Neutrophil activation by polychlorinated biphenyls: Structure-activity relationship

Polychlorinated biphenyls (PCBs) rapidly stimulate polymorphonuclear leukoc ytes (neutrophils) in vitro to produce superoxide anion (O-2(-)). This resp onse results from activation of various intracellular signal transduction p athways and appears to occur in a structure-specific fashion. Individual PC B congeners, varying in pattern and extent of chlorination, were tested for their ability to stimulate production of O-2(-) and/or to enhance the resp onse to protein kinase C activation by phorbol myristate acetate (PMA). Neu trophils were isolated from retired breeder, male, Sprague-Dawley rats and exposed to either vehicle, 10 or 50 mu M PCB for 30 min at 37 degrees C. PM A (0 or 20 ng/ml) was added for an additional 10 min, and O-2(-) generated during the incubation period was measured. 2,2'-Dichlorobiphenyl (2,2'-DCB) , 2,4'-DCB, or 3,3'-DCB (50 mu M) stimulated neutrophils to produce O-2(-). Incubation of neutrophils with 4,4'-DCB, 3,3',4,4',5-pentachlorobiphenyl ( 3,3',4,4',5-PeCB), 3,3',4,5,5'-PeCB, or 2,2',3,3',4,4'-hexachlorobiphenyl ( 2,2',3,3',4,4'-HCB) did not result in generation of O-2(-). Of the various congeners, 2,4'-DCB elicited the greatest production of O-2(-). Exposure to 10 mu M 2,2'-DCB, 2,4'-DCB, 3,3'-DCB, or 2,2',3,3',4,4'-HCB prior to addit ion of PMA caused a significant increase in the amount of 0, produced, grea ter than that seen with either compound alone. PMA-stimulated O-2(-) produc tion was unaffected by prior exposure to 4,4'-DCB, 3,3',4,4',5-PeCB, or 3,3 ',4,5,5'-PeCB. In separate experiments, 3,3',4,4',5-PeCB inhibited the amou nt of O-2(-) produced in response to activation with either 3,3'-DCB or 2,4 '-DCB. Thus, it appears that congeners which are noncoplanar are capable of stimulating neutrophil O-2(-) production. Coplanar congeners with high aff inity for the Ah receptor do not activate neutrophils to produce O-2(-) and may inhibit this response. These results are consistent with the hypothesi s that PCBs stimulate neutrophil O-2(-) production by a mechanism that is s tructure-specific and dependent on the chlorine substitution pattern of the biphenyl rings. Molecular modeling suggested that the sum of atomic charge s on chlorine atoms is the most important descriptor for congeners which st imulate O-2(-) production. The angle of rotation and the difference in ener gy between the highest occupied molecular orbital and the lowest unoccupied molecular orbital are integrative descriptors which, along with the sum of chlorine atomic charges, are associated with this biological activity. (C) 1998 Society of Toxicology.