Superfund Research Program
Oxidative Stress and PCB Exposure in Mammalian Cells
Project Leader: Douglas R. Spitz
Co-Investigators: Prabhat C. Goswami, Larry W. Robertson
Grant Number: P42ES013661
Funding Period: 2006 - 2015
Project Summary (2006-2010)
Recent evidence from this 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 risk of prostate and breast cancer. This project is investigating 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, these researchers are testing the hypothesis that mitochondrial 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. Project investigators are determining 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. Additionally, they are determining 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. Finally, the investigators are determining 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.