Propanil (3,4-dichloropropionanilide) is one of the most extensively used and economically important acylanilide herbicides in the United States. As such, humans are occupationally exposed to propanil. Propanil is hydrolyzed to 3,4-dichloroaniline (DCA) and propionic acid in the liver, and both propanil and DCA have been shown to have a number of toxic and immunotoxic effects in humans and in mice. The liver is also a primary target organ for the replication and clearance of many viral and bacterial infections. In this proposal we describe experiments to examine the effect of propanil on immunity to infection in the liver. Infection by Listeria monocytogenes, a species of gram positive, intracellular bacteria, has been used as a model system to study immunity in the liver. During the initial infection by L. monocytogenes, innate immune mechanisms mediated by neutrophils, Kupffer cells and natural killer cells are important for resistance. In the later stages of infection, the development of Listeria-specific effector T cells are vital to complete clearance of the bacteria and long lasting immunity. The cyotokine, interferon-gamma (IFN-gamma), is produced in the early and late stages of infection and is essential for resistance to L. monocytogenes. Our preliminary data demonstrate that propanil decreased resistance to L. monocytogenes infection in the spleen and liver, and suppressed the production of IFN-gamma during the infection. Based on these observations, we hypothesize that propanil decreases resistance to infection by suppressing the production of IFN-gamma. We will test our hypothesize by determining whether administration of exogenous IFN-gamma restores resistance to infection in propanil-treated mice. We will also determine if propanil is hepatotoxic. Additional experiments will fully assess the ability of cells to produce IFN-gamma and determine the mechanism of decreased IFN-gamma production at the molecular level. Although the importance of the liver in toxin metabolism and immunity are well known, there have been few studies to determine the effects of toxins on liver immune function. The studies proposed here will provide critically important information about the effects of environmental toxins on the immune response in a well characterized, biologically relevant system. In addition, they will enhance our understanding of the effects of environmental toxins on liver immune function and on the immunotoxicity of amide-class herbicides.
