Biomarkers Of Health Risks Associated With Environmental Exposure To ArsenicEPA Grant Number: R832735
Title: Biomarkers Of Health Risks Associated With Environmental Exposure To Arsenic
Investigators: Stýblo, Miroslav , García-Vargas, Gonzalo G , Del Razo, Luz M.
Current Investigators: Stýblo, Miroslav , García-Vargas, Gonzalo G , Del Razo, Luz M. , Loomis, Dana , Ethan, Lange , Drobna, Zuzana
Institution: University of North Carolina at Chapel Hill
Current Institution: University of North Carolina at Chapel Hill , University of Nevada - Reno
EPA Project Officer: Callan, Richard
Project Period: February 13, 2006 through February 12, 2009 (Extended to February 12, 2010)
Project Amount: $749,988
RFA: Early Indicators of Environmentally Induced Disease (2004) RFA Text | Recipients Lists
Chronic exposures to inorganic arsenic (iAs) have been associated with increased incidences of skin cancer, cancers of internal organs, and of a variety of noncancerous diseases, including type-2 diabetes mellitus. Reports from this and other laboratories suggest that metabolism of iAs that yields highly toxic intermediates, methylarsonous acid (MAsIII) and dimethylarsinous acid (DMAsIII), plays a significant role in determining the extent and character of adverse health effects associated with exposure to iAs. The goal of the proposed project is to examine relationship between the metabolism of iAs and biomarkers of these effects.
(a) To examine interindividual variations in urinary profiles of MAsIII and DMAsIII in individuals exposed to iAs in drinking water. (b) To characterize the relationship between urinary levels of MAsIII and DMAsIII and markers of carcinogenic and diabetogenic effects of iAs. (c) To examine the role of genetic polymorphism for arsenic (+3 oxidation state) methyltransferase (AS3MT) in modulation of the metabolism and adverse health effects of iAs. (d) To study the genotype-phenotype relationship using recombinant genetic variants of AS3MT.
Study participants will be recruited among the residents (adults and children) of Zimapan and Lagunera regions (Mexico) who are exposed to a wide range of iAs concentrations in drinking water. Metabolites of iAs, including MAsIII and DMAsIII, will be analyzed in freshly collected urines. Markers of (pre)carcinogenic and diabetogenic effects of iAs will be examined, including skin lesions, concentration of transforming growth factor-α (TGF-α) in the urine and in exfoliated bladder epithelial cells, fasting glucose and insulin concentrations and hemoglobin A1c levels in the blood, and results of oral glucose tolerance test. AS3MT genotypes will be analyzed, using blood RNA. The genetic variants of AS3MT found in the study participants will then be cloned, and expressed. Purified recombinant AS3MT variants will be used in an in vitro assay system to further examine links between the specific genotypes and the pattern of iAs metabolism. Finally, relationships between the markers of adverse health effects, the AS3MT genotypes, and the in vivo and in vitro metabolic patterns for iAs will be characterized.
Given the results of preliminary studies, we expect to find positive correlations between the urinary levels of MAsIII and/or DMAsIII and markers of adverse health effects in exposed individuals. We also expect to link specific metabolic profiles for iAs to specific AS3MT genotypes. Ultimately, this project will provide a set of metabolic, biochemical, and genetic biomarkers that, taken together, may significantly improve the assessment of health risks associated with chronic exposures to iAs and identification of individuals with increased susceptibility to toxic and cancer promoting effects associated with these exposures.