N-acetylcysteine (NAC) diminishes the severity of PCB 126-induced fatty liver in male rodents

Lai, Ian K.; Dhakal, Kiran; Gadupudi, Gopi S.; Li, Miao; Ludewig, Gabriele; Robertson, Larry W.; Olivier, Alicia K.

doi:10.1016/j.tox.2012.07.007

Cited by 44 publications

(40 citation statements)

References 54 publications

(57 reference statements)

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“…To evaluate the function of PCB-adducted cytochrome c as electron acceptor the NADPH-Cytochrome c Reductase Activity assay was adapted from a protocol described previously (Wu et al 2009) using liver microsomes as source of NADPH-cytochrome c reductase. The microsomes were prepared as published previously (Lai et al 2012, Lai et al 2013). Microsomes were obtained from liver homogenate of male Sprague-Dawley rats (Harlan, Indianapolis, IN) treated with 400 μmol of phenobarbital (PB, saline) and 100 μmol β-naphthoflavone in soybean oil per kilogram body weight for three consecutive days.…”

Section: Methodsmentioning

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: Methodsmentioning

confidence: 99%

Cytochrome c adducts with PCB quinoid metabolites

Teesch

Murry

et al. 2015

Environ Sci Pollut Res

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“…Rats were originally treated as described (Lai et al , 2012). Briefly, male Sprague-Dawley rats, fed a standard AIN-93G diet, received a single intraperitoneal injection of either vehicle (stripped corn oil, 5 ml/kg body weight) or vehicle with 5 µmol/kg body weight (1.63 mg/kg body weight) PCB 126.…”

Section: Methodsmentioning

confidence: 99%

“…Briefly, male Sprague-Dawley rats, fed a standard AIN-93G diet, received a single intraperitoneal injection of either vehicle (stripped corn oil, 5 ml/kg body weight) or vehicle with 5 µmol/kg body weight (1.63 mg/kg body weight) PCB 126. After two weeks rats were euthanized and tissues prepared as described (Lai et al , 2012). Formalin-fixed, paraffin-embedded liver sections (4 µm) were deparaffinized and rehydrated.…”

Section: Methodsmentioning

confidence: 99%

PCB 126 perturbs hypoxia-induced HIF-1α activity and glucose consumption in human HepG2 cells

Vorrink

Sarsour

Olivier

et al. 2014

Experimental and Toxicologic Pathology

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Aerobic organisms strongly depend on the availability of oxygen for respiration and countless other metabolic processes to maintain cellular homeostasis. Under certain conditions, the amount of available oxygen can be limited. To support survival in environments with limited oxygen supply, hypoxia-inducible factors (HIFs) reprogram vital components of cellular metabolism. HIF-1α is an important mediator of acute and adaptive responses to hypoxic stress. Interestingly, the heterodimeric partner required by HIF-1α to function as transcription factor, known as ARNT, is also an essential part of the aryl hydrocarbon receptor (AhR) transcription factor complex. Thus, via ARNT a crosstalk exists between these two pathways that might affect HIF-1α-mediated processes. In this study we sought to assess the effect of the AhR agonist PCB 126 on HIF-1α activity as well as on HIF-1α-regulated targets involved in cellular metabolism in human HepG2 cells. Our results show that PCB 126 reduced HIF-1α localization to the nucleus. Furthermore, in an in vivo setting, rats exposed to parenteral PCB 126 also displayed reduced hepatocyte nuclear localization of HIF-1α. Additionally, HepG2 cells exposed to PCB126 displayed reduced hypoxia-regulated HRE-luciferase reporter gene expression as well as a reduction in glucose consumption in conditions of hypoxia. In summary, this study reveals that HIF-1α-regulated cellular metabolic processes are negatively affected by PCB 126 which might ultimately affect adaptive responses and cell survival in hypoxic environments.

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“…Exposure to both technical PCB mixtures and individual PCB congeners, either alone or in combination with a high fat diet, affects the fatty acid, polar lipid and triacylglyceride (TAG) composition of the liver (Azaïs-Braesco et al, 1990; Borlakoglu et al, 1990; Borlakoglu et al, 1991). PCB 126, a highly toxic PCB congener, is of particular concern because both histopathological evaluations and gravimetric lipid determinations demonstrate that exposure to PCB 126 results in hepatic lipid accumulation in rodent studies (Boucher et al, 2015; Lai et al, 2010a; Lai et al, 2011; Lai et al, 2012; Wu et al, 2016). The steatosis in the liver of PCB 126-exposed rats is accompanied by significant changes in the balance of polyunsaturated fatty acids (PUFAs) and major lipid classes in the liver of PCB 126 exposed rats (Matsusue et al, 1997, 1999).…”

Section: Introductionmentioning

confidence: 99%

“…Exposure to PCB 126 causes wasting syndrome and alters redox and metal homeostasis in rodent models (Klaren et al, 2015; Lai et al, 2010a; Lai et al, 2011; Lai et al, 2012) by mechanisms involving the AhR (van den Berg et al, 2006). PCB 126 exposure also decreases hepatic glucose levels, followed by a decrease in peroxisomal fatty acid oxidation in male rats (Gadupudi et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Identification of lipidomic markers of chronic 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126) exposure in the male rat liver

Kania-Korwel

Wang

et al. 2017

Toxicology

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Exposure to PCB 126, an environmentally relevant aryl hydrocarbon receptor agonist, is an environmental factor causing hepatic steatosis in rodent models; however, the lipidome of PCB 126-exposed rats has not been investigated in-depth. The objective of the present study was therefore to characterize dose-dependent changes in the lipid profile in the liver of male Sprague-Dawley rats exposed to PCB 126. Rats were exposed for three month to intraperitoneal injections of 0.01, 0.05 and 0.2 μmol/kg bw PCB 126 in corn oil. Control animals were exposed in parallel and received corn oil alone. Lipids were extracted from whole liver homogenate and levels of polar lipids and fatty acids incorporated into triglycerides (FATAGs) were determined with tandem mass spectrometry using electrospray ionization. PCB 126 exposure increased the hepatic content of polar lipids and FATAGs. Protein adjusted levels of several polar lipid classes, in particular phosphatidylserine levels, decreased, whereas FATAGs levels typically increased with increasing PCB 126 dose. Sensitive, dose-dependent endpoints of PCB 126 exposure included an increase in levels of adrenic acid incorporated into triglycerides and changes in levels of certain ether-linked phospholipid and 1-alkyl/1-alkenyldiacylglycerol species, as determined using partial least square discriminant analysis (PLS-DA) and ANOVA. These changes in the composition of polar lipids and fatty acid in the liver of PCB 126 exposed rats identified several novel markers of PCB 126-mediated fatty liver disease that need to be validated in further studies.

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N-acetylcysteine (NAC) diminishes the severity of PCB 126-induced fatty liver in male rodents

Cited by 44 publications

References 54 publications

Cytochrome c adducts with PCB quinoid metabolites

Cytochrome c adducts with PCB quinoid metabolites

PCB 126 perturbs hypoxia-induced HIF-1α activity and glucose consumption in human HepG2 cells

Identification of lipidomic markers of chronic 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126) exposure in the male rat liver

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