The impact of polychlorinated biphenyls (PCBs) on neuroimmune interactions in fish: An indirect mechanism of PCB-induced immunotoxicity

Polychlorinated biphenyls (PCBs) are a class of contaminants widely dispersed throughout the environment and, as such, have been detected in nearly every environmental compartment including the atmosphere, soil, water, and biota. The toxicological effects of PCB exposure have been well-studied in mammals and fish, and results from these studies have demonstrated the particular sensitivity of the immune and nervous systems to PCB-induced toxicity. Until very recently, PCB-induced toxicity was believed to be solely mediated through aryl hydrocarbon receptor (AhR) binding. However, because some PCB congeners, specifically noncoplanar congeners, have little affinity for this cytoplasmic receptor but can still produce toxicity in exposed organisms, suggestions of a non-AhR-mediated mechanism of action have emerged. Given the extensive crosstalk between the immune system and serotonergic portions of the central nervous system, and the fact that the serotonergic system is a target for PCB-induced toxicity, PCB-induced alterations in the serotonergic axis appears a plausible mechanism by which noncoplanar PCBs may induce their immunotoxic effects. Therefore, studies were performed, using a fish model, to determine whether alterations in the nervous system could mediate PCB-induced immunotoxicity.; Results from the first portion of the studies examining coplanar (PCB 126) and noncoplanar (PCB 153) PCB-induced immune dysfunction demonstrated that the selected fish model (i.e., bluegill sunfish, Lepomis macrochirus ) was sensitive to PCB-induced innate and cellular immune dysfunction. Moreover, PCB-induced effects on the immune response were more dramatic in fish exposed to noncoplanar PCB 153 compared to those exposed to coplanar PCB 126.; To determine if alterations in the serotonergic system could influence the immune response, the role of serotonin (5-HT) in normal bluegill immune function and the effect of PCB exposure on the serotonergic system were examined. Results demonstrated that both innate and cellular immune parameters of bluegill were altered following in vivo/vitro alterations in whole brain 5-HT synthesis and concentrations, suggesting a requirement for this neurotransmitter (NT) in immune regulation. In addition, examination of bluegill whole brain and spleen following PCB exposure revealed dramatic significant decreases in 5-HT and norepinephrine (NE) levels in the brain induced by both congeners, but no significant changes in 5-HT or NE levels in the spleen. Furthermore, hypothalamic synthesis of 5-HT was up-regulated in bluegill treated with PCB 153. Taken together, results from these studies provide the basis for the hypothesis that PCB-induced changes in the serotonergic system could lead to altered immune responsiveness in bluegill. To specifically demonstrate that decreased whole brain 5-HT levels were responsible for the observed PCB-induced immunotoxicity in bluegill, the effect of increasing endogenous 5-HT levels on immune outcome were examined. Results revealed that noncoplanar PCB 153-induced immunotoxicity could, in some cases, be abrogated following endogenous increases in whole brain 5-HT levels, indicating that the PCB-induced decrease in whole brain 5-HT levels may have been responsible for the observed immunotoxicity.; Overall, this study highlights the necessity of examining non-AhR-mediated pathways as potential mechanisms of PCB-induced toxicity, specifically immunotoxicity. In addition, the bluegill sunfish has emerged as a useful model for examining toxicant-induced disruption of the neuroimmune axis. Importantly, this study has demonstrated, for the first time in any fish or mammalian model, that PCB-induced alterations of the nervous system (specifically, the serotonergic system) leads to immune dysfunction, underscoring the significance of indirect mechanisms of action in PCB-induced immunotoxicity. Since binding and activation of the AhR has historically been thought to be a prerequisite for...