Polychlorinated Biphenyl Quinone Induces Endoplasmic Reticulum Stress, Unfolded Protein Response, and Calcium Release

Xu, Dan; Su, Chuanyang; Song, Xiufang; Shi, Qiong; Fu, Juanli; Hu, Lihua; Xia, Xiaomin; Song, Erqun; Song, Yang

doi:10.1021/acs.chemrestox.5b00124

Cited by 23 publications

(20 citation statements)

References 59 publications

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“…In addition, the release of cytochrome c into the cytoplasm activates caspase-dependent apoptosis (Spierings et al 2005). PCB3 quinone was reported to increase oxidative stress in the mitochondria of human cells in culture and to inhibit the mitochondrial electron chain; PCB29 quinone caused an increase in mitochondrial oxidative stress, a transfer of cytochrome c from the mitochondria into the cytoplasm, and induced caspase-dependent apoptosis (Xiao et al 2014, Xiao et al 2013, Xu et al 2014, Xu et al 2015, Zhu et al 2009). These reports suggest that cytochrome c may play a crucial role in PCB quinone toxicity.…”

Section: Introductionmentioning

confidence: 99%

Cytochrome c adducts with PCB quinoid metabolites

Teesch

Murry

et al. 2015

Environ Sci Pollut Res

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PCBs are a group of 209 individual congeners widely used as industrial chemicals. PCBs are found as by-products in dye and paint manufacture and are legacy, ubiquitous and persistent as human and environmental contaminants. PCBs with fewer chlorine atoms may be metabolized to hydroxy- and dihydroxy- metabolites and further oxidized to quinoid metabolites both in vitro and in vivo. Specifically, quinoid metabolites may form adducts on nucleophilic sites within cells. We hypothesized that the PCB-quinones covalently bind to cytochrome c and thereby cause defects in the function of cytochrome c. In this study synthetic PCB quinones (2-(4’-chlorophenyl)-1,4-benzoquinone, 2-(3’, 5’-dichlorophenyl)-1,4-benzoquinone, 2-(3’,4’, 5’-trichlorophenyl)-1,4-benzoquinone, and 2-(4’-chlorophenyl)-3,6-dichloro-1,4-benzoquinone) were incubated with cytochrome c, and adducts were detected by LC-MS and MALDI TOF. SDS PAGE gel electrophoresis was employed to separate the adducted proteins, while trypsin digestion and LC-MS/MS were applied to identify the amino acid binding sites on cytochrome c. Conformation change of cytochrome c after binding with PCB3-para-quinone was investigated by SYBYL-X simulation and cytochrome c function was examined. We found that more than one molecule of PCB-quinone may bind to one molecule of cytochrome c. Lysine and glutamic acid were identified as the predominant binding sites. Software simulation showed conformation changes of adducted cytochrome c. Additionally, cross-linking of cytochrome c was observed on the SDS PAGE gel. Cytochrome c was found to be in the reduced form after incubation with PCB quinones. These data provide evidence that the covalent binding of PCB quinone metabolites to cytochrome c may be included among the toxic effects of PCBs.

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Section: Introductionmentioning

confidence: 99%

Cytochrome c adducts with PCB quinoid metabolites

Teesch

Murry

et al. 2015

Environ Sci Pollut Res

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“…Moreover, Ca 2+ signaling is associated with many tumorigenic pathways, and deregulation of Ca 2+ homeostasis decreases cellular proliferation and leads to cell apoptosis [ 51 - 53 ]. Importantly, disruption of cytosolic Ca 2+ homeostasis triggers mitochondrial ROS production [ 16 ]. The generation of excessive ROS even induces apoptosis in HepG2 cells [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

“…Ca 2+ transport into and out of the endoplasmic reticulum or sarcoplasmic reticulum--which stores calcium--plays a key role in buffering cytosolic Ca 2+ concentrations [ 13 - 15 ]. Thus, an increase in cytosolic Ca 2+ affects mitochondrial Ca 2+ concentrations [ 16 ]. Once mitochondrial Ca 2+ overload occurs, a regulatory network of mitochondrial-dependent apoptosis may be activated.…”

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confidence: 99%

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Failure of Elevating Calcium Induces Oxidative Stress Tolerance and Imparts Cisplatin Resistance in Ovarian Cancer Cells

