In recent years, it has been suggested that oxidative stress could contribute to biological effects of polychlorinated biphenyl (PCB) exposures. During the current period of support we 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 ?mu?M, 3-5 d) significantly increased mitochondria-generated reactive oxygen species (ROS) levels resulting in DNA damage, changes in MnSOD activity and cyclin D1 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 D1 protein turnover, while higher concentrations (3-20 micro molar) enhanced cyclin D1 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 D1 protein levels were also associated with changes in pyruvate kinase and hexokinase II protein levels. These results led us to hypothesize that redox signaling mediated by ROS (O{2}* and H2O2) disrupts coordinate regulation of SOD2 and cyclin D1 expression, which contributes to both stimulatory and cytostatic effects of PCBs on cellular proliferation.
Aim 1 : Determine if PCB-induced ROS-signaling perturbs transitions between quiescent (G{0}) and proliferative (G{1}, S, G{2}, and M) growth in human epithelial (breast and lung), and lung fibroblasts cultured in vitro.
Aim 2 : Determine the mechanisms regulating SOD2 activity in PCB-treated quiescent and proliferating epithelial and fibroblast cells cultured In vitro.
Aim 3 : Determine the mechanisms regulating cyclin D1 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 D1 expressions in vivo in breast, liver, and lung tissues of C57BL/6 Floxed SOD2 mice. Determine if application of small molecular weight antioxidants could suppress these effects.

Public Health Relevance

The proposed research is innovative because of the hypothesis that inter-organelle communication via ROS-signaling is essential to prevent aberrant proliferation following PCB-induced oxidative injury. The application of antioxidants being tested is also innovative because it could lead to the development of viable redox-based countermeasures to mitigate PCB-induced abnormalities in cellular growth.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
Project #
5P42ES013661-08
Application #
8451603
Study Section
Special Emphasis Panel (ZES1-LWJ-M)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
8
Fiscal Year
2013
Total Cost
$251,731
Indirect Cost
$87,951
Name
University of Iowa
Department
Type
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Uwimana, Eric; Li, Xueshu; Lehmler, Hans-Joachim (2018) Human Liver Microsomes Atropselectively Metabolize 2,2',3,4',6-Pentachlorobiphenyl (PCB 91) to a 1,2-Shift Product as the Major Metabolite. Environ Sci Technol 52:6000-6008
Herkert, Nicholas J; Hornbuckle, Keri C (2018) Effects of room airflow on accurate determination of PUF-PAS sampling rates in the indoor environment. Environ Sci Process Impacts 20:757-766
Herkert, Nicholas J; Spak, Scott N; Smith, Austen et al. (2018) Calibration and evaluation of PUF-PAS sampling rates across the Global Atmospheric Passive Sampling (GAPS) network. Environ Sci Process Impacts 20:210-219
Dhakal, Kiran; Gadupudi, Gopi S; Lehmler, Hans-Joachim et al. (2018) Sources and toxicities of phenolic polychlorinated biphenyls (OH-PCBs). Environ Sci Pollut Res Int 25:16277-16290
Enayah, Sabah H; Vanle, Brigitte C; Fuortes, Laurence J et al. (2018) PCB95 and PCB153 change dopamine levels and turn-over in PC12 cells. Toxicology 394:93-101
Klinefelter, Kelsey; Hooven, Molly Kromme; Bates, Chloe et al. (2018) Genetic differences in the aryl hydrocarbon receptor and CYP1A2 affect sensitivity to developmental polychlorinated biphenyl exposure in mice: relevance to studies of human neurological disorders. Mamm Genome 29:112-127
Gourronc, Francoise A; Robertson, Larry W; Klingelhutz, Aloysius J (2018) A delayed proinflammatory response of human preadipocytes to PCB126 is dependent on the aryl hydrocarbon receptor. Environ Sci Pollut Res Int 25:16481-16492
Alam, Sinthia; Carter, Gwendolyn S; Krager, Kimberly J et al. (2018) PCB11 Metabolite, 3,3'-Dichlorobiphenyl-4-ol, Exposure Alters the Expression of Genes Governing Fatty Acid Metabolism in the Absence of Functional Sirtuin 3: Examining the Contribution of MnSOD. Antioxidants (Basel) 7:
Li, Xueshu; Holland, Erika B; Feng, Wei et al. (2018) Authentication of synthetic environmental contaminants and their (bio)transformation products in toxicology: polychlorinated biphenyls as an example. Environ Sci Pollut Res Int 25:16508-16521
Sethi, Sunjay; Keil, Kimberly P; Lein, Pamela J (2018) 3,3'-Dichlorobiphenyl (PCB 11) promotes dendritic arborization in primary rat cortical neurons via a CREB-dependent mechanism. Arch Toxicol 92:3337-3345

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