Responses Of paraoxonase 1 to dioxin-like pcb 126 ( 3,3',4,4',5-pentachlorobiphenyl): mechanisms and consequences

Polychlorinated biphenyls (PCBs) are ubiquitous environmental pollutants that have been associated with various adverse health effects in humans and wildlife. Dioxinlike PCBs elicit a broad spectrum of biochemical and toxic changes including cardiovascular disorders. Paraoxonase 1 (PON1), an antioxidant enzyme, prevents oxidative stress and plays key roles in the pathogenesis of atherosclerosis. The overall goal of this dissertation is to investigate the mechanism and role of PON1 in the antioxidant defense to the exposure of 3, 3’, 4, 4’, 5-pentachlorobiphenyl (PCB 126), the most potent congener in PCB family. My overall hypothesis is that: The up-regulation of PON1 is an antioxidant response to PCB 126 exposure, which involves the Ah receptor (AhR) and results in changes in the PON1 protein level and activity which in turn has an influence on the oxidative stress status. First, the responses of PON1 gene expression and activities in serum and liver upon the PCB126 treatment were evaluated in the rat model. I found that PCB 126 upregulated PON1, gene expression and activities, in a time and dose dependent manner. Next, I investigated the molecular mechanism of this response. My results show that the up-regulation of PON1 by PCB 126 involves the AhR and the XRE-like sequence in the gene promoter region. The up-regulation of PON1 was tissue specific, and this response probably protected liver and serum from lipid oxidation to some extent. The structure-activity relationship studies with PCB congeners indicate that the up-regulation of PON1 was specific to dioxin-like PCB 126. Other different AhR ligands displayed different PON1 induction capabilities. Also, reduction of PON1 activity was found in male rats dosed with non-dioxin-like PCBs. Finally I investigated the interaction, and possible protection, of other antioxidants (Se and NAC) on the response to PCB 126. I found that these antioxidants reduced the magnitude of the response of PON1 to the PCB 126 exposure in liver. Both