Immunomodulatory effects of chronic low dose arsenic exposure

Toxic metals are a major health concern in the environment and particularly in Superfund and other toxic waste sites. Arsenic (As) is considered the number one environmental chemical of human health concern both in the U.S. and worldwide. It is estimated that As exposure results in adverse health effects for approximately 25 million people in the United States and up to 1 billion people worldwide. Recent epidemiological data has indicated that chronic exposure to As can significantly increase the risk of non-malignant lung disease in human population. The goal of the studies outlined in this dissertation is the identify how As exposure may lead to the development of chronic lung diseases. We hypothesize that chronic exposure to low doses of arsenic compromises the innate immune response, leading to an increased susceptibility to infectious disease. The first aim was to develop a mouse model of low dose As exposure. The second aim was examine global mRNA changes by microarray in the lungs of mice exposed chronically to As, specifically investigating whether As preferentially affects gene and protein expression related to immune function as part of its mechanism of toxicant action. The third aim was to investigate if the observed changes in immune related gene and protein expression lead to a compromised response to respiratory influenza infection. The fourth aim was to specifically investigate the effect of low dose As exposure on the migration of dendritic cells, as part of the mechanism behind altered responses to influenza infection. To our knowledge, these studies are the first to show that environmentally relevant levels of As lead to a severely compromised immune response to respiratory infection in a mouse model. The aberrant responses observed in these studies following As exposure may place exposed individuals at risk for development of chronic lung diseases, which has been observed in As-exposed human populations.