Polychlorinated biphenyl quinone-induced genotoxicity, oxidative DNA damage and γ-H2AX formation in HepG2 cells

Dong, Hui; Su, Chuanyang; Xia, Xiaomin; Li, Lingrui; Song, Erqun; Song, Yang

doi:10.1016/j.cbi.2014.01.016

Cited by 23 publications

(25 citation statements)

References 47 publications

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“…The downstream kinase of p38, heat shock protein 27, has been implicated in the oxidative stress-induced formation of actin stress fibers and cytoskeletal reorganization (27). Interestingly, our previous studies strongly suggested that oxidative stress plays important roles in PCB29-pQ-induced toxicity, which can be eliminated by antioxidant treatments (15,39). However, the effects of antioxidants on PCB29-pQ-induced EC dysfunction is worth further investigation.…”

Section: Discussionmentioning

confidence: 94%

“…Upon absorption, PCB is metabolically activated by cytochrome P-450 and oxidized into arene oxide or radical intermediates, which can form covalent adducts with cellular components, like DNA and proteins (44). Hydroxylated PCB metabolites have been identified as the most abundant metabolites (18), and their oxidized forms, PCB quinones, have been suggested to induce oxidative DNA damage, genotoxicity, and mitochondria-mediated cell apoptosis in our previous studies (15,39,70). In the current study, we assessed the effect of PCB29-pQ on HUVEC permeability and junction disassembly.…”

Section: Discussionmentioning

confidence: 99%

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Polychlorinated biphenyl quinone induces endothelial barrier dysregulation by setting the cross talk between VE-cadherin, focal adhesion, and MAPK signaling

Zhang

Feng

Bai

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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biphenyl quinone induces endothelial barrier dysregulation by setting the cross talk between VE-cadherin, focal adhesion, and MAPK signaling. Am J Physiol Heart Circ Physiol 308: H1205-H1214, 2015. First published March 13, 2015; doi:10.1152/ajpheart.00005.2015.-Environmental hazardous material polychlorinated biphenyl (PCB) exposure is associated with vascular endothelial dysfunction, which may increase the risk of cardiovascular diseases and cancer metastasis. Our previous studies illustrated the cytotoxic, antiproliferative, and genotoxic effects of a synthetic, quinone-type, highly reactive metabolite of PCB, 2,3,5-trichloro-6-phenyl-[1,4]benzoquinone (PCB29-pQ). Here, we used it as the model compound to investigate its effects on vascular endothelial integrity and permeability. We demonstrated that noncytotoxic doses of PCB29-pQ induced vascular endothelial (VE)-cadherin junction disassembly by increasing the phosphorylation of VE-cadherin at Y658. We also found that focal adhesion assembly was required for PCB29-pQ-induced junction breakdown. Focal adhesion site-associated actin stress fibers may serve as holding points for cytoskeletal tension to regulate the cellular contractility. PCB29-pQ exposure promoted the association of actin stress fibers with paxillincontaining focal adhesion sites and enlarged the size/number of focal adhesions. In addition, PCB29-pQ treatment induced phosphorylation of paxillin at Y118. By using pharmacological inhibition, we further demonstrated that p38 activation was necessary for paxillin phosphorylation, whereas extracellular signal-regulated kinases-1/2 activation regulated VE-cadherin phosphorylation. In conclusion, these results indicated that PCB29-pQ stimulates endothelial hyperpermeability by mediating VE-cadherin disassembly, junction breakdown, and focal adhesion formation. Intervention strategies targeting focal adhesion and MAPK signaling could be used as therapeutic approaches for preventing adverse cardiovascular health effects induced by environmental toxicants such as PCBs.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Polychlorinated biphenyl quinone induces endothelial barrier dysregulation by setting the cross talk between VE-cadherin, focal adhesion, and MAPK signaling

Zhang

Feng

Bai

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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“…The relationship between DNA damage and sustained exposure to environmental pollutants is widely described in the scientific literature and is probably linked to the redox signaling triggered by OCPs [ 32 ]. For some pesticides, the processes leading to alterations in the cellular homeostasis are partially understood, but commonly recognized mechanisms include their enzymatic conversion to secondary reactive products, depletion of cellular antioxidant defenses and/or impairment of antioxidant enzyme functions [ 33 ].…”

Section: Resultsmentioning

confidence: 99%

β-Hexachlorocyclohexane: A Small Molecule with a Big Impact on Human Cellular Biochemistry

et al. 2020

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Organochlorine pesticides (OCPs) belong to a heterogeneous class of organic compounds blacklisted by the Stockholm Convention in 2009 due to their harmful impact on human health. Among OCPs, β-hexachlorocyclohexane (β-HCH) is one of the most widespread and, at the same time, poorly studied environmental contaminant. Due to its physicochemical properties, β-HCH is the most hazardous of all HCH isomers; therefore, clarifying the mechanisms underlying its molecular action could provide further elements to draw the biochemical profile of this OCP. For this purpose, LNCaP and HepG2 cell lines were used as models and were subjected to immunoblot, immunofluorescence, and RT-qPCR analysis to follow the expression and mRNA levels, together with the distribution, of key biomolecules involved in the intracellular responses to β-HCH. In parallel, variations in redox homeostasis and cellular bioenergetic profile were monitored to have a complete overview of β-HCH effects. Obtained results strongly support the hypothesis that β-HCH could be an endocrine disrupting chemical as well as an activator of AhR signaling, promoting the establishment of an oxidative stress condition and a cellular metabolic shift toward aerobic glycolysis. In this altered context, β-HCH can also induce DNA damage through H2AX phosphorylation, demonstrating its multifaceted mechanisms of action.

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“…14,15 Hydroquinone has the ability to induce HO-1 expression, 16 whereas its derivatives, like quinone, quercetin, kaempferol, or tert-butylhydroquinone, activate HO-1 and NQO1 expression. [17][18][19] A hydroquinone derivative, 4-Acetoxyphenol (4-AC), has been shown to be a potent activator of the NRF2-ARE pathway in motor neurons. 20 It was also identified as an a-synuclein modulator that can possibly prevent or slow down the onset or progression of Parkinson's disease.…”

mentioning

confidence: 99%

4-Acetoxyphenol Prevents RPE Oxidative Stress–Induced Necrosis by Functioning as an NRF2 Stabilizer

Hanus

Kolkin

Chimienti

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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Polychlorinated biphenyl quinone-induced genotoxicity, oxidative DNA damage and γ-H2AX formation in HepG2 cells

Cited by 23 publications

References 47 publications

Polychlorinated biphenyl quinone induces endothelial barrier dysregulation by setting the cross talk between VE-cadherin, focal adhesion, and MAPK signaling

Polychlorinated biphenyl quinone induces endothelial barrier dysregulation by setting the cross talk between VE-cadherin, focal adhesion, and MAPK signaling

β-Hexachlorocyclohexane: A Small Molecule with a Big Impact on Human Cellular Biochemistry

4-Acetoxyphenol Prevents RPE Oxidative Stress–Induced Necrosis by Functioning as an NRF2 Stabilizer

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