MSU Superfund Projects and Cores:

Project 1: Characterization of the Pathways Linking Ah Receptor Activation with Altered B Cell Differentiation Using an Integrated Experimental and Computational Modeling Approach

Project 2: Dissecting the Signaling Network for Ah Receptor-mediated Bcell Toxicity

Project 3: Non-Additive Ah Receptor Ligand Interactions

Project 4: Influence of Ah Receptor Ligands on Inflammatory Responses: Consequences for Tissue Injury and Gene Expression

Project 5: A Proteomic Analysis of the AHR signaling Network

Project 6: Molecular Insight into Polyaromatic Toxicant Degradation by Microbial Communities

Project 7: Geochemical Controls on the Adsorption, Bioavailability, and Long-term Environmental Fate of Dioxins, PCBs, and PAHs

Core A: Administration

Core B: Research Translation

Core C: Computational Modeling of Mammalian Biomolecular Response

Core D: Biomedical Informatics

Core E: Environmental Molecular Analysis

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Link to the NIEHS SBRP site

Superfund Project 4

Influence of Ah Receptor Ligands on Inflammatory Responses:
Consequences for Tissue Injury and Gene Expression

The factors that cause normally harmless episodes of inflammation to culminate in disease are largely unknown but likely include genetic and environmental influences. Exposure to environmental chemicals such as aryl hydrocarbon receptor (AhR) ligands could contribute to individual susceptibility to disease by enhancing inflammatory responses or by providing a stimulus that precipitates injury in the presence of inflammation. Indeed, in preliminary studies, mice developed liver injury when coexposed to TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) and the inflammatory stimulus, lipopolysaccharide (LPS), each at doses that alone did not cause liver damage.

The goal of the research is to test the hypothesis that Ah receptor ligands enhance inflammatory responses that can lead to tissue injury. Consistent with the overall goal of the Program Project, the tissue of interest for this project is liver. This hypothesis will be tested by first evaluating the development of LPS-induced inflammation in mice exposed to AhR ligands and by delineating the dose-response relationship for AhR ligand-induced liver injury in the absence and presence of inflammation. The AhR ligands to be used are TCDD and 3,3’,4,4’,5-pentachlorobiphenyl (PCB 126). Mice will be treated with AhR ligands alone or in combination at doses that are not hepatotoxic. They will then be treated with a small dose of LPS that induces inflammation but alone does not cause liver injury. Markers of inflammation and liver injury will be assessed and time-courses and dose-response relationships established. Global changes in hepatic gene expression and DNA methylation in these dose-response and time-course studies will be determined and will be compared to biochemical and histological changes in liver as well as to markers of inflammation.

Both neutrophils and the hemostatic system, including plasminogen activator inhibitor-1 (PAI-1), are critical to liver injury in many models of chemical-inflammation interactions. To begin to understand inflammatory mediators that contribute to liver injury during AhR-inflammation interactions, the roles of these factors will be investigated in mice exposed to TCDD in the presence of inflammation. In preliminary studies treatment of mice with either TCDD or LPS increased serum concentration of PAI-1 expression, but the combination had a synergistic effect. Accordingly, a computational description of the biochemical pathways by which AhR ligands induce changes in expression of PAI-1 in the absence and presence of inflammation will be developed.

The results of these studies collectively will provide information about consequences of the interactions between inflammatory responses and AhR ligands and about molecular mechanisms involved in this interaction.

Patricia E. Ganey, Ph.D.
Project Leader
Michigan State University

Jay I. Goodman, Ph.D.
Co-Investigator
Michigan State University

Robert A. Roth, Ph.D.
Co-Investigator
Michigan State University