Document Type

Dissertation

Date of Degree

Spring 2016

Degree Name

PhD (Doctor of Philosophy)

Degree In

Human Toxicology

First Advisor

Larry W. Robertson

Abstract

The prevalent and ongoing exposures to polychlorinated biphenyls (PCBs) demands an understanding of the threat they pose and also a means in which to mitigate their potential toxicity. This thesis set out to investigate a phenomenon associated with a specific PCB congener, 3,3',4,4',5-pentachlorobiphenyl (PCB126), for the underpinnings of its mechanism, and also its usefulness as a toxin against which to establish a mitigative strategy. The phenomenon in particular is the disruption of hepatic trace elements, specifically an increase in copper and decreases in zinc, selenium, iron, and manganese in the liver. Four questions were posed to address the overarching goals: 1) When does micronutrient disruption occur in the context of liver pathology? 2) What metal transporters or chaperones are involved? 3) Can the previously shown beneficial micronutrient, zinc, alter the disruption and improve outcome? 4) What is occurring spatially within the liver acinus where micronutrients are distributed? By answering these four questions, a fundamental understanding of this occurrence will be ascertained.

A chronology of PCB126-hepatotoxicity showed onset of liver pathology at 36 hours and later alterations in micronutrients at 3 days, suggesting disruption of hepatic trace elements is likely the result of liver degeneration. In addition, a key metal transport protein, metallothionein, was induced by PCB126. Utilizing a double knockout animal model, metallothionein was shown to abrogate some toxicity but had little involvement of micronutrient perturbation. Previous investigations have suggested the unique property of zinc in rescuing/preventing hepatic damage by a variety of toxic agents. Dietary zinc had a modest effect in ameliorating PCB126 hepatotoxicity and preserving micronutrient homeostasis. This suggests that the mitigative potential of zinc supplementation on PCB126 exposure is limited. Finally, a fine spatial investigation of the liver acinus was conducted to establish the levels of trace elements from the portal triad to the central vein. In addition, novel findings of high concentrations of extracellular zinc were discovered. In all, this dissertation has shown that disruption of hepatic micronutrients caused by PCB126 are likely the result of liver degeneration by means of disturbing the spatial trace element gradients and provides appropriate context for therapeutic/preventive strategies against PCBs.

Public Abstract

Exposure to environmental pollutants is ongoing and poses a serious threat to human health. This dissertation describes studies designed to investigate a phenomenon associated with a known environmental contaminant, PCB126, similar in mode of action to the contaminate found in Agent Orange. Specifically, alterations in hepatic trace elements including copper, zinc, selenium, and manganese that occur after exposure to PCB126. A better understanding of how it occurs and whether it can be used as a means of protecting against exposure was the initial objective. This was assessed by addressing four questions: 1) When does it happen? 2) What proteins are involved? 3) Does a well-known therapy work? 4) Why does it happen? The changes in trace elements in the liver appears to happen after onset of other damage, in particular the expansion of the endoplasmic reticulum and the accumulation of lipids, and a common protein associated with several trace elements is likely not involved. An established therapy, supplementation of the diet with zinc, was only marginally successful in protecting against damage. Changes in the spatial element gradients within the functional unit of the liver are likely the reason for alterations in liver metals seen. In all, this dissertation provides deeper insights into phenomena associated with a common environmental agent and a possible means in protecting from exposure.

Keywords

publicabstract, Disruption, Metallothionein, Micronutrient, PCB, Trace Elements, Zinc

Pages

xiv, 117

Bibliography

104-117

Copyright

Copyright 2016 William Delbert Klaren

Included in

Toxicology Commons

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