Mechanisms Involved in the Non-Coplanar PCB-Induced Modulation of Phagocytosis in Marine Mammals, Humans, and Mice
Contaminant-induced immunosuppression by organochlorines (OC), particularly polychlorinated biphenyls (PCBs), has been associated with adverse health effects in marine mammals and humans. Accumulating evidence suggests that non-coplanar, non dioxin-like PCBs, abundant in the tissues of marine mammals and humans and traditionally considered 'safe', can modulate key leukocyte functions. This study characterized the immunomodulatory potential of mixtures of OCs on leukocyte phagocytosis, the first line of defense against invading, foreign or other unwanted cells or particles, and compared the relative sensitivity between marine mammal, humans, and mice. Calcium mobilization and biochemical inhibitors were utilized to better characterize the mechanism(s) involved in the modulation of phagocytosis. The immunodulatory effects of three non-coplanar PCB congeners (138, 153, 180), one coplanar PCB (169, the most toxic coplanar PCB), as well as 2,3,7,8-TCDD (dioxin, the most toxic OC), and all possible mixtures were tested upon in vitro exposure. Results demonstrated 1) all species were not equally sensitive to the effects of organochlorines on phagocytosis, 2) phylogeny could not predict toxicity, 3) reduction in phagocytosis was mediated specifically by non-coplanar OCs through a poorly understood AhR-independent pathway, 4) calcium mobilization may have partially mediated the effects of non-coplanar PCBs on phagocytosis in bottlenose dolphins or beluga whales, 5) G-protein pathways may be involved in the modulation of phagocytosis in bottlenose dolphins, and 6) the effects on phagocytosis could not be accurately predicted by either the currently used toxic equivalency (TEQ) approach or the mouse model, thus undermining the use of the traditional models in the risk assessment for OC mixtures containing non-coplanar congeners. A better understanding of the mechanisms involved in the modulation of phagocytosis by non-coplanar PCBs will help explain differences in susceptibility between different species and the assessment of risks upon exposure to these ubiquitous environmental pollutants.