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

Return to the MSU Superfund Main Page

Link to the NIEHS SBRP site

Superfund Project 1:

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

The overall goal of this 5 year research plan is two-fold: (a) to characterize the molecular mechanism for impairment of B cell differentiation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and dioxin-like compounds; and (b) to develop a computational model describing the biochemical pathways that regulate B cell differentiation and the interaction of this pathway with the aryl hydrocarbon reception (AhR). 

Previous studies have established the B cell as a sensitive cellular target for TCDD as evidenced by suppression of immunoglobulin (Ig)M through a direct effect on B cells involving the AhR. Moreover, suppression of the IgM response by TCDD is mediated at the level of transcription and, in part, occurs through AhR binding to dioxin response elements (DRE) in regulatory domains within the Ig heavy chain (IgH) 3 (proportional to) enhancer. 

Importantly, in addition to IgH suppression, the Ig kappa light chain, IgM joining chain (J chain) and X-box protein1 (XBP1), which are essential for IgM assembly and secretion, are also markedly suppressed by TCDD suggesting the involvement of additional targets other than just the IgH 3 (proportional to) enhancer. Moreover, TCDD alters the levels of B lymphocyte-induced maturation protein1 (Blimp1), a master regulatory of B cell differentiation and its downstream target, Pax5, a transcriptional repressor of B cell differentiation, which represses IgH, Ig kappa, J chain and XBP1. 

We also show that TCDD treatment of B cells: (a) altered the magnitude of DNA methylation and MRNA levels of DNA methylating enzymes, Dnmt3b, which putatively influences the expression of genes crucial to B cell differentiation, including Pax5; (b) is functionally antagonized by IFNg; and (c) rapidly induces the suppressor of cytokine signaling-2 (SOCS-2), a protein that negatively regulates signaling through cytokine receptors coupled to the JAK/STAT pathway, such as the IFNgamma receptor (IFNgammaR). 

The project objective is to test the hypothesis: Suppression of the primary humoral immune response by AhR agonists is mediated through changes in the B cell differentiation program via a mechanism that is blocked by IFNgamma. A computational description of the biochemical pathway of B cell differentiation and the direct interactions of AhR agonists on this pathway, will provide a mechanistic approach for predicting the effects of AhR agonists, alone and in combination as complex mixtures, on the pathway and on humoral immune responses.

Norbert E. Kaminski, Ph.D.
Principal Investigator and Project Leader
Michigan State University

Rory B. Conolly, Sc.D.
Co-Investigator
U.S. Environmental Protection Agency

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

Barbara L. Kaplan, Ph.D.
Co-Investigator
Michigan State University