Research Project 2
Oxidative Stress and PCB Exposure in Mammalian Cells
Recent evidence from our group and others has suggested
that exposure to polychlorinated biphenyls (PCBs) can cause metabolic
oxidative stress in mammalian cells contributing to cell injury and the
biological effects of PCBs. Chronic metabolic oxidative stress has also
been strongly implicated in degenerative diseases associated with genomic
instability, carcinogenesis, and aging. PCB exposure has also been implicated
in increased the risk of prostate and breast cancer.
Project 2 will investigate the involvement of metabolic oxidative stress
in mechanisms of injury and growth disturbances seen in human prostate
and breast epithelial cells during PCB exposure. Preliminary results show
that exposure of prostate epithelial cells (PrECB) and breast epithelial
cells (MCF10A) to PCBs and PCB metabolites cause increased superoxide
production and disruptions in glutathione metabolism consistent with induction
of metabolic oxidative stress as well as perturbations in cell growth.
Specifically the current proposal will test the hypothesis that mitochondria!
production of reactive oxygen species (ROS; i.e., superoxide and hydrogen
peroxide) causes oxidative stress during PCB exposure and this increased
production of ROS contributes to the biological effects of PCBs on cell
growth in prostate and breast epithelial cells.
Aim#1 will determine if exposure to PCBs or PCB metabolites induces oxidative
stress in prostate and breast epithelial cells that contributes to PCB-induced
alterations in cell proliferation and cytotoxicity.
Aim#2 will determine which specific ROS (i.e., superoxide, hydrogen peroxide,
and organic hydroperoxides) and sites of production contribute to oxidative
stress and PCB-induced growth disturbances and cytotoxicity in prostate
and breast epithelial cells.
Aim#3 will determine if manipulation of intracellular thiols or selenium
supplementation can modify PCB-induced oxidative stress and growth disturbances
in human prostate and breast epithelial cells.
The long-term goal of these studies is to provide a rigorous mechanistic
understanding of the involvement of metabolic oxidative stress in PCB-induced
effects on prostate and breast epithelial cell growth that may contribute
carcinogenesis and identify manipulations of antioxidant mechanisms that
can protect human prostate and breast epithelial cells from PCB exposure.
Project Leader: Douglas R. Spitz, PhD
Dr. Spitz, the University of Iowa, is a well-established investigator
in the field of Free Radical Cancer Biology and Radiation Biology. He
is responsible for the overall direction of the project including experimental
design, data interpretation, manuscript preparation, and supervision of
all personnel involved with the studies.
Co-Project Leader: Prabhat C. Goswami, PhD
Dr. Goswami supervises and collaborates on all the experiments
designed to determine if alterations in cell cycle checkpoints and redistribution
contribute to the biological effects of PCBs. Dr. Goswami is a recognized
expert on cell cycle regulation and the role of redox changes in cell
cycle regulation.
Co-Project Leader: Larry W. Robertson, PhD, MPH, University of Iowa
Dr. Robertson is a recognized expert on PCB toxicity to breast and prostate.
