Organic and inorganic arsenic compounds sensitize human bronchial epithelial cells to hydrogen peroxide-induced DNA damage Public Deposited

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  • March 21, 2019
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  • Molinelli, Alejandro Raul
    • Affiliation: School of Medicine, Curriculum in Toxicology
Abstract
  • Arsenic is an environmental contaminant that can induce lung cancer via ingestion or inhalation. Arsenic undergoes a series of metabolic changes in the body were the inorganic species of the semi-metal (commonly found in the environment) undergo a series of redox and methylation reactions. Recent evidence suggests that organic trivalent arsenicals might be more cytotoxic and genotoxic than inorganic arsenicals. Several hypotheses have been proposed to explain its carcinogenic mode of action but no definitive conclusion has been documented. However, multiple studies suggest that arsenic might potentiate the effects of other agents. The purpose of this project was to evaluate the cytotoxicity and DNA damage potential of organic (dimethylarsine iodide, DMAs3+) and inorganic (sodium arsenite, iAs3+) arsenic compounds to human bronchial epithelial cells and whether the arsenicals had any effect on hydrogen peroxide-induced DNA damage. Hydrogen peroxide is present in the airways due to cellular metabolism, and is increased in response to inflammation. We found that DMAs3+ was more cytotoxic and induced more DNA damage (as assessed via the alkaline single cell gel electrophoresis assay) than iAs3+ after exposure for 4 h in the BEAS- 2B (transformed human bronchial epithelium) cell line. However, both arsenic compounds sensitized the BEAS-2B cells to H2O2-induced DNA damage. Upon further examination of the factors that could account for the sensitization we found that the BEAS-2B cells accumulate more As after exposure to DMAs3+ than after exposure to iAs3+. This finding could partly explain the sensitization observed, thus, we assessed whether blocking As efflux transporters would affect the sensitization to H2O2. However, no significant changes were observed between the cells that had received the efflux transporter inhibitors and the controls. We also assessed whether reduced glutathione (GSH) was involved in the results observed. After increasing or decreasing cellular GSH we observed that DMAs3+-induced sensitization of the cells to H2O2-induced DNA damage is dependent on the levels of GSH. An increase in GSH levels attenuates the sensitization, and a decrease in GSH increases the sensitization. It is possible that GSH serves a protective role in airway epithelial cells by scavenging methylated arsenic compounds.
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  • Madden, Michael
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