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

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

doi:10.1007/s00204-014-1407-3

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

Journal article

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Peer reviewed

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

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

Archives of toxicology, Vol.90(2), pp.319-332

02/2016

DOI: 10.1007/s00204-014-1407-3

PMCID: PMC4441874

PMID: 25417049

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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.

Cell Line

Pentose Phosphate Pathway - drug effects

Membrane Proteins - genetics

Humans

Mitochondria - metabolism

Mitochondria - drug effects

Thyroid Hormones - genetics

Biphenyl Compounds - toxicity

Carrier Proteins - genetics

Succinate Dehydrogenase - genetics

Carrier Proteins - metabolism

Keratinocytes - drug effects

Keratinocytes - metabolism

Thyroid Hormones - metabolism

Adenosine Triphosphate - metabolism

Benzoquinones - toxicity

Succinate Dehydrogenase - metabolism

Membrane Proteins - metabolism

Oxidative Stress - drug effects

Hexokinase - metabolism

ISRP Project 2 2015-2020

Synthesis Core

Details

Title: Subtitle: Succinate dehydrogenase activity regulates PCB3-quinone-induced metabolic oxidative stress and toxicity in HaCaT human keratinocytes
Creators: Wusheng Xiao - Free Radical and Radiation Biology Division, Department of Radiation Oncology, B180 Medical Laboratories, The University of Iowa, Iowa City, IA, 52242, USA
Ehab H Sarsour - Free Radical and Radiation Biology Division, Department of Radiation Oncology, B180 Medical Laboratories, The University of Iowa, Iowa City, IA, 52242, USA
Brett A Wagner - Free Radical and Radiation Biology Division, Department of Radiation Oncology, B180 Medical Laboratories, The University of Iowa, Iowa City, IA, 52242, USA
Claire M Doskey - Free Radical and Radiation Biology Division, Department of Radiation Oncology, B180 Medical Laboratories, The University of Iowa, Iowa City, IA, 52242, USA
Garry R Buettner - Free Radical and Radiation Biology Division, Department of Radiation Oncology, B180 Medical Laboratories, The University of Iowa, Iowa City, IA, 52242, USA
Frederick E Domann - Free Radical and Radiation Biology Division, Department of Radiation Oncology, B180 Medical Laboratories, The University of Iowa, Iowa City, IA, 52242, USA
Prabhat C Goswami - Free Radical and Radiation Biology Division, Department of Radiation Oncology, B180 Medical Laboratories, The University of Iowa, Iowa City, IA, 52242, USA. prabhat-goswami@uiowa.edu
Resource Type: Journal article
Publication Details: Archives of toxicology, Vol.90(2), pp.319-332
DOI: 10.1007/s00204-014-1407-3
PMID: 25417049
PMCID: PMC4441874
NLM abbreviation: Arch Toxicol
ISSN: 0340-5761
eISSN: 1432-0738
Publisher: Germany
Grant note: P42 ES013661 / NIEHS NIH HHS 2R01CA111365 / NCI NIH HHS P42ES013661 / NIEHS NIH HHS R01 CA111365 / NCI NIH HHS P30CA086862 / NCI NIH HHS P30 CA086862 / NCI NIH HHS R01 CA169046 / NCI NIH HHS
Language: English
Date published: 02/2016
Academic Unit: Pathology; Surgery; Radiation Oncology; Iowa Superfund Research Program
Record Identifier: 9984047799002771

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