Non-Coplanar PCB-Mediated Modulation of Human Leukocyte Phagocytosis: A New Mechanism for Immunotoxicity

Abstract

Organochlorine (OC) contaminants, notably polychlorinated biphenyls (PCBs) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), are ubiquitous in all ecosystems and found in the tissues of humans and wildlife. Although the immunotoxicity of coplanar, dioxinlike PCBs is well documented, the adverse effects exerted by non-coplanar, non-dioxinlike PCBs have received little attention. Direct causal relationship between PCB and dioxin exposure and the observed detrimental effects on the immune system has yet to be fully established in humans. The immunomodulatory potential of toxic coplanar PCB 169 and TCDD and abundant non-coplanar PCBs 138, 153, and 180 on human leukocyte phagocytosis, an important innate immune function that initiates the clearance of pathogens, was tested upon in vitro exposure. Mixture and concentration-response experiments demonstrated a suppression of phagocytosis by non-coplanar PCBs suggesting a previously unrecognized aryl hydrocarbon receptor (AhR)-independent pathway. Regression analysis revealed that reduction of phagocytosis was mostly explained by the non-coplanar congeners. The effects on phagocytosis could not be accurately predicted by either the currently used toxic equivalence (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. Our results are cause for concern as they suggest an AhR-independent pathway through which non-coplanar PCBs modulate phagocytosis, the immune system's first line of defense, possibly increasing the risk to developing infectious disease.

Residential Exposure to Polychlorinated Biphenyls and Organochlorine Pesticides and Risk of Childhood Leukemia

“…PCBs are thought to exert their carcinogenic effect through several possible mechanisms, depending on the specific congener and tumor site. These include binding to the aryl hydrocarbon receptor, promotion of cell proliferation or inhibition of apoptosis, and toxicity to immune cells (Levin et al 2005; Safe 1993; Tryphonas 1994; Wolff et al 1997). All of the PCB congeners that we measured have demonstrated immunotoxic effects (Harper et al 1995; Wolff et al 1997) and, except for PCB-105, were individually associated with elevated risk of ALL.…”

Non-coplanar polychlorinated biphenyl (PCB)-induced immunotoxicity is coincident with alterations in the serotonergic system

“…Although still an area of great debate, authors of the study suggested that the PCB-induced suppression of lymphocyte proliferation most likely occurred via an AhR-independent mechanism. Other studies have also reported a decreased lymphoproliferative response following exposure to noncoplanar PCB congeners, adding strength to the controversial argument for immunotoxic effects that could occur via an AhR-independent mechanism of action (De Guise et al, 1998;Nakata et al, 2002;Lyche et al, 2004;Levin et al, 2005;Duffy and Zelikoff, 2006).…”

Serum Concentrations of Antibodies Against Vaccine Toxoids in Children Exposed Perinatally to Immunotoxicants

“…Several studies have reported associations between developmental PCB exposures and a variety of immune function parameters (Belles-Isles et al 2002; Bilrha et al 2003; Levin et al 2005), with some studies focusing on immunoglobulin concentrations at different ages (Dewailly et al 2000; Nagayama et al 1998; Weisglas-Kuperus et al 2000). Among immune system properties that are feasible and appropriate for population studies, vaccination responses are of substantial public health relevance (van Loveren et al 1999).…”