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ToxSci Advance Access published online on March 31, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh108
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received November 19, 2003; accepted February 20, 2004
© 2004 Toxicological Sciences © Society of Toxicology 2004; all rights reserved.

Neurotoxicology

Ortho-Substituted but Not Coplanar PCBs Rapidly Kill Cerebellar Granule Cells

Yuansheng Tan 1, Renji Song 2, David Lawrence 3, and David O. Carpenter 4*

1 University at Albany, School of Public Health, Department of Environmental Health and Toxicology, University at Albany, Rensselaer, NY 12144
2 Wadsworth Center for Laboratories and Research, New York State Department of Health, and School of Public Health, University at Albany, Albany, NY 12201
3 Wadsworth Center for Laboratories and Research, New York State Department of Health, Albany, NY 12201; University at Albany, School of Public Health, Department of Environmental Health and Toxicology, Rensselaer NY 12144
4 University at Albany, Institute for Health and the Environment, and School of Public Health, Department of Environmental Health and Toxicology, Rensselaer NY 12144

* To whom correspondence should be addressed. E-mail: carpent{at}uamail.albany.edu.


  Abstract

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 ([Ca2+]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 µM) killed neurons to different degrees within 30 min. Loss of viability was accompanied by increased [Ca2+]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 µM), had no effects on membrane integrity, [Ca2+]i or {Delta}{psi}m in this time period of exposure. In Ca2+-free Tyrode's medium, there was no [Ca2+]i increase after exposure to the ortho-substituted congeners, but also no reduction in loss of membrane integrity, suggesting Ca2+ influx was not the cause of viability loss. The mitochondrial uncoupler, carbonyl cyanide m-chlorophenyl-hydrazone (CCCP) (1-2 µM), 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.

Key Words: PCBs, Flow Cytometry, Cerebellar Granule Cells, Intracellular Calcium Concentration, Viability, Membrane Integrity .


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