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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

University of Iowa

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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Project Summary (2010-2015)

In recent years, it has been suggested that oxidative stress could contribute to biological effects of polychlorinated biphenyl (PCB) exposures. During the previous period of support researchers used in vitro cultures of human non-malignant breast (MCF10A) and prostate (RWPE-1) epithelial cells to determine the cellular effects of PCB 3, PCB 77, PCB 153, Aroclor 1254, and 2-(4-chlorophenyl)benzo-1,4-quinone (4-CI-BQ, a metabolite of PCB 3). 4-CI-BQ and PCB 153 (3 pM, 3-5 d) significantly increased mitochondria-generated reactive oxygen species (ROS) levels resulting in DNA damage, changes in MnSOD activity and cyclin DI protein levels, inhibition in cell proliferation, and increased cytotoxicity. Antioxidant-treatment of cells prior to and following the PCB treatment ameliorated these effects. Interestingly, 1 micro molar of PCB 153 treatment decreased cyclin DI protein turnover, while higher concentrations (3-20 micro molar) enhancedcyclin DI degradation. This biphasic response of PCB 153 was associated with a small increase in cell number for the lower concentrations, and inhibition in cell proliferation for the higher concentrations. PCB 153-induced changes in cyclin DI protein levels were also associated with changes in pyruvate kinase and hexokinase II protein levels.

These results led Dr. Goswami to hypothesize that redox signaling mediated by ROS (O2 and H2O2) disrupts coordinate regulation of SOD2 and cyclin DI expression, which contributes to both stimulatory and cytostatic effects of PCBs on cellular proliferation. The aims for the current project are to:

Aim 1: Determine if PCB-induced ROS-signaling perturbs transitions between quiescent (Go) and proliferative (Gi, S, G2, and M) growth in human epithelial (breast and lung), and lung fibroblasts cultured in vitro.
Aim 2: Determine the mechanisms regulating S0D2 activity in PCB-treated quiescent and proliferating epithelial and fibroblast cells cultured In vitro.
Aim 3: Determine the mechanisms regulating cyclin DI protein levels in PCB-treated epithelial and fibroblast cells cultured in vitro.
Aim 4: Determine whether loss of SOD2 expression perturbs PCB-induced alterations in cyclin DI expressions in vivo in breast, liver, and lung tissues of C57BL/6 Floxed S0D2 mice. Determine if application of small molecular weight antioxidants could suppress these effects.

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