy generating enzymes of the mitochondria is a significant cause of the oxidative stress and mitochondrial damage observed upon arsenic exposure. These interactions as well as the ensuing oxidant stress will be examined to identify potential biomarkers of arsenic-induced damage as distinct from exposure.
Aim 1 of this proposal is to characterize the nature of the mitochondrial oxidative stress induced by sulfhydryl reactive arsenite using enzyme kinetic measurements of the Kreb's cycle and electron transport enzymes. We will quantify this disruption of mitochondrial oxidative metabolism in order to characterize the role of the mitochondria in arsenic-induced oxidative stress. Classical enzyme kinetics and arsenic binding studies in vitro and in a cell based system will be used to establish the site(s) of inhibition.
Aim 2 of this proposal is to identify biomarkers of arsenite toxicity and oxidative stress. A family of arsenylated enzyme conjugates, including the mono- and dimtheylarsenic analogs of arsenite, will be synthesized as standards for analysis of biological samples and as antigens for polyclonal antibody generation. Classical markers of oxidative stress in the mitochondria and genomic extracts will also be monitored.
Aim 3 of this proposal will establish a proteomics profile of arsenicals in yeast. The emphasis will be on identifying sentinel proteins as biomarkers of arsenic-specific toxicity.
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