Circadian control of polycyclic aromatic hydrocarbon-induced dysregulation of endothelial tight junctions and mitochondrial bioenergetics.

ABSTRACT

The study evaluates the impact of environmental toxicants, such as polycyclic aromatic hydrocarbons (PAHs), on circadian regulations and functions of brain endothelial cells, which form the main structural element of the blood-brain barrier (BBB). PAH are lipophilic and highly toxic environmental pollutants that accumulate in human and animal tissues. Environmental factors related to climate change, such as an increase in frequency and intensity of wildfires or enhanced strength of hurricanes or tropical cyclones, may lead to redistribution of these toxicants and enhanced human exposure. These natural disasters are also associated with disruption of circadian rhythms in affected populations, linking increased exposure to environmental toxicants to alterations of circadian rhythm pathways. Several vital physiological processes are coordinated by circadian rhythms, and disruption of the circadian clock can contribute to the development of several diseases. The blood-brain barrier (BBB) is crucial for protecting the brain from blood-borne harmful substances, and its integrity is influenced by circadian rhythms. Exposure of brain endothelial cells to a human and environmentally-relevant PAH mixture resulted in dose-dependent alterations of expression of critical circadian modulators, such as Clock, Bmal1, Cry1/2, and Per1/2. Moreover, silencing of the circadian Clock gene potentiated the impact of PAHs on the expression of the main tight junction genes and proteins (namely, claudin-5, occludin, JAM-2, and ZO-2), as well as mitochondrial bioenergetics. Findings from this study contribute to a better understanding of pathological influence of PAH-induced health effects, especially those related to circadian rhythm disruption.