Phospholipase A2-Mediated Ca2+ Influx by 2,2′,4,6-Tetrachlorobiphenyl in PC12 Cells

Abstract

Polychlorinated biphenyls (PCBs) are a group of persistent and widespread environmental pollutants, and known to affect signaling molecules. Phospholipase A2 (PLA2) mediates cellular destructive processes as well as normal physiological responses in neuronal cells. In this study, we examined whether PLA2 can be activated by PCBs in PC12 cells. Of the congeners tested, ortho-substituted PCBs were found to induce PLA2 activation. PLA2 activation by 2,2′,4,6-tetrachlorobiphenyl (TeCB), the most potent congener, was inhibited by bromoenol lactone (BEL), a calcium-independent PLA2 (iPLA2) inhibitor, and methyl arachidonyl fluorophosphonate (MAFP), a cytosolic PLA2 and iPLA2 inhibitor. In the case of Ca2+, although 2,2′,4,6-TeCB increased [Ca2+]i in the presence of extracellular Ca2+, PLA2 activation was not inhibited by EGTA and 1,2-bis (o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetra (acetoxy-methyl) ester, an extracellular and an intracellular Ca2+ chelator, respectively. On the other hand, 2,2′,4,6-TeCB-induced Ca2+ increase was partially inhibited by BEL and MAFP. In addition, 2,2′,4,6-TeCB induced apoptotic cell death in these cells. Taken together, our results suggest that ortho-substituted PCBs might induce apoptosis through PLA2-mediated Ca2+ influx, which provides a clue to understand the mechanism of neurotoxic effects of ortho-substituted PCBs.