Polychlorinated-biphenyl-induced oxidative stress and cytotoxicity can be mitigated by antioxidants after exposure.
PCBs and PCB metabolites have been suggested to cause cytotoxicity by inducing oxidative stress, but the effectiveness of antioxidant intervention after exposure has not been established. Exponentially growing MCF-10A human breast and RWPE-1 human prostate epithelial cells continuously exposed for 5 days to 3 microM PCBs [Aroclor 1254 (Aroclor), PCB153, and the 2-(4-chlorophenyl)-1,4-benzoquinone metabolite of PCB3 (4ClBQ)] were found to exhibit growth inhibition and clonogenic cell killing, with 4ClBQ having the most pronounced effects. These PCBs were also found to increase steady-state levels of intracellular O(2)(*-) and H(2)O(2) (as determined by dihydroethidium, MitoSOX red, and 5-(and 6)-carboxy-2',7'-dichlorodihydrofluorescein diacetate oxidation). These PCBs also caused 1.5- to 5.0-fold increases in MnSOD activity in MCF-10A cells and 2.5- to 5-fold increases in CuZnSOD activity in RWPE-1 cells. Measurement of MitoSOX red oxidation with confocal microscopy coupled with colocalization of MitoTracker green in MCF-10A and RWPE-1 cells supported the hypothesis that PCBs caused increased steady-state levels of O(2)(*-) in mitochondria. Finally, treatment with either N-acetylcysteine (NAC) or the combination of polyethylene glycol (PEG)-conjugated CuZnSOD and PEG-catalase added 1 h after PCBs significantly protected these cells from PCB toxicity. These results support the hypothesis that exposure of exponentially growing human breast and prostate epithelial cells to PCBs causes increased steady-state levels of intracellular O(2)(*-) and H(2)O(2), induction of MnSOD or CuZnSOD activity, and clonogenic cell killing that could be inhibited by a clinically relevant thiol antioxidant, NAC, as well as by catalase and superoxide dismutase after PCB exposure.
Free Radical and Radiation Biology Program, B180 Medical Laboratories, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA.
Yueming
Y
Zhu
Amanda L
AL
Kalen
Ling
L
Li
Hans-J
HJ
Lehmler
Larry W
LW
Robertson
Prabhat C
PC
Goswami
Douglas R
DR
Spitz
Nukhet
N
Aykin-Burns
D000975:Antioxidants / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004785:Environmental Pollutants / Q000037:antagonists & inhibitors* / Q000633:toxicity; D006801:Humans; D018384:Oxidative Stress / Q000187:drug effects*; D011078:Polychlorinated Biphenyls / Q000037:antagonists & inhibitors* / Q000633:toxicity; D013482:Superoxide Dismutase / Q000378:metabolism
D000975:Antioxidants; D004785:Environmental Pollutants; D011078:Polychlorinated Biphenyls; D013482:Superoxide Dismutase