Exposure to polychlorinated biphenyls selectively dysregulates endothelial circadian clock and endothelial toxicity

Abstract

Polychlorinated biphenyls (PCBs) are lipophilic and persistent environmental toxicants, which pose health threats to the exposed population. Among several organs and cell types, vascular tissue and endothelial cells are especially prone to PCB-induced toxicity. Exposure to PCBs can exert detrimental impacts on biological pathways, expression of transcription factors, and tight junction proteins that are integral to the functionality of endothelial cells. Because biological and cellular processes are tightly regulated by circadian rhythms, and disruption of the circadian system may cause several diseases, we evaluated if exposure to PCBs can alter the expression of the major endothelial circadian regulators. In addition, we studied if dysregulation of circadian rhythms by silencing the brain and muscle ARNT-like 1 (Bmal1) gene can contribute to alterations of brain endothelial cells in response to PCB treatment. We demonstrated that diminished expression of Bmal1 enhances PCB-induced dysregulation of tight junction complexes, such as the expression of occludin, JAM-2, ZO-1, and ZO-2 especially at pathologically relevant longer PCB exposure times. Overall, the obtained results imply that dysregulation of the circadian clock is involved in endothelial toxicity of PCBs. The findings provide new insights for toxicological studies focused on the interactions between environmental pollutants and regulation of circadian rhythms.

Keywords: Bmal1; Circadian rhythm; Environmental pollutants; Polychlorinated biphenyls; Tight junction.