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EFFECTS OF PCB 84 ATROPISOMERS ON [3H]-PHORBOL ESTER BINDING IN RAT CEREBELLAR GRANULE CELLS AND 45CA2+-UPTAKE IN RAT CEREBELLUM.
Lehmler, H. J., L. W. Robertson, A W. Garrison, AND PRS Kodavanti. EFFECTS OF PCB 84 ATROPISOMERS ON [3H]-PHORBOL ESTER BINDING IN RAT CEREBELLAR GRANULE CELLS AND 45CA2+-UPTAKE IN RAT CEREBELLUM. Presented at Society of Toxicology, New Orleans, LA, March 06 - 10, 2005.
There is evidence that Polychlorinated biphenyl (PCB) congeners with ortho substituents have potential to cause neurotoxicity. Many PCB congeners implicated in these neurotoxic effects are chiral. It is currently unknown if the enantiomers of a chiral PCB congeners have different neurotoxic effects. We herein report the effect of racemic 2,2',3,3',6-pentachlorobiphenyl (PCB 84) and its enantiomers on two neurochemical measures, PKC translocation as determined by [3H]phorobol ester binding in cerebellar granule cells and Ca2+ sequestration as determined by 45Ca2+ uptake by microsomes isolated from adult rat cerebellum. Milligram quantities of the PCB 84 enantiomers were separated using HPLC. The (+)- and (-)-PCB samples were enantiomerically pure as determined by chiral GC. Both (+)- and (-)-PCB 84 increased [3H]phorobol ester binding in a concentration-dependent manner with (-)-PCB 84 being slightly more potent. Racemic PCB 84 was significantly more potent compared to the pure enantiomers alone. This suggests a synergistic increase of [3H]phorobol ester binding by the PCB 84 enantiomers. (-)- and (+)-PCB 84 both inhibited microsomal 45Ca2+ uptake to a similar extent, whereas racemic PCB 84 was more potent at inhibiting 45Ca2+ uptake compared to either enantiomer. In microsomes both PCB 84 enantiomers apparently cause a synergistic inhibition of 45Ca2+ uptake. These results indicate that PCB 84 enantiomers alone have similar potencies in both assays whereas a synergistic effect can be observed for the racemic mixture. These findings may have important implications for understanding the mechanism of neurotoxicity of chiral PCB congeners (Supported by ES 012475 and ES 07380 from NIH; this abstract does not necessarily reflect USEPA policy).