Polychlorinated biphenyls (PCBs) modulate signal transductions cascades leading to diverse functional change with 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. non-coplanar). It is generally accepted that coplanar PCBs mediate their effects through the aryl hydrocarbon receptor (AhR). However, non-coplanar 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. Previous results and preliminary data are discussed which suggest that immediate early response by terminally differentiated polymorphonuclear neutrophils (PMNs) are modulated by PCBs primarily in an AhR-independent manner. Moreover, the response by PMNs to PCB treatment is characterized by cellular activation. Conversely, B-cells, which are not terminally differentiated cells, are marked sensitivity to inhibition by PCBs. Moreover, the profile of PCB- mediated B-cell inhibition follows a structure-activity relationship concordant with AhR binding affinity. Collectively, these findings indicate that PCBs activate multiple signaling cascades in leukocytes and that the toxicity exerted by any given congener is cell type-dependent. In light of these findings, the overall goal of this 5 year research plan is to test the following HYPOTHESIS: In leukocytes, PCBs activate multiple signal transduction cascades dependently and independently of the AhR. Immediately-early leukocyte responses are altered by PCBs through the rapid modulation of protein kinases (i.e., Src and MAP kinases) both dependently and independently of the AhR; whereas, delayed responses are AhR-dependent and mediated transcriptionally through the regulation of genes under the control of DREs. A multifaceted approach will be used to test this hypothesis using the following specific aims (SA): In SA#1, we will determine the role of c-Src in PCB-mediated alterations of leukocyte function. In SA#2, we will characterize the role of MAP kinases in PCB-mediated alterations or leukocyte function. In SA#3, we will characterize the modulation of critical genes by PCBs as a putative mechanism of altered leukocyte function. Lastly, in SA#4 we will characterize the mechanism responsible for the antagonistic interactions between coplanar and non-coplanar PCB congeners in alterations of leukocyte function. We believe that the successful completion of these specific aims will provide important new insight into the basic mechanism(s) by which PCBs modulate the immune system.
Showing the most recent 10 out of 417 publications
