ToxSci Advance Access published online on March 31, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh119
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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1 University at Albany, School of Public Health, Department of Environmental Health and Toxicology, University at Albany, Rensselaer, NY 12144
* To whom correspondence should be addressed. E-mail: carpent{at}uamail.albany.edu.
Our previous studies have demonstrated that ortho-substituted PCBs cause a rapid cell death in both thymocytes and cerebellar granule cell neurons, whereas coplanar congeners are without effect at comparable concentrations and exposure times. We have demonstrated that multiple membrane components are altered by these exposures, including the plasma membrane, mitochondria and endoplasmic reticulum. The present experiments were designed to test the hypothesis that because of their stereochemistry, ortho-substituted congeners cause a greater disruption of membrane integrity than do coplanar congeners, and that this membrane disruption results in altered cellular function and to cell death. To test this hypothesis we have measured fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene (DPH) in thymocytes, cerebellar granule cells and lipid bilayer vesicles upon exposure to an ortho-substituted PCB congener (PCB 52) and a coplanar congener (PCB 77), and compared results obtained in these studies to those from flow cytometric studies of plasma membrane permeability to large molecules and elevations of intracellular calcium in living cells. The fluorescence polarization of the DPH probe, which inserts into the lipid bilayer, reflects changes in membrane fluidity. In all three preparations we found that whereas fluorescence polarization was unchanged upon exposure to PCB 77, it was reduced significantly by PCB 52, reflecting an increase in membrane fluidity. These observations are consistent with the hypothesis that ortho-substituted PCBs disrupt membrane structure, which alters the function of membrane proteins. In the two cell types we have studied, the disruption is sufficient to cause death of the cell within a brief time.
© 2004 Toxicological Sciences © Society of Toxicology 2004; all rights reserved.
Neurotoxicology
Ortho-Substituted PCBS Kill Cells by Altering Membrane Structure
2 University at Albany, School of Public Health, Department of Biomedical Sciences, Rensselaer NY 12144
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
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