Ortho-substituted but not coplanar PCBs rapidly kill cerebellar granule cells.
Several PCB congeners were assessed for their cytotoxicity on cerebellar granule cells in an attempt to compare their structure-activity relationship as potential neurotoxicants and to assess the mechanisms associated with their toxicity. Flow cytometry was used to monitor the changes of a number of biochemical endpoints: membrane integrity, intracellular free calcium concentration ([Ca(2+)](i)), reactive oxygen species (ROS) production, mitochondrial membrane potential (Delta psi(m)), and cell size. The non-coplanar, ortho-substituted congeners, PCB 8 (2,4'-dichlorobiphenyl), PCB 28 (2,4,4'-trichlorobiphenyl), PCB 47 (2,4,2',4'-tetrachlorobiphenyl), and PCB 52 (2,5,2',5'-tetrachlorobiphenyl) (10 microM) killed neurons to different degrees within 30 min. Loss of viability was accompanied by increased [Ca(2+)](i) and decreased Delta psi(m). No significant changes of ROS level were observed during exposure. The coplanar congeners, PCB 77 (3,4,3',4'-tetrachlorobiphenyl), PCB 80 (3,5,3',5'-tetrachlorobiphenyl), and PCB 81 (3,4,5,4'-tetrachlorobiphenyl) (10 microM), had no effects on membrane integrity, [Ca(2+)](i) or Delta psi(m) in this time period of exposure. In Ca(2+)-free Tyrode's medium, there was no [Ca(2+)](i) increase after exposure to the ortho-substituted congeners, but also no reduction in loss of membrane integrity, suggesting Ca(2+) influx was not the cause of viability loss. The mitochondrial uncoupler, carbonyl cyanide m-chlorophenyl hydrazone (CCCP) (1-2 microM), caused a large decrease of Delta psi(m), but only a slight loss of viability, which suggested that Delta psi(m) is not the primary cause of PCB 52-induced cell death. These studies show that ortho-substituted PCBs are toxic to cerebellar granule cells; however, their toxic action is not secondary to elevation of intracellular calcium, a change in mitochondrial membrane potential, or free radical generation.
Tan
Yuansheng
Y
University at Albany, School of Public Health, Department of Environmental Health and Toxicology, University at Albany, Rensselaer, New York 12144, USA.
Song
Renji
R
Lawrence
David
D
Carpenter
David O
DO
D000818:Animals; D002118:Calcium / Q000009:adverse effects / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology* / Q000187:drug effects*; D003594:Cytoplasmic Granules / Q000187:drug effects*; D005434:Flow Cytometry / Q000379:methods; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D011078:Polychlorinated Biphenyls / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D013997:Time Factors
D011078:Polychlorinated Biphenyls; D002118:Calcium