芳香烃受体
肝细胞
细胞外
化学
雄激素受体
芘
细胞内
苯并(a)芘
多环芳烃
细胞生物学
微泡
小泡
生物化学
生物物理学
转录因子
致癌物
生物
膜
环境化学
核受体
体外
基因
小RNA
有机化学
作者
Nettie van Meteren,Dominique Lagadic‐Gossmann,Martine Chevanne,Isabelle Gallais,Dimitri Gobart,Agnès Burel,Simon Bucher,Nathalie Grova,Bernard Fromenty,Brice M. R. Appenzeller,Soizic Chevance,Fabienne Gauffre,Eric Le Ferrec,Odile Sergent
标识
DOI:10.1093/toxsci/kfz157
摘要
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. Extracellular vesicles 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 3 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 3 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, 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.
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