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dc.contributor.author van Meteren, Nettie
dc.contributor.author Lagadic-Gossmann, Dominique
dc.contributor.author Chevanne, Martine
dc.contributor.author Gallais, Isabelle
dc.contributor.author Gobart, Dimitri
dc.contributor.author Burel, Agnès
dc.contributor.author Chevance, Soizic
dc.contributor.author Gauffre, Fabienne
dc.contributor.author Le Ferrec, Eric
dc.contributor.author Sergent, Odile
dc.date.accessioned 2019-07-11T15:49:08Z
dc.date.available 2019-07-11T15:49:08Z
dc.date.issued 2019-07-11
dc.identifier doi:10.5061/dryad.3n39r6k
dc.identifier.uri http://hdl.handle.net/10255/dryad.216291
dc.description Extracellular vesicles (EVs) are membrane enclosed nanostructures released by cells into the extracellular environment. As major actors of physiological intercellular communication, they have been shown to be pathogenic mediators of several liver diseases. EVs also appear to be potential actors of drug-induced liver injury, but nothing is known concerning environmental pollutants. We aimed to study the impact of polycyclic aromatic hydrocarbons (PAHs), major contaminants, on hepatocyte-derived EV production, with a special focus on hepatocyte death. Three PAHs were selected, based on their presence in food and their affinity for the aryl hydrocarbon receptor (AhR): benzo(a)pyrene (BP), dibenzo(a,h)anthracene (DBA), and pyrene (PYR). Treatment of primary rat and WIF-B9 hepatocytes by all three PAHs increased the release of EVs, mainly comprised of exosomes, in parallel with modifying exosome protein marker expression and inducing apoptosis. Moreover, PAH treatment of rodents for three months also led to increased EV levels in plasma. The EV release involved CYP metabolism and the activation of the transcription factor, the AhR, for BP and DBA and another transcription factor, the constitutive androstane receptor (CAR), for PYR. Furthermore, all PAHs increased cholesterol levels in EVs but only BP and DBA were able to reduce the cholesterol content of total cell membranes. All cholesterol changes very likely participated in the increase in EV release and cell death. Finally, we studied changes in cell membrane fluidity caused by BP and DBA due to cholesterol depletion. Our data showed increased cell membrane fluidity, which contributed to hepatocyte EV release and cell death.
dc.relation.haspart doi:10.5061/dryad.3n39r6k/1
dc.relation.haspart doi:10.5061/dryad.3n39r6k/2
dc.relation.haspart doi:10.5061/dryad.3n39r6k/3
dc.relation.haspart doi:10.5061/dryad.3n39r6k/4
dc.relation.haspart doi:10.5061/dryad.3n39r6k/5
dc.relation.haspart doi:10.5061/dryad.3n39r6k/6
dc.relation.haspart doi:10.5061/dryad.3n39r6k/7
dc.relation.haspart doi:10.5061/dryad.3n39r6k/8
dc.relation.haspart doi:10.5061/dryad.3n39r6k/9
dc.relation.haspart doi:10.5061/dryad.3n39r6k/10
dc.relation.haspart doi:10.5061/dryad.3n39r6k/11
dc.relation.haspart doi:10.5061/dryad.3n39r6k/12
dc.relation.haspart doi:10.5061/dryad.3n39r6k/13
dc.subject Hepatocytes
dc.subject Extracellular vesicles
dc.subject Exosome
dc.subject Aryl hydrocarbon Receptor
dc.subject Polycyclic aromatic hydrocarbons
dc.subject Cell death
dc.title Data from: Polycyclic aromatic hydrocarbons can trigger hepatocyte release of extracellular vesicles by various mechanisms of action depending on their affinity for the aryl hydrocarbon receptor.
dc.type Article *
dc.contributor.correspondingAuthor Sergent, Odile
prism.publicationName Toxicological Sciences

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Title Figure S1
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Description Figure S1: Dose and time response exposure in terms of cell death and proliferation in WIF-B9 cells upon PAH exposure in terms of cell death and proliferation.
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Title Figure S2
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Description Figure S2. Original pictures of western-blots from which some results are extracted for a presentation in figure 2C.
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Title Figure S3
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Description Figure S3 : PAHs do not affect the size of EVs released by WIF-B9 cells.
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Title Figure S4
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Description Figure S4 : PAHs do not affect the size of EVs released by primary rat hepatocytes.
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Title Figure S5
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Description Figure S5 : mRNA expression of CYP1A1, CYP1A2, CYP1B1 and CYP2C6 in WIF-B9 cells and primary rat hepatocytes.
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Title Figure S6
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Description Figure S6 : CYP1 activity in WIF-B9 and primary rat hepatocytes.
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Title Figure S7
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Description Figure S7 : Cell death and EV release of WIF-B9 cells and primary rat hepatocytes exposed to AhR agonist TCDD.
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Title Figure S8
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Description Figure S8 : Effects of pravastatin on cholesterol content of hepatocytes (A,B) and EVs (E) and also on bulk membrane fluidity (C,D).
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Title Supplementary Table S1
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Description Table S1: Selected PAH properties.
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Title Supplementary Table S2
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Description Table S2: Concentration of PAHs in human serum and daily intake of PAHs.
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Title Supplementary Table S3
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Description Table S3: Pre-treatment of WIF-B9 and primary rat hepatocytes.
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Title Supplementary Table S4
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Description Table S4 : Culture medium volume needed for EV isolation.
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Title Supplementary Table S5
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Description Table S5 : List of primers used for RT-qPCR experiments.
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