The blood brain barrier as a target of 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity mediated by the aryl hydrocarbon receptor

The Aryl-hydrocarbon Receptor (AhR) is a ligand-dependent transcription factor that modulates the toxicity of various polycyclic aromatic hydrocarbons (PAH), including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TODD). These compounds are potent environmental contaminants that have demonstrated the capacity to alter central nervous system (CNS) function. However, the specific cell targets and mechanisms of this neurotoxicity are not fully understood. Interestingly, the role that cerebral vascular endothelial cells may play in the development of this toxicity has never been examined. This vascular system maintains neuronal homeostasis and function by providing a metabolic and physical barrier that regulates the exchange of nutrients and oxygen as well as protects against toxic insult. Pathophysiological alterations to the integrity of this barrier system could alter neuronal function and represent the initial steps in the progression of TCDD-induced neurotoxicity. There is evidence demonstrating that the peripheral endothelium is a primary target of TCDD toxicity, which further supports the need to investigate CNS endothelial cell TCDD toxicity. The studies described in this thesis were designed to address the hypothesis that CNS endothelial cells are vulnerable to TCDD toxicity which may impair barrier function. In vitro studies have demonstrated that primary endothelial cells and astrocytes, the two main cell types comprising the blood brain barrier, possess the AhR machinery to respond to TCDD insult. An in vitro blood brain barrier model was developed and characterized to elaborate upon these findings and assess functional endpoints of toxicity. In addition, in vivo studies utilizing focused microarray technology were implemented to evaluate TCDD induced alterations in capillary gene expression in adult mice. These studies have identified that TCDD upregulates endothelial expression of numerous inflammatory mediators which have the capacity to alter barrier integrity. The biological significance of these findings was substantiated with analysis of protein expression. Together these data demonstrate that the cerebral vasculature is a target of TCDD toxicity and implicate a novel pathway for the initiation of TCDD induced neurotoxicity.