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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Final Progress Reports: University of Iowa: Oxidative Stress and PCB Exposure in Mammalian Cells

Superfund Research Program

Oxidative Stress and PCB Exposure in Mammalian Cells

Project Leader: Prabhat C. Goswami
Co-Investigators: Douglas R. Spitz, Frederick E. Domann
Grant Number: P42ES013661
Funding Period: 2006 - 2015
View this project in the NIH Research Portfolio Online Reporting Tools (RePORT)

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Final Progress Reports

Year:   2014  2009 

The research objective for the Oxidative Stress and PCB Exposure in Mammalian Cells project is to determine if oxidative stress regulates polychlorinated biphenyl (PCB)-induced perturbations in cellular proliferation and cytotoxicty in in vitro cultures of human mammary and prostate epithelial cells. Electron paramagnetic resonance spectroscopy measurements of MCF-10A human mammary epithelial cells incubated with 2-(4-chlorophenyl)benzo-1,4-quinone (4-Cl-BQ), a metabolite of PCB-3, demonstrated the formation of a semiquinone radical, suggesting that redox-cycling of 4-Cl-BQ can induce oxidative stress. In addition PCB-induced oxidative stress was associated with an increase in the frequency of micronuclei and phosphorylated histone H2AX, both markers of DNA damage. Treatment of cells with catalase blunted the PCB-induced increase in micronuclei frequency and H2AX phosphorylation. These results were consistent with a significant PCB-induced inhibition in cell proliferation and an increase in clonogenic cell killing being mediated by metabolic production of hydrogen peroxide.

Additional studies showed that exponentially growing asynchronous cultures of human MCF-10A breast and RWPE-1 prostate epithelial cells incubated with daily replenishment of media containing three micro-molar of PCBs (Aroclor 1254, PCB-153, and 4-Cl-BQ) for five days demonstrated increased steady-state levels of intracellular reactive oxygen species (ROS; superoxide and hydrogen peroxide). Microscopic evaluations indicated that PCB-induced superoxide was of mitochondrial origin. Furthermore, cells incubated with 4-Cl-BQ exhibited a significant increase in Mn-superoxide dismutase activity in MCF-10A cells, while RWPE-1 cells showed an increase in CuZn-superoxide dismutase activity. The increase in the superoxide levels may have stimulated the activity of superoxide dismutase to cope with the oxidative stress. Finally, treatment with a thiol antioxidant (N-acetyl-L-cysteine) or antioxidant enzymes (pegylated-CuZnSOD+catalase) following PCB exposure inhibited the toxicity of PCBs, supporting the hypothesis that oxidative stress was causally related to PCB-induced cytotoxicity and could be mitigated using antioxidants following exposure.

Overall results from this project suggest that cellular ROS can be a significant factor in PCB-induced cytotoxicity and that application of antioxidants after PCB exposure could be a viable redox-based countermeasure for PCB-exposed individuals.

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