Effect of polychlorinated biphenyl microbial transformation processes on immunological responses in murine splenocytes.

摘要

Accidental and intentional releases, as well as global transport processes, have resulted in widespread environmental contamination of polychlorinated biphenyls (PCBs). Although PCBs are released into the environment as a commercial mixture, their congener profiles are altered in exposed organisms and in the environment as a result of metabolic and environmental transformation processes. Studies were initiated to determine the immunological effects of PCBs, specifically the responses of lipopolysaccharide (LPS)-stimulated splenocytes following PCB exposure, and how these effects may change with microbial degradation processes. In individual congener studies, a preferential inhibition of LPS-induced splenocyte proliferation was observed following exposure to multi- ortho-substituted congeners. This inhibition was independent of the number of chlorines per biphenyl and the aqueous solubility of the congeners. Antibody secretion was not influenced by substitution pattern but was directly inhibited as a result of decreased LPS-stimulated proliferation. Expression of the aryl hydrocarbon receptor (AhR) in LPS-induced splenocytes was not decreased by exposure to Aroclor 1242, nor was it affected by exposure to fractions of ortho and non-ortho-substituted congeners, thus providing evidence of an AhR-independent mechanism of the observed immunological effects. Further examination of the mechanism of action of PCBs in LPS-stimulated splenocytes revealed an interruption of cell cycle progression, specifically by the multi-ortho-substituted 2,2′-CB, that was not observed following exposure to the non-ortho-substituted 4,4′-CB. This interruption of cell cycle progression by 2,2′-CB was further linked to a decreased expression of cyclin D2, a cell cycle regulatory protein. Studies addressed how these immunological effects may be altered following microbial PCB degradation processes. No change in the inhibition of LPS-induced splenocyte proliferation was observed following aerobic microbial degradation, which produces a mixture enriched in more heavily chlorinated congeners in addition to degradation intermediates and endproducts, such as chlorohydroxybiphenyls and chlorobenzoates. The immunological effects of PCBs were also examined following anaerobic reductive dechlorination, a process that results in an accumulation of lesser-chlorinated congeners with ortho substitutions. Dechlorinated Aroclor 1242 inhibited LPS-induced splenocyte proliferation, cell cycle progression, and cyclin D2 expression at similar levels as observed with the parent Aroclor 1242. These studies emphasize the toxicological potential of congeners with multiple ortho substitutions, which are of interest since these congeners accumulate in exposed organisms and in the environment. In addition, a mechanism of action of the immunological effects of PCBs in LPS-stimulated splenocytes is demonstrated.