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

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 ([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.

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

“…We found that orthosubstituted but not coplanar PCB congeners caused an increase in membrane fluidity than was correlated in time and concentration with rapid cell death of both neurons [37] and thymocytes [38]. We also found that low concentrations of toxaphene (10-20 ppm) caused a decrease in membrane fluidity, but still triggered significant cell death [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].…”

“…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).…”