The overall goal of this project is to understand the altering effects of infection and inflammation on the hepatic toxicity of environmental chemicals. Infectious agents that influence liver function can alter the biological processing of many foreign chemicals. These perturbations to liver function may influence an individual's susceptibility to environmental exposures. Therefore, understanding the biochemical associations between infectious agents and organ function are of critical importance for safety assessment in human populations. To investigate the impact of inflammation and infection on the toxicity of environmental chemicals, this project will study two liver toxins: arsenic and aflatoxin B1. Both chemicals are classified as human carcinogens by the International Agency for Research on Cancer (IARC). Arsenic is a ubiquitous environmental contaminant of global water supplies and is associated with hepatic portal hypertension and liver fibrosis in human populations. Aflatoxin B1 is a fungal toxin present in food supplies and is strongly associated with increased risk for the development of hepatocellular carcinoma (HCC). To study the interaction between these toxins and infection, we will infect mice with enteric bacterial pathogens (C. rodentium or H. hepaticus) to promote liver inflammation and then challenge mice with either arsenic or aflatoxin B1 to study the resulting combined toxicological outcomes. Both bacteria are infectious agents of the intestine that are model organisms of human pathogens. This work will test the hypothesis that enteric pathogens producing hepatic inflammation will increase the toxicity of environmental agents that target the liver.
Specific aim one will investigate the effects of acute liver inflammation during exposure to low-dose arsenic and the effects of arsenic exposure during chronic liver inflammation. This work will result in the development of new biochemical analyses to assess the role of oxidative damage in tissues associated with disease progression.
Specific aim two will determine how inflammation alters the biological processing of aflatoxin B1 and the resulting effects on macromolecular damage associated with the bioactivation of aflatoxin B1. Using the mouse as a model for human exposures, these studies will provide a biochemical basis for the combined effects of pathogenic microbes and environmental chemicals.
The joint effects of infection and chemical exposure can produce enhanced toxicity in human populations. This proposal will investigate the biochemical and mechanistic events that contribute to these effects with the intent of identifying individuals who are at the greatest risk of environmental exposures.