Document Type

Dissertation

Date of Degree

Spring 2014

Degree Name

PhD (Doctor of Philosophy)

Degree In

Human Toxicology

First Advisor

Michael W. Duffel

Abstract

In recent years, lower-chlorinated, airborne congeners of polychlorinated biphenyls (PCBs) have evolved as an emerging class of potentially hazardous environmental contaminants. Previous work has demonstrated that sulfation is a major metabolic pathway for these PCBs in vitro and in vivo; however, their metabolic fate and toxicities have not been explored. Hypothyroxinemia is among the most prevalent adverse health effects associated with PCB exposure in human populations and is an assumed cause of a variety of neurodevelopmental effects observed in infants following prenatal PCB exposure. The displacement of L-thyroxine (T4) from binding sites on transthyretin (TTR), a major T4 transport protein and trans-placental carrier of thyroid hormones, is thought to be a significant contributing factor in PCB-induced hypothyroxinemia. Structural similarities between sulfated metabolites of PCBs and T4 led to the central hypothesis that PCB sulfates are bioactive metabolites that exhibit high affinity binding to T4 binding sites on human TTR. An examination of the ability of six lower-chlorinated PCB sulfates to bind to human TTR in vitro, as well as subsequent computational modeling, revealed that these compounds interact with the high-affinity binding site in a non-covalent manner and with affinities comparable to T4. Corroborating evidence for the binding of PCB sulfates stems from their ability to inhibit the formation of TTR amyloid fibrils through stabilization of the protein's native conformation. Fibrillar TTR aggregates are the cause of amyloidoses like senile systemic amyloidosis, familial amyloid polyneuropathy and familial amyloid cardiomyopathy. All PCB sulfates examined were effective inhibitors of TTR fibrillogenesis with equal or higher efficiencies than some of the best previously described inhibitors. In vivo exposure of male Sprague-Dawley rats to a model PCB sulfate, 4-PCB 11 sulfate, resulted in rapid and widespread distribution of the metabolite to various organs, including the brain. Consequently, there is a strong indication for a potential role of PCB sulfates in thyroid disruption and inter-tissue transport of PCBs, and the binding of PCB sulfates to TTR may also provide structural information for improved design of anti-amyloid therapeutics. To date there are no analytical procedures for the quantification of PCB sulfates available, and exposure levels in human populations remain unknown. This study provides, for the first time, evidence that PCB sulfates, if present in human serum samples, are not extracted by current standard protocols for the analysis of PCBs and their metabolites. Consequently, PCB sulfates may have been overlooked in the past decades resulting in potential underestimation of total PCB exposure levels in exposed populations. Based on this finding, an efficient approach for the quantitative extraction of PCB sulfates from a variety of biological samples was developed. This procedure, coupled with quantitative mass spectrometry, has been validated for the future screening of human serum samples, and it was successfully applied to determine the tissue distribution and elimination profile of 4-PCB 11 sulfate in male Sprague-Dawley rats.

Keywords

Amyloid Disease, PCBs, Polychlorinated Biphenyls, Thyroid Disruption, Transthyretin

Pages

xv, 149 pages

Bibliography

Includes bibliographical references (pages 129-149).

Copyright

Copyright 2014 Fabian Alexander Grimm

Included in

Toxicology Commons

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