Polychlorinated biphenyls induce proteolysis of zonula occludens proteins in human brain microvessel endothelial cells

Polychlorinated biphenyl (PCB) congeners and related compounds exhibit a broad range of adverse biological effects, from carcinogenesis and tumor‐promotion to neurotoxicity. The mechanisms by which PCBs cause neurotoxic effects are still not completely understood. The blood‐brain barrier (BBB) is a physical and metabolic barrier separating the microenvironment of the central nervous system from the peripheral circulation and is mainly composed of endothelial cells connected by tight junctions. Zonula occludens (ZO) are major cytosolic proteins of tight junction complex which link the transmembrane tight junction proteins to the cytoskeleton. In the present study, we studied the effects of several highly‐chlorinated PCBs, such as 2,2′,4,5,5′‐pentachlorobiphenyl, 2,3′,4,4′,5‐pentachlorobiphenyl, 3,3′,4,4′,5‐pentachlorobiphenyl, and 2,2′,4,4′,5,5′‐hexachlorobiphenyl on ZO protein expression. Exposure of human brain endothelial cells to PCB congeners decreased steady protein levels of ZO‐1 and ZO‐2 without mRNA changes. In addition, different highly‐chlorinated PCB congeners increased permeability across the monolayers of brain endothelial cell. These data suggest that PCB‐mediated alterations of ZO protein expression may disrupt the BBB integrity and thus contribute to the development of the neurotoxic effects in the CNS. Supported by NIH/NIEHS (P42 ES 07380).