Environmental Arsenic Exposure and Hematotoxicity

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Project Summary Anemia adversely impacts the health of more than a billion people worldwide. A strong association between anemia and arsenic (As) exposure has been reported in epidemiological studies from multiple countries. However, the mechanistic bases for the association between As exposure and anemia is not fully understood. Previous research by our group provides evidence of arsenic hematotoxicity spanning from humans to mouse models. Our previous work focused on establishing the role of inorganic arsenite (As3+) as a hematotoxicant, particularly by determining the effects of As3+ on the zinc finger transcription factor GATA-1, which is essential for normal red blood cell (RBC) development (i.e. erythropoiesis). Based on this work, we found that As exposure causes anemia via the suppression of early erythroid progenitor cell development. We provide further evidence that this inhibition of RBC development occurs as a result of disruptions to GATA-1 function. These findings provide essential information regarding a molecular mechanism of As-induced inhibition of erythropoiesis, but also highlight an area requiring further investigation. Many studies suggest that the As3+ metabolite, monomethylarsonous acid (MMA3+) may be the major form of As responsible for toxicity observed in vivo; however, few studies have been performed to directly evaluate the role of As metabolism in the tissue distribution of arsenicals and subsequent toxicity at these sites. The proposed Focus Research Project will provide novel information regarding the role of As metabolism as a potential mediator of the observed hematotoxicity. The studies proposed in Aim 1 will address this important knowledge gap by examining the role of As metabolites in the hematotoxicity observed following As3+ and MMA3+ exposures, in vivo and in vitro. Aim 2 will investigate mechanisms of As metabolism-mediated inhibition of erythropoiesis by comparing the effects of As3+ to MMA3+ on important protein regulators of erythropoiesis. Outcomes from the proposed research will provide critical information essential for understanding the role of As metabolism in As-associated anemias and other hematological disorders.