Wang

et al. 2016

Aging and disease

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Cisplatin is a commonly used chemotherapeutic drug, used for the treatment of malignant ovarian cancer, but acquired resistance limits its application. There is therefore an overwhelming need to understand the mechanism of cisplatin resistance in ovarian cancer, that is, ovarian cancer cells are insensitive to cisplatin treatment. Here, we show that failure of elevating calcium and oxidative stress tolerance play key roles in cisplatin resistance in ovarian cancer cell lines. Cisplatin induces an increase in oxidative stress and alters intracellular Ca2+ concentration, including cytosolic and mitochondrial Ca2+ in cisplatin-sensitive SKOV3 cells, but not in cisplatin-resistant SKOV3/DDP cells. Cisplatin induces mitochondrial damage and triggers the mitochondrial apoptotic pathway in cisplatin-sensitive SKOV3 cells, but rarely in cisplatin-resistant SKOV3/DDP cells. Inhibition of calcium signaling attenuates cisplatin-induced oxidative stress and intracellular Ca2+ overload in cisplatin-sensitive SKOV3 cells. Moreover, in vivo xenograft models of nude mouse, cisplatin significantly reduced the growth rates of tumors originating from SKOV3 cells, but not that of SKOV3/DDP cells. Collectively, our data indicate that failure of calcium up-regulation mediates cisplatin resistance by alleviating oxidative stress in ovarian cancer cells. Our results highlight potential therapeutic strategies to improve cisplatin resistance.

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“…In addition to glyphosate, many other neotoxins (industrial and agricultural toxins derived synthetically) in mass use are not safe for humans and other living things in that they add to the problem of ER stress and the apoptotic final solution of the UPR. These include polychlorinated biphenyl quinone [226].…”

Section: Glyphosate and Many Neotoxins Induces Er Stressmentioning

confidence: 99%

Autism is an Acquired Cellular Detoxification Deficiency Syndrome with Heterogeneous Genetic Predisposition

Lw¹

2018

Autism Open Access

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Neurodevelopmental disorders, including autism spectrum disorders, have a complex biological and medical basis involving diverse genetic risk and myriad environmental exposures. Teasing apart the role of specific stressors is made challenging due to the large number of apparently contributing associations, gene x environment interactions and phenomimicry. Historically, these conditions have been rare, making causality assessment at the population level infeasible. Only a few vaccines have been tested for association with autism, and it has been shown that improved diagnosis only explains a percentage of the increase in diagnosis. Now the rates are so high in some countries that public school programs cannot handle to large numbers of special needs students, and professionals are quitting their jobs due to security concerns. Here, I present a mechanistic biomedical process model (theory) of the pathophysiology of autism that reconciles the apparent paradox between the high degree of causal heterogeneity in environmental toxins, the absence of common "autism genes" and the high degree of genetic concordance (heritability) of ASD and ASD-like traits. In brief, the environmental toxin sampling liability for ASD varies among families involving different local exposures following injury to normal cellular endoplasmic detoxification and mitochondrial processes from toxic metals. The literature strongly supports that autism is most accurately seen as an acquired cellular detoxification deficiency syndrome with heterogeneous genetic predisposition that manifests pathophysiologic consequences of accumulated, runaway cellular toxicity. At a more general level, it is a form of a toxicant-induced loss of tolerance of toxins, and of chronic and sustained ER overload ("ER hyperstress"), contributing to neuronal and glial apoptosis via the unfolded protein response (UPR). Inherited risk of impaired cellular detoxification and circulating metal re-toxification in neurons and glial cells accompanied by chronic UPR is key. This model explains the aberrant protein disorder observed in ASD; the great diversity of genes that are found to have low, but real contributions to ASD risk and the sensitivity of individuals with ASD to environmental toxins. The hindrance of detoxification and loss of cellular energetics leads to apoptosis, release of cytokines and chronic neuroinflammation and microglial activation, all observed hallmarks of ASD. Interference with the development of normal complex (redundant) synapses leads to a pathological variation in neuronal differentiation, axon and dendrite outgrowth, and synaptic protein expression. The most general outcomes are overall simplification of gross synaptic anatomy and, neurofunctionally, a loss of inhibitory feedback and aberrations in long-term connections between distant regions of the brain. Failed resolution of the ER stress response leads to redistribution of neurotoxic metals, and the impaired neurocellular processes lead to subsequent accumulation of a variety of additional types o...

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Polychlorinated Biphenyl Quinone Induces Endoplasmic Reticulum Stress, Unfolded Protein Response, and Calcium Release

Cited by 23 publications

References 59 publications

Cytochrome c adducts with PCB quinoid metabolites

Cytochrome c adducts with PCB quinoid metabolites

Failure of Elevating Calcium Induces Oxidative Stress Tolerance and Imparts Cisplatin Resistance in Ovarian Cancer Cells

Autism is an Acquired Cellular Detoxification Deficiency Syndrome with Heterogeneous Genetic Predisposition

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