Superfund Research Program
Activation of AhR-Dependent and AhR-Independent Signaling Cascades in PCB-Induced Immune Dysfunction
Project Leaders: Norbert E. Kaminski, Burra V. Madhukar, Patricia E. Ganey
Grant Number: P42ES004911
Funding Period: 2000-2020
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Project Summary (2000-2006)
The goal of this project is to investigate the hypothesis that, in leukocytes, polychlorinated biphenyls (PCBs) activate multiple signal transduction cascades dependently and independently of the AhR. Previous work has shown that PCBs modulate signal transduction cascades leading to diverse functional changes within a variety of cells. The pathways activated or inhibited by PCBs are common among cell types and different between classes of congeners (i.e., coplanar vs. noncoplanar). It is generally accepted that coplanar PCBs mediate their effects through the aryl hydrocarbon receptor (AhR). However, noncoplanar PCBs are low affinity ligands for the AhR, and also exert biological effects including activation or disruption of signal transduction pathways leading to altered cell function. Investigators are extending this work by determining the role of protein kinases in PCB-mediated alterations of leukocyte function. Additionally, the researchers are characterizing the modulation of critical genes by PCBs and the antagonistic interaction between coplanar and noncoplanar PCB congeners in alterations of leukocyte function. Results will provide important new insight into the mechanism(s) by which PCBs modulate the immune system.