title: Presence and functional activity of the aryl hydrocarbon receptor in isolated murine cerebral vascular endothelial cells and astrocytes.
abstract: Numerous functions regulated by the central nervous system (CNS) are targeted by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); however, the cell specific targets and mechanisms of toxicity are unknown. Outside of the brain, the peripheral vascular endothelium has been identified as a significant cellular target of TCDD toxicity resulting in apoptosis, edema, hemorrhaging and vascular dysfunction. Possible effects of TCDD in the vascular endothelium of the CNS have not been examined. Cellular dysfunction in this endothelium may disrupt function of the blood-brain barrier (BBB), which could severely compromise neuronal homeostasis and potentiate neurotoxicity. TCDD toxicity is mediated primarily by the aryl hydrocarbon receptor (AhR), a ligand activated transcription factor that modulates the expression of a large battery of genes. This study examined the presence and functional activity of the AhR in response to TCDD in endothelial cells and astrocytes, the two primary components of the BBB. Primary mouse cortical endothelial cells and astrocytes express the AhR, as shown by immunocytochemical and western blot analyses. AhR activity was assessed by time- and concentration-dependent analyses of CYP1A1 and CYP1B1 protein expression following TCDD treatment. Both CYP1A1 and CYP1B1 proteins were induced in endothelial cells after 4 and 8h, respectively, while only CYP1B1 protein induction was detected in astrocytes after 16h. The CYP450 protein induction was sustained for greater than 72h in both cell types. These changes in protein expression were dependent on AhR activity as indicated by the inhibition of these responses by a receptor antagonist. Together these data indicate endothelial cells and astrocytes are responsive to TCDD through the AhR-mediated pathway and therefore could be targets of toxicity.
authors.affiliation: Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Box EHSC, 575 Elmwood Avenue, Rochester, NY 14642, USA.
authors.forename: Carissa R
authors.initials: CR
authors.lastname: Filbrandt
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Wu
authors.forename: Berislav
authors.initials: B
authors.lastname: Zlokovic
authors.forename: Lisa
authors.initials: L
authors.lastname: Opanashuk
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Gasiewicz
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology*; D002469:Cell Separation; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*
chemical_list: D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon