Specific Non-Coplanar PCB-Mediated Modulation of Bottlenose Dolphin and Beluga Whale Phagocytosis Upon in Vitro Exposure

Abstract

Contaminant-induced immunosuppression by organochlorines (OC), particularly polychlorinated biphenyls (PCBs), has been suspected as a cofactor in the deaths of thousands of marine mammals. One important innate defense mechanism is phagocytosis, the ability of cells to ingest extracellular macromolecules. The present study was aimed at characterizing the immunomodulatory potential of representative OCs on phagocytosis in bottlenose dolphins and beluga whales. The ability of peripheral blood leukocytes to engulf fluorescent microspheres was evaluated using flow cytometry. The immunomodulatory effects of three non-coplanar PCB congeners, 138, 153, and 180, one coplanar PCB, 169, and 2,3,7,8-TCDD and all possible mixtures (26) were tested upon in vitro exposure. In both species, all mixtures containing at least two non-coplanar PCBs significantly reduced both neutrophil and monocyte phagocytosis, with effects more marked in dolphins than in belugas. Coplanar OCs, on their own or when added to non-coplanar congeners, did not further modulate phagocytosis, suggesting an Ah receptor-independent mechanism. Concentration-response experiments with individual congeners further demonstrated a non-coplanar PCB-induced suppression of phagocytosis, while coplanar congeners produced no consistent effects. Our results suggest simple additive interactions of chemicals in a mixture. However, calculation of toxic equivalency (TEQs) failed to predict the experimentally induced immunomodulatory effects of OCs on dolphin and beluga phagocytosis, confirming the Ah receptor-independent nature of the effects on phagocytosis. Overall, our results suggest that non-AhR mechanisms may explain one facet of immunotoxicity (phagocytosis), something that is not captured using the TEQ approach. This is the first report demonstrating the immunomodulatory effects of OCs on dolphin and beluga phagocytosis, and the first overall demonstration of immunomodulatory effects on phagocytosis mediated specifically by non-coplanar PCBs.

2,2′,4,4′-Tetrachlorobiphenyl upregulates cyclooxygenase-2 in HL-60 cells via p38 mitogen-activated protein kinase and NF-κB

“…Noncoplanar PCBs cause a variety of adverse effects, including increased release and decreased synthesis of insulin in rat insulinoma cells (Fischer et al 1996), changes in the concentrations and distribution of dopamine and 5-hydroxytryptamine in female rat brains (Chu et al 1996), increases in rat liver weight (Lecavalier et al 1997), reduced phagocytosis by neutrophils and monocytes in marine mammals (Levin et al 2004), and modulation of superoxide anion production in rat neutrophils (Brown and Ganey, 1995). PCBs also affect the regulation of a number of genes, the most studied being cytochromes P450 in liver (Chubb et al 2004).…”

Toxicology of Marine Mammals: New Developments and Opportunities

“…bottlenose dolphins (Tursiops truncatus), beluga whales (Delphinapterus leucas) and pinnipeds, while studied compounds are organohalogenated, i.e. PCBs (polychlorinated biphenyls), organochlorine and brominated compounds Levin et al 2004Levin et al , 2007Mori et al 2006). Nevertheless, there are also studies reporting immunotoxicity in relation to heavy metal exposure (e.g.…”

“…In addition, Levin et al (2004) have found that bottlenose dolphins are more sensitive to organochlorine mixtures than beluga whales thereby pointing towards a species-specific sensitivity. Various studies have also shown that organochlorine compounds can have an AhRindependent mechanism of action, thereby indicating that the sensitivity of marine mammals could not be predicted from results obtained from other species (Levin et al 2004(Levin et al , 2007Mori et al 2006). As bioassays are based on specific cell lines derived from other species like rodents or humans, one can argue that the observed responses to contaminant mixtures are not necessarily the same as the responses experienced by marine mammals in the wild.…”

“…Several studies have underlined how mixtures can have a stronger effect on immune system than individual compounds Levin et al 2004Levin et al , 2007Mori et al 2006). In addition, Levin et al (2004) have found that bottlenose dolphins are more sensitive to organochlorine mixtures than beluga whales thereby pointing towards a species-specific sensitivity.…”

“…Fossi et al 2006Fossi et al , 2008Marsili et al 2008;Spinsanti et al 2008) and on the evaluation of immunotoxicity and metabolic activity for pollutant breakdown or biotransformation (e.g. Boon et al 1998;De Guise et al 1998;Kim et al 1998;White et al 2000;Nakata et al 2002;Levin et al 2004Levin et al , 2007Mori et al 2006;Wilson et al 2007;Camara Pellissò et al 2008). Several of these studies use blood samples collected from animals held in controlled environments that are trained for blood sampling.…”