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Patricia K. Tithof,¹ Elizabeth Schiamberg,¹ Marc Peters-Golden,³ and Patricia E. Ganey^1,2

¹Department of Pharmacology and Toxicology and ²Department of Medicine and Institute for Environmental Toxicology, Michigan State University, East Lansing, MI 48824 USA; ³Department of Medicine, University of Michigan, Ann Arbor, MI 48106 USA

Abstract
Aroclor 1242, a mixture of polychlorinated biphenyls (PCBs) , activates neutrophils to produce superoxide anion (O₂^-) by a mechanism that involves phospholipase C-dependent hydrolysis of membrane phosphoinositides ; however, subsequent signal transduction mechanisms are unknown. We undertook this study to determine whether phospholipase A₂-dependent release of arachidonic acid is involved in PCB-induced O₂^- production. We measured O₂^- production in vitro in glycogen-elicited, rat neutrophils in the presence and absence of the inhibitors of phospholipase A₂: quinacrine, 4-bromophenacyl bromide (BPB) , and manoalide. All three agents significantly decreased the amount of O₂^- detected during stimulation of neutrophils with Aroclor 1242. Similar inhibition occurred when neutrophils were activated with the classical stimuli, formyl-methionyl-leucyl-phenylalanine (fMLP) or phorbol myristate acetate. The effects of BPB and manoalide were not a result of cytotoxicity or other nonspecific effects, although data suggest that quinacrine is an O₂^- scavenger. Significant release of ³H-arachidonic acid preceded O₂^- production in neutrophils stimulated with Aroclor 1242 or fMLP. Manoalide, at a concentration that abolished O₂^- production, also inhibited the release of ³H-arachidonate. Aspirin, zileuton, or WEB 2086 did not affect Aroclor 1242-induced O₂^- production, suggesting that eicosanoids and platelet-activating factor are not needed for neutrophil activation by PCBs. Activation of phospholipase A₂ and O₂^- production do not appear to involve the Ah receptor because a congener with low affinity, but not one with high affinity for this receptor, stimulated the release of arachidonic acid and O₂^-. These data suggest that Aroclor 1242 stimulates neutrophils to produce O₂^- by a mechanism that involves phospholipase A₂-dependent release of arachidonic acid. Key words: arachidonic acid, 4-bromophenacyl bromide, manoalide, PCBs, quinacrine, signal transduction, superoxide anion. Environ Health Perspect 104:52-58 (1996)

Address correspondence to P. E. Ganey, Department of Pharmacology and Toxicology, Life Sciences Building, Michigan State University, East Lansing, MI 48824 USA.

We extend special thanks to Kirsten Ruehle for her invaluable assistance in conducting these experiments and to Margarita Contreras for her advice and guidance. This work was supported by NIH grant ESO4911.

Received 25 July 1995 ; accepted 29 September 1995.