Ortho-Substituted PCBs Kill Cells by Altering Membrane Structure

Abstract

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.

In Vitro Effects of Environmentally Relevant Polybrominated Diphenyl Ether (PBDE) Congeners on Calcium Buffering Mechanisms in Rat Brain

“…It has been demonstrated that ortho-substituted PCB congeners (but not coplanar congeners) alter calcium homeostasis by inducing changes in the integrity of mitochondrial and ER membranes which is accompanied by a decrease in mitochondrial membrane potential and accumulation of intracellular calcium [58]. It has also been shown that PCB 47 and PCB 52 (non-coplanar congeners; 10 lM) significantly compromised plasma membrane integrity concomitant with an accumulation of intracellular calcium [59]. Disruption of membrane structure, whether it is the plasma membrane or those of intracellular organelles, can cause changes in ion permeabilities through voltage or ligand gated channels as well as changes in activity of membrane bound enzymes [59].…”

“…It has also been shown that PCB 47 and PCB 52 (non-coplanar congeners; 10 lM) significantly compromised plasma membrane integrity concomitant with an accumulation of intracellular calcium [59]. Disruption of membrane structure, whether it is the plasma membrane or those of intracellular organelles, can cause changes in ion permeabilities through voltage or ligand gated channels as well as changes in activity of membrane bound enzymes [59]. These nonspecific effects could certainly contribute to loss of calcium sequestration as presented in the current report.…”

Omega-3 and Omega-6 Fatty Acids Kill Thymocytes and Increase Membrane Fluidity

“…Some environmental contaminants, such as orthosubstituted polychlorinated biphenyls (PCBs), cause an increase in membrane fluidity in neurons and thymocytes but also cause a rapid cell death in isolated cell systems [12]. Toxaphene, a chlorinated pesticide, decreases membrane fluidity and also causes acute cell death in thymocytes [13].…”

Substituents modulate biphenyl penetration into lipid membranes

“…There have been many studies on the potential toxicity of substituted BPs in vivo [2,17,18] but very little work has been carried out on the evaluation of the molecular characteristics responsible for their toxicity and the mechanism of their interaction at a cellular and plasma membrane level. According to some studies, non-planar o-substituted BPs increased the cell membrane leakiness and decreased the membrane integrity compared to the planar BPs [17][18][19]. While other studies have shown the non-planar o-substituted molecules to be less active compared to the planar p-substituted molecules because of the steric hindrance of the osubstituted species which influences their penetration into the phospholipid membrane [20][21][22].…”