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Final Progress Reports: University of Iowa: PCBs and Cytosolic Phenol and Steroid Sulfotransferases

Superfund Research Program

PCBs and Cytosolic Phenol and Steroid Sulfotransferases

Project Leader: Michael W. Duffel
Grant Number: P42ES013661
Funding Period: 2006-2020
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Final Progress Reports

Year:   2019  2014  2009 

The primary focus of the research carried out in this project continues to be on the interactions of hydroxylated metabolites of PCBs (i.e., OH-PCBs) with mammalian cytosolic sulfotransferases (SULTs) and on the fates and biological activities of their sulfated metabolites (i.e., PCB sulfates). With completion of the proposed studies for Specific Aim 2 in the previous project period, researchers have turned their attention to completion of the final remaining studies in Aims 1 and 3. With respect to Aim 1, researchers have published studies on the mechanism of interactions of 15 OH-PCBs with human sulfotransferase hSULT2A1. This provides an improved understanding of these PCB metabolites as both substrates and inhibitors of this enzyme that plays a key role in the metabolism and action of many hydroxysteroids.

A major effort during the current project period has been on the potential biological effects of PCB sulfates in relation to those effects of the OH-PCBs from which they are metabolically derived (Aim 3). Researchers have extended previous investigations on the ability of PCB sulfates to bind with high affinity to transthyretin (TTR), a major thyroid hormone transport protein. These PCB sulfates can stabilize TTR, thus preventing its formation of amyloid fibrils (a process that has been associated with diseases such as senile systemic amyloidosis, familial amyloid cardiomyopathy, and familial amyloid polyneuropathy). A manuscript on these results has been accepted for publication. Researchers are completing studies on the binding of PCB sulfates and related OH-PCBs to the major drug-binding sites in human serum albumin (HSA), and beginning the preparation of a manuscript for publication of these results. During the current project period, researchers have also completed analysis of a study on the distribution of PCB 11 sulfate in male Sprague-Dawley rats following a single i.v. injection at a relatively low dose. The results indicate that PCB 11 sulfate is taken up rapidly by tissues, and it is not excreted in the urine. Moreover, following uptake in tissues, this PCB sulfate is subject to further metabolism. Studies on bile-canulated rats indicated that some of the PCB 11 sulfate was excreted in the bile, although either further metabolism or reabsorption occurred, since negligible amounts of the PCB 11 sulfate were observed in the feces. Thus, these studies call into question previous assumptions that sulfation of OH-PCBs always leads to rapid excretion of the PCB sulfate in the urine. Once again, the ability of these sulfates to bind to serum proteins and to distribute into tissues suggests that these PCB metabolites may have additional biological activities/toxicities. These experiments required development of analytical methods for analysis of the PCB sulfate in body fluids and tissues, and these methods have now been applied to analysis of human serum samples. Researchers have conducted a preliminary experiment to determine PCB 11 sulfate in 46 human serum samples derived from the AESOP Study (Characterization of Exposures of Urban and Rural Cohorts to Airborne PCBs), and have detected this metabolite by LC/MS/MS in 22 subjects at concentrations ranging from a trace (≥ 2:1 signal:noise) to 60 nM. Researchers are currently completing analysis of these data and will be preparing a manuscript to report this first determination of a PCB sulfate in human serum.

In further exploration of the roles of cytosolic sulfotransferases (SULTs) in the metabolism and toxicities of semi-volatile PCBs, researchers have developed bacterial expression systems and purification methods for two major human SULTs (i.e., SULT1E1 and SULT1A1*1) that are important in catalyzing sulfation of the steroid hormone estradiol. This has enabled experiments on the interaction of OH-PCBs and PCB sulfates on these enzymes that are important in the termination of estrogen signaling by sulfation of the hormone. Studies on the interaction of OH-PCBs and PCB sulfates with these two SULTs are ongoing.

As an additional component of studies in Aim 3 on the biological activities/toxicities of the PCB sulfates and the OH-PCBs from which they are metabolically derived, researchers have initiated studies on their cytotoxicity in a neuronal cell line (i.e., rat N27 cells). The rationale for these studies stems from demonstrated neurotoxicity of several lower-chlorinated PCBs. Researchers have found that several PCB sulfates, as well as their OH-PCB precursors are toxic to these cells. Further investigation of the selectivity of toxicity of these PCB sulfates is currently underway.

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