Arsenic is recognized as a carcinogen for human skin, bladder, and lung, following either ingestion or inhalation; however the exact mode of action of environmentally relevant exposure has not been determined. Because arsenic in the environment exists in several oxidative states and can interact with thiols, it is thought that arsenic toxicity is mediated through oxidative stress. Production of oxygen radicals following acute in vitro exposures has been demonstrated. However, our research has chosen to focus on the role of oxidative stress following whole animal exposure to environmentally relevant doses of arsenic. Following a 28-d inhalation of arsenic or cigarette smoke or both, there was a significant decrease in both the reduced and total glutathione levels in the combined arsenic and smoke group compared to groups exposed to arsenic or smoke alone. This correlated with a 5-fold increase in DNA oxidation. Lungs processed for immunohistochemistry localization of 8-oxo-dG showed increased staining in nuclei of airway epithelium and subadjacent interstitial cells. Increases in DNA oxidation were not due to increased inflammation. Although inhalation of arsenic is an important occupational exposure, the majority of human exposures occurs through ingestion of arsenic. Our recent work has been devoted to the identification of altered pulmonary gene and protein expression following ingestion of environmentally relevant levels of arsenic in drinking water. We have found that, following chronic exposure, arsenic leads to misregulation of a number of genes and proteins in the lung. A large percentage of the altered genes and proteins are known to be regulated by redox-sensitive transcription factors, (SP1, NF κB, AP-1), suggesting that, at environmentally relevant levels of chronic exposure, arsenic may be acting through alteration of cellular redox status. Validation of the alterations seen in animal models of exposure is being carried out in humans.
ASJC Scopus subject areas
- Pharmacology, Toxicology and Pharmaceutics(all)
- Pharmacology (medical)