Document Type

Dissertation

Date of Degree

Fall 2011

Degree Name

PhD (Doctor of Philosophy)

Degree In

Human Toxicology

First Advisor

Gabriele Ludewig

Abstract

PCB126 is the most potent agonist of the aryl hydrocarbon receptor (AhR) in the whole family of chlorinated biphenyls (PCBs), a class of persistent organic pollutants that are classified as probable human carcinogens. It exerts systematic toxicities in animals mainly through the AhR pathway and generates cellular oxidative stress which might damage cellular macromolecules. The goal of this thesis is to elucidate the mechanisms of PCB126 toxicity in the aspect of AhR-related oxidative stress. Reactive superoxide radicals could be generated as the result of electron leakage in the catalytic cycles of cytochrome P450 (CYP) enzymes which are super-induced by sustained AhR activation in response to PCB126. In addition, the disruption of mitochondrial electron transport chain caused by AhR ligands also contributes to the production of superoxide radicals. Correspondingly in this thesis, the impact of PCB126 on the expression of the recently-discovered, TCDD-inducible microsomal CYP2S1 enzyme was studied. Then the regulation of mitochondrial antioxidant enzyme MnSOD in response to PCB126 was investigated. Lastly, a microarray study on classic AhR ligands of β-naphthoflavone and 3-methylcholanthrene was conducted to explore possible mechanisms of AhR-associated toxicities and to find explanations for the regulation of CYP2S1 as well as MnSOD after PCB126 exposure. It was found that CYP2S1 was only weakly or not at all regulated by PCB126 in rats. As for MnSOD, although its messenger and protein levels were induced by PCB126, its enzymatic activity was significantly reduced in the liver, probably through post-translational mechanisms. Although dietary manganese supplementation did not reverse the loss of MnSOD activity due to PCB126 exposure, it significantly protected against liver hypertrophy caused by PCB126. Microarray study results were consistent with previous findings and indicated that in addition to changed expression of a number of CYPs, metal homeostasis as well as mitochondria functions were also affected by AhR ligands. Overall, both CYP enzymes and the mitochondria contribute to the AhR-mediated toxicities of PCB126 that are associated with a disturbance of cellular redox homeostasis.

Keywords

AhR, CYP2S1, MnSOD, oxidative stress, PCB126, rat

Pages

2, xiii, 184 pages

Bibliography

Includes bibliographical references (pages 159-184).

Copyright

Copyright 2011 Bingxuan Wang

Included in

Toxicology Commons

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