Impact/Purpose:

This project focuses on the capacity of individuals to metabolize inorganic arsenic as a determinant in susceptibility. Its objectives are to:

1) identify genetic polymorphisms for enzymes that metabolize arsenic;

2) examine arsenic-protein interactions to gain insight into the mode of toxicity for this metalloid.

Understanding the role of genetic susceptibility in the control of arsenic metabolism will benefit the risk assessment process by identifying subpopulations of individuals who are genetically predisposed to greater susceptibility to the toxic or carcinogenic effects of chronic arsenic exposure. Factors identified in this research as modifiers of the metabolism and toxicity of arsenic can be incorporated into quantitative models which describe the systemic and cellular metabolism of arsenic and its mode(s) of action as a toxin and carcinogen. This approach will extend current modeling efforts that examine the fate of other forms of arsenic (i.e., total arsenic or total methylated arsenic) and improve the utility of these models in risk assessment. Taken together, the research effort examining the genotypic and phenotypic control of metabolism, toxicity, and carcinogenicity of arsenic will contribute to the Agency,s periodic reevaluation of risk assessments for this element in water, air, pesticides, and other media.

Description:

This research will study the role of genetic factors in the expression of arsenic toxicity. The project will determine whether the interindividual variation in response is related to differences in the capacity to metabolize inorganic arsenic, if these differences in metabolic capacity are primarily determined by the kinetic properties of the enzymes that catalyze the reduction of pentavalent arsenic and the methylation of arsenicals, if the kinetic properties of these enzymes are determined by their primary sequence (hence, by the genotypes for these proteins), and whether control of the expression of these genes may be an important in determination of the capacity for metabolism of arsenic. As a corollary to these postulates, this research will determine if there is a linkage between the genotypes for these enzymes and the disease susceptibility phenotype which is manifested by the capacity of cells or organisms to metabolize inorganic arsenic. It is likely that polymorphisms in the genes which encode these proteins determine their catalytic activities and that the transcriptional regulation of these genes affects their expression. If susceptibility to the adverse effects of chronic exposure to inorganic arsenic is related to capacity to produce methylated metabolites, then genotypes for these critical enzymes are highly relevant to predicting the hazard associated with chronic exposure to this metalloid. Studies of genotypic-phenotypic relations in human cells and in individuals are important steps in estimating the role of interindividual variation in determination of susceptibility. Specifically, this research will include studies of genotype-phenotype correlations for arsenic methyltransferase in humans; polymorphisms at the gene for glutathione transferase omega; arsenicals and purified proteins or synthetic peptide amino acid sequences of importance in arsenic metabolism (MMA(V) reductase and Cyt19) or mechanism of action; interactions of dietary folate deficiency and arsenic (i.e., evaluations of gene expression changes in association with enhanced DNA fragility and possible alterations in methylation patterns); and the transcriptional control of Cyt19 (arsenic (III) methyltransferase) and the expression pattern of Cyt 19 in various human tissues.

Record Details: