Research Project 3
PCBs and Hydroxysteroid (Alcohol) Sulfotransferases
Polychlorinated biphenyls (PCBs) are metabolized in humans
and other mammals to hydroxylated derivatives (OHPCBs), and these metabolites
play significant roles in chemical carcinogenesis, endocrine hormone disruption,
and other toxic responses. OHPCBs inhibit phenol sulfotransferases that
are involved in the metabolism of thyroid hormone and estrogens, but little
is known about the interactions of PCBs and OHPCBs with another major
family of sulfotransferases, the hydroxysteroid (alcohol) sulfotransferases,
which are involved both in hormone metabolism and chemical carcinogenesis.
The long term goal of this research is to better understand the effects
of PCBs and OHPCBs on the catalytic function and regulation of sulfotransferases
and to elucidate the relationships between these effects and the roles
that PCBs and OHPCBs have in adverse health effects. The primary objective
of the work proposed for the present project is to address the gap in
our knowledge related to the effects of PCBs and OHPCBs on the hydroxysteroid
sulfotransferases. The central hypothesis for this project is that certain
PCBs and hydroxylated metabolites of PCBs can regulate catalytic function
and/or expression of hydroxysteroid sulfotransferases.
This hypothesis will be tested by pursuing three specific aims:
1) to study 30-quantitative structure-activity relationships for OHPCBs
as inhibitors and substrates of two model hydroxysteroid sulfotransferases:
rat STa and human SULT2A1;
2) to explore the effects of changes in the ratio of oxidized to reduced
glutathione (one result of the generation of reactive oxygen species from
PCB-metabolism as studied in Project 1 and Project 2) on the catalytic
function of rat STa and human SULT2A1 with OHPCBs as substrates and inhibitors;
and
3) to study changes in the levels of expression of rat STa mediated by
PCBs and OHPCBs. This research will yield significant new insight into
the effects that semi-volatile PCBs and OHPCBs have in regulating hydroxysteroid
sulfotransferases that are important in steroid hormone homeostasis as
well as in the metabolic activation of carcinogenic hydroxyalkyl polycyclic
aromatic hydrocarbons.
Project Leader: Michael W. Duffel, PhD
Dr. Duffel is responsible for overall direction of the project,
including the planning and design of all experiments, data collection,
analysis and interpretation of results, preparation of manuscripts, and
progress reports. In addition to experimental design of all phases of
Project 3, he will coordinate joint studies with Project
1 of the isbrp, and interact directly with both the Synthesis
Core and the Analytical Core
for preparation of OHPCBs and the analysis of peptide disulfides, respectively.
Co-Project Leader: Larry W. Robertson, PhD, MPH
Dr. Robertson will be directly involved in the design and interpretation
of the results of all in vivo studies on the effects of PCBs and OHPCBs
in rats. Treatment of rats in Specific Aim 3 of this project will be done
jointly with Project 1, and Dr. Robertson and
Dr. Duffel will coordinate all aspects of the treatment and acquisition
of tissues from rats treated with these agents.
Co-Project Leader: Hans J. Lehmler, PhD
Dr. Lehmler will provide expertise in those portions of the 3D-QSAR studies
under Specific Aim 1 that relate to crystal structure- and computationally-based
analysis of torsion angles in PCBs and OHPCBs. Although the major portion
of Dr. Lehmler's isbrp effort is in the Synthesis
Core, and that Core will provide synthesis of PCBs and OHPCBs to Project
3, his involvement in guiding conformational analyses of torsion angles
of these compounds for Project 3 is additional to his direction of the
Synthesis Core.
