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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Succinate dehydrogenase activity regulates PCB3-quinone-induced metabolic oxidative stress and toxicity in HaCaT human keratinocytes.

Authors: Xiao, Wusheng; Sarsour, Ehab H; Wagner, Brett A; Doskey, Claire M; Buettner, Garry R; Domann, Frederick E; Goswami, Prabhat C

Published In Arch Toxicol, (2016 Feb)

Abstract: Polychlorinated biphenyls (PCBs) and their metabolites are environmental pollutants that are known to have adverse health effects. 1-(4-Chlorophenyl)-benzo-2,5-quinone (4-ClBQ), a quinone metabolite of 4-monochlorobiphenyl (PCB3, present in the environment and human blood) is toxic to human skin keratinocytes, and breast and prostate epithelial cells. This study investigates the hypothesis that 4-ClBQ-induced metabolic oxidative stress regulates toxicity in human keratinocytes. Results from Seahorse XF96 Analyzer showed that the 4-ClBQ treatment increased extracellular acidification rate, proton production rate, oxygen consumption rate and ATP content, indicative of metabolic oxidative stress. Results from a q-RT-PCR assay showed significant increases in the mRNA levels of hexokinase 2 (hk2), pyruvate kinase M2 (pkm2) and glucose-6-phosphate dehydrogenase (g6pd), and decreases in the mRNA levels of succinate dehydrogenase (complex II) subunit C and D (sdhc and sdhd). Pharmacological inhibition of G6PD-activity enhanced the toxicity of 4-ClBQ, suggesting that the protective function of the pentose phosphate pathway is functional in 4-ClBQ-treated cells. The decrease in sdhc and sdhd expression was associated with a significant decrease in complex II activity and increase in mitochondrial levels of ROS. Overexpression of sdhc and sdhd suppressed 4-ClBQ-induced inhibition of complex II activity, increase in mitochondrial levels of ROS, and toxicity. These results suggest that the 4-ClBQ treatment induces metabolic oxidative stress in HaCaT cells, and while the protective function of the pentose phosphate pathway is active, inhibition of complex II activity sensitizes HaCaT cells to 4-ClBQ-induced toxicity.

PubMed ID: 25417049 Exiting the NIEHS site

MeSH Terms: Adenosine Triphosphate/metabolism; Benzoquinones/toxicity*; Biphenyl Compounds/toxicity; Carrier Proteins/genetics; Carrier Proteins/metabolism; Cell Line; Hexokinase/metabolism; Humans; Keratinocytes/drug effects*; Keratinocytes/metabolism; Membrane Proteins/genetics; Membrane Proteins/metabolism; Mitochondria/drug effects; Mitochondria/metabolism; Oxidative Stress/drug effects*; Pentose Phosphate Pathway/drug effects; Succinate Dehydrogenase/genetics; Succinate Dehydrogenase/metabolism*; Thyroid Hormones/genetics; Thyroid Hormones/metabolism

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