Chronic arsenic (As) exposure is considered the number one chemical of environmental health concern in the US 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. <P> 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. 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. It is thought that recurrent respiratory infections play a major role in the development of bronchiectasis. In addition, respiratory infections by viruses such as influenza are a significant cause of morbidity and mortality worldwide. Identifying risk factors that affect such infections and their health effects, including environmental exposures to toxicants, such as As, could have a substantial and immediate impact on public health.<P> A recent preliminary study by the applicant demonstrated that exposure of adult mice to As in drinking water compromised their response to a subsequent respiratory influenza infection. The basis for this effect appeared to be related to direct effects of As on the immune response. <P> The overall goal of the proposed research is to determine the underlying mechanism for this effect, focusing in particular on early life exposures. Specifically, we propose to utilize an animal model to investigate the role of in utero As exposure on immune system dysfunction to test the hypothesis that in utero As exposure (via maternal drinking water exposure) followed by a sublethal dose of Influenza A will lead to increased immunopathology in the lung due to a dysfunction CD8+ T cell antiviral response. <P> This hypothesis will be investigated through the following specific aims: 1) Determine the critical time window for inducing immunopathology as a result of in utero and postnatal low dose As exposure (10 ppb) using a mouse adapted strain of H1N1 influenza (PR8) and standardized measures for assessing immunopathology; and 2) Determine the specific role of cytotoxic CD8+ T cells in the increased immunopathology, principally using a transgenic T cell receptor mouse model. <P> There is growing concern about in utero and early childhood exposures to environmental agents and the special nature of these exposures with respect to long term adverse effects on human health. The immune system appears to be specifically vulnerable to early challenges. Understanding the mechanism by which early life exposure to As adversely affects the ability of the immune system to respond effectively to viral and other infections could have a profound impact on our understanding of the overall contribution of such immuno-modulation on a variety of disease risks. <P> PUBLIC HEALTH RELEVANCE: Arsenic (As) exposure is a significant environmental health concern and there is particular concern about in utero and early childhood exposures for this effect. Identifying the mechanism for the effects of in utero As exposure on the developing immune system may provide new clues as to the role of As in increased risk of a wide variety of adult onset diseases. Additionally, the impact of As exposure on the potential for a pandemic flu outbreak could have a significant and immediate impact on public health, considering that many of the geographic areas with confirmed human cases of avian flu or H1N1 (swine) flu are known to overlap geographically with populations that also have significantly elevated As exposures, such as in Southeast Asia and Mexico.