Arsenic Exposure: Effects on Oxidative Stress, Gene Regulation and the Extracellular Matrix in the Lung

Abstract

The mechanisms of arsenic's atherogenicity, toxicity and carcinogenicity remain to be elucidated. The lung is an established target of arsenic exposure. Therefore, the present studies address the effects of arsenic on the lung and examine the role of arsenic-induced oxidative stress as a mechanism of action. Both inhalation and ingestion exposure models were used to address this question. Since oxidative damage of DNA has been linked to cancer, we determined the synergistic ability of aerosolized arsenic and cigarette smoke to increase DNA oxidation in the lung. To test this hypothesis male Syrian golden hamsters were exposed to room air, aerosolized arsenic trioxide, cigarette smoke, or both smoke and arsenic for up to 28 days. Our results show that in the 28 day group there was a significant increase in DNA oxidation, and a significant decrease in both the reduced and total glutathione levels in the combined arsenic/ cigarette smoke group when compared with arsenic or cigarette smoke alone. Using an ingestion model, we determined whether arsenic exposure could lead to misregulation of oxidative stress sensitive genes. To investigate this hypothesis, C57BL/6 mice ingested drinking water with or without 50 ppb arsenic for five or eight weeks. Six independent Affymetrix mouse 430(A) arrays were used. We ranked differentially expressed genes in ascending order by the p-values and a limited number of altered genes were classified as redox sensitive genes and these included Hsp105, Hspa1b, Osp94 and Dnaja1. Of particular interest were the matrix genes that had been down regulated. Down regulation was validated using real time PCR. Staining for elastin, collagen and smooth muscle actin demonstrated phenotypic changes. We also identified twenty proteins as being altered (5 up- and 15 down-regulated) by 50 ppb arsenic exposure for eight weeks. Analysis of potential protein function indicated that nucleus/nuclear transport proteins, cancer related proteins, and cytoskeleton related proteins were altered by arsenic.These data, both inhalation and ingestion, support the hypothesis that arsenic acts, at least in part, through oxidative stress/redox sensitive pathways. These data provide useful molecular targets and biomarkers for future study of the sites of action of inorganic arsenic exposure.