In Utero Arsenic and H1N1 Influenza-the Role of CD8+ T Cells in Immunopathology
Arsenic (As) is considered the number one chemical risk of environmental health concern in the U.S. and worldwide, and has been associated with increased risk of a wide variety of serious illnesses including various cancers, cardiovascular disease, diabetes and other significant non-cancer disease risks. The primary route of exposure is through ingestion of drinking water that has been contaminated with inorganic As from natural geological sources. Epidemiological evidence from an As-exposed population in Chile demonstrated that in utero and early childhood exposure to As was associated with a 46-fold increase in the risk of death from bronchiectasis decades after cessation of exposure. These observations have since been confirmed in other As-exposed populations in Bangladesh and Argentina. The extraordinary magnitude and unexpected residual aspect of this risk warrants further investigation into the underlying mechanism and the connection between early life As exposure and adult disease. We have found that exposure to As in drinking water, at levels found in many natural water sources, significantly diminishes the ability to clear H1N1 influenza infection, impairs CD8+ T cell responses, and prolongs both virus carriage as well as the inflammatory response. We have also found that airway remodeling is evident in these animals long after virus clearance, suggesting a mechanism that links the altered inflammatory response with the epidemiological phenotype of bronchiectasis in exposed individuals. In this study we will examine whether similar effects are evident after exposure in utero, following infection after exposed pups mature. Determination of a delayed effect of in utero exposure ground-water levels of arsenic on response to infection and airway inflammation and remodeling will be an important step in understanding potential epigenetic determinants of toxicity later in life.