Superfund Research Program
Vascular Mechanisms of PCB-Induced Brain Metastases
Project Leader: Michal Toborek (University of Miami)
Grant Number: P42ES007380
Funding Period: 2000-2014
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Final Progress Reports
The main hypothesis of the proposal for the Vascular Mechanisms of PCB-induced Brain Metastases Project is that specific PCB congeners can induce dysfunction of brain endothelial cells, disrupt the blood-brain barrier (BBB), and increase formation of brain metastases. The main structural and functions elements of the BBB are tight junctions, which seal the neighboring endothelial cells and are responsible for the barrier function of the brain endothelium; as a result, the researchers associated with this project examined the effects of coplanar and non-coplanar PCBs on expression of tight junction proteins in human brain microvascular endothelial cells (HBMEC). Treatment with PCBs markedly decreased levels of tight junction proteins, such as zonula occludens (ZO)-1 and ZO-2. These effects are important because they can directly affect the integrity of the BBB.
Dr. Michal Toborek and his team evaluated the signaling mechanisms that may be involved in PCB-mediated disruption of the BBB. In collaboration with the Superfund Chemicals, Nutrition, and Endothelial Cell Dysfunction Project, Toborek examined whether caveolae-associated signaling can contribute to PCB153-induced dysregulation of tight junction protein expression. Exposure of HBMEC to PCB153 induced phosphorylation of caveolin-1, which is a major structural and regulatory component of caveolae. In addition, several caveolae-associated kinases, such as Src family kinase, Ras, and RhoA, were activated within 10 min of PCB153 exposure. Caveolae-disrupting agent, methyl-beta-cyclodextrin (MβCD), or siRNA silencing of caveolin-1, efficiently blocked PCB153-induced phosphorylation of several signaling molecules, including caveolin-1, Src kinase, Akt, and JAK family kinases. These data suggest that caveolae and related signaling mechanisms may be involved in PCB-induced disruption of tight junction proteins and, thus, contribute to the development of the neurotoxic effects of PCBs in the CNS.
Recent experiments focused on the role of multispecific drug-efflux pumps, such as P-glycoprotein (P-gp), in PCB-induced alterations of the BBB. As a primary gatekeeper of the BBB, P-gp acts as a major impediment to central nervous system CNS pharmacotherapy. Toborek investigated the effects of specific PCB congeners on expression and activity of P-gp. Treatment of HBMEC with PCB 126 and 153 dose-dependently increased P-gp protein levels. PCB-mediated changes in P-gp expression correlated with increased rhodamine 123 efflux, indicating the upregulation of transporter functions of P-gp. Rhodamine 123 accumulation was modulated by a variety of P-gp inhibitors. These results suggest that PCB-induced overexpression of P-gp in brain microvessels may reduce the efficacy of pharmacological treatments of the CNS disorders in PCB-exposed population.