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Research Projects
My project in Dr. Zacharewski Lab involves toxicogenomic examination
of the hepatotoxic effects of PCB126 in C57BL/6 mice. Polychlorinated
biphenyls (PCBs) are persistent environmental contaminants which
exhibit potent dioxin-like properties and are suspected to cause
adverse health effects in humans and wildlife. The commercial
use of PCBs in open and closed systems has been prohibited since
1977, however, they still remain “priority pollutants”.
The most potent dioxin is 2,3,7,8-TCDD which is also the one
most widely studied in Dr. Zacharewski Lab.
These compounds act as ligands for the cytosolic aryl hydrocarbon
receptor (AhR). Ligand binding to the AhR results in its translocation
to the nucleus where it forms a heterodimer with aryl hydrocarbon
nuclear transporter (Arnt). The AhR-Arnt heterodimer then binds
to dioxin responsive elements (DREs) resulting in alterations
in gene expression. Many lines of evidence suggest that the
toxic effects of dioxins and PCBs are due to the continuous
and inappropriate activation of target genes.
The goal of my project is to characterize the temporal hepatic
gene expression response of immature ovariectomized C57BL/6
mice treated with 3,3’,4,4’,5 – pentachlorobiphenyl
(PCB126) to develop a better understanding of its toxic mechanisms
of action. PCB-126 was chosen as a model PCB as it is one of
the most toxic and environmentally relevant congeners. The Toxic
Equivalence Factor (TEF) for PCB126 is 0.1 when compared to
TCDD (TEF = 1) and therefore a dose of 300 ug/kg PCB126 was
chosen to facilitate comparisons to previous studies that used
30 ug/kg TCDD.
PCB126-mediated changes in hepatic gene expression profiles
will be examined using custom, in-house developed mouse cDNA
microarrays consisting of 13,361 features representing 8516
genes. Significant changes in gene expression will be verified
using quantitative real-time PCR. Responses will be interpreted
along physiological endpoints such as histopathology, clinical
chemistry and hepatic triglyceride analysis to phenotypically
anchor changes in gene expression and aid in data interpretation.
Hepatic concentrations of PCB126 will also be determined to
anchor changes in gene expression to tissue levels of this compound.
Collectively, these data will provide an increased understanding
of the hepatotoxic effects of PCB-126 and its potenial mechanisms
of action.
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