Ortho-Substituted PCBs Kill Thymocytes

Abstract

The effects of exposure of acutely dissociated rat thymocytes to various polychlorinated biphenyl (PCB) congeners were examined using flow cytometry. Non-planar, ortho-substituted congeners caused a rapid cell death at low micromolar concentrations, while coplanar, dioxin-like congeners at the same concentration were without significant effect. The most potent of the congeners studied was PCB 52 (2,2',5,5'-tetrachlorobiphenyl), which had an IC50 of 3.96 microM at 20 min. Prior to loss of viability there was a decrease in mitochondrial membrane potential Delta Psi m, an accumulation of intracellular calcium, and a progressive leakiness of the plasma membrane. Application of PCB 52 in calcium-free medium reduced the calcium accumulation, but did not reduce cell death. Agents that depolarized mitochondria also did not induce the same degree of cell death caused by PCB 52. Cyclosporin A, which prevents opening of the mitochondria permeability transition channel, protected against cell death but did not protect against mitochondrial depolarization or calcium accumulation. Rapamycin and FK 506 at high concentration provided partial protection against cell death. These observations indicate that the ortho-substituted PCB 52 disrupts plasma, mitochondrial and endoplasmic reticulum membranes. We hypothesize that PCB 52 incorporates into lipid bilayers and with its bulky, three-dimensional ortho-substituted congener structure disrupts membrane function to a greater degree than coplanar congeners.

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

“…The effects of the toxicants demonstrated in this report may partially be attributed to compromised membrane integrity. 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].…”

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].…”

“…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].…”

Levels and potential health hazards of PCBs in shallow groundwater of an e-waste recycling area, China

“…PCBs have been shown to have toxic effects on various organs including tissues of the nervous, reproductive, and immunologic systems (Buck et al 2000;Hennig et al 2002;Tan et al 2003Tan et al , 2004Bemis and Seegal 2004). In general, the toxicological effects of PCBs vary at the congener level (Safe 1992) and PCBs become more toxic with increasing chlorine content (Tanabe 1988).…”