Perfluorooctanoic acid exposure induces endoplasmic reticulum stress in the liver and its effects are ameliorated by 4-phenylbutyrate

Perfluoroalkyl acids (PFAAs) are a group of widely used anthropogenic compounds. As one of the most dominant PFAAs, perfluorooctanoic acid (PFOA) has been suggested to induce hepatotoxicity and several other toxicological effects. However, details on the mechanisms for PFOA-induced hepatotoxicity st...

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Veröffentlicht in:Free radical biology & medicine 2015-10, Vol.87, p.300-311
Hauptverfasser: Yan, Shengmin, Zhang, Hongxia, Wang, Jianshe, Zheng, Fei, Dai, Jiayin
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Wang, Jianshe
Zheng, Fei
Dai, Jiayin
description Perfluoroalkyl acids (PFAAs) are a group of widely used anthropogenic compounds. As one of the most dominant PFAAs, perfluorooctanoic acid (PFOA) has been suggested to induce hepatotoxicity and several other toxicological effects. However, details on the mechanisms for PFOA-induced hepatotoxicity still need to be elucidated. In this study, we observed the occurrence of endoplasmic reticulum (ER) stress in mouse livers and HepG2 cells after PFOA exposure using several familiar markers for the unfolded protein response (UPR). ER stress in HepG2 cells after PFOA exposure was not significantly influenced by autophagy inhibition or stimulation. The antioxidant defense system was significantly disturbed in mouse livers after PFOA exposure, and reactive oxygen species (ROS) were increased in cells exposed to PFOA for 24 h. However, N-acetyl-L-cysteine (NAC) pretreatment did not satisfactorily alleviate the UPR in cells exposed to PFOA even though the increase of ROS was less evident. Furthermore, exposure of HepG2 cells to PFOA in the presence of sodium 4-phenylbutyrate (4-PBA), a chemical chaperone and ER stress inhibitor, suggested that 4-PBA alleviated the UPR and autophagosome accumulation induced by PFOA in cells. In addition, several toxicological effects attributed to PFOA exposure, including cell cycle arrest, proteolytic activity impairment, and neutral lipid accumulation, were also improved by 4-PBA cotreatment in cells. In vivo study demonstrated that PFOA-induced lipid metabolism perturbation and liver injury were partially ameliorated by 4-PBA in mice after 28 days of exposure. These findings demonstrated that PFOA-induced ER stress leading to UPR might play an important role in PFOA-induced hepatotoxic effects, and chemical chaperone 4-PBA could ameliorate the effects. [Display omitted] •Perfluorononanoic acid (PFOA) induces hepatic endoplasmic reticulum (ER) stress.•PFOA exposure disturbs the hepatic antioxidant defense system in mice.•Antioxidant pretreatment did not influence ER stress induced by PFOA in vitro.•Sodium 4-phenylbutyrate (4-PBA) ameliorates the hepatotoxic effects of PFOA.
doi_str_mv 10.1016/j.freeradbiomed.2015.06.043
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As one of the most dominant PFAAs, perfluorooctanoic acid (PFOA) has been suggested to induce hepatotoxicity and several other toxicological effects. However, details on the mechanisms for PFOA-induced hepatotoxicity still need to be elucidated. In this study, we observed the occurrence of endoplasmic reticulum (ER) stress in mouse livers and HepG2 cells after PFOA exposure using several familiar markers for the unfolded protein response (UPR). ER stress in HepG2 cells after PFOA exposure was not significantly influenced by autophagy inhibition or stimulation. The antioxidant defense system was significantly disturbed in mouse livers after PFOA exposure, and reactive oxygen species (ROS) were increased in cells exposed to PFOA for 24 h. However, N-acetyl-L-cysteine (NAC) pretreatment did not satisfactorily alleviate the UPR in cells exposed to PFOA even though the increase of ROS was less evident. Furthermore, exposure of HepG2 cells to PFOA in the presence of sodium 4-phenylbutyrate (4-PBA), a chemical chaperone and ER stress inhibitor, suggested that 4-PBA alleviated the UPR and autophagosome accumulation induced by PFOA in cells. In addition, several toxicological effects attributed to PFOA exposure, including cell cycle arrest, proteolytic activity impairment, and neutral lipid accumulation, were also improved by 4-PBA cotreatment in cells. In vivo study demonstrated that PFOA-induced lipid metabolism perturbation and liver injury were partially ameliorated by 4-PBA in mice after 28 days of exposure. These findings demonstrated that PFOA-induced ER stress leading to UPR might play an important role in PFOA-induced hepatotoxic effects, and chemical chaperone 4-PBA could ameliorate the effects. [Display omitted] •Perfluorononanoic acid (PFOA) induces hepatic endoplasmic reticulum (ER) stress.•PFOA exposure disturbs the hepatic antioxidant defense system in mice.•Antioxidant pretreatment did not influence ER stress induced by PFOA in vitro.•Sodium 4-phenylbutyrate (4-PBA) ameliorates the hepatotoxic effects of PFOA.</description><identifier>ISSN: 0891-5849</identifier><identifier>EISSN: 1873-4596</identifier><identifier>DOI: 10.1016/j.freeradbiomed.2015.06.043</identifier><identifier>PMID: 26159507</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Apoptosis - drug effects ; Caprylates - toxicity ; Chemical and Drug Induced Liver Injury - drug therapy ; Chemical and Drug Induced Liver Injury - metabolism ; Chemical and Drug Induced Liver Injury - pathology ; Endoplasmic Reticulum Stress - drug effects ; Fluorocarbons - toxicity ; Hep G2 Cells ; Hepatotoxicity ; Humans ; Lipid metabolism ; Lipid Metabolism - drug effects ; Liver - drug effects ; Liver - metabolism ; Liver - pathology ; Liver injury ; Mice ; Oxidative stress ; Phenylbutyrates - administration &amp; dosage ; Reactive Oxygen Species - metabolism ; Signal Transduction - drug effects ; Sodium 4-phenylbutyrate ; Unfolded Protein Response - drug effects</subject><ispartof>Free radical biology &amp; medicine, 2015-10, Vol.87, p.300-311</ispartof><rights>2015</rights><rights>Copyright © 2015. 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Furthermore, exposure of HepG2 cells to PFOA in the presence of sodium 4-phenylbutyrate (4-PBA), a chemical chaperone and ER stress inhibitor, suggested that 4-PBA alleviated the UPR and autophagosome accumulation induced by PFOA in cells. In addition, several toxicological effects attributed to PFOA exposure, including cell cycle arrest, proteolytic activity impairment, and neutral lipid accumulation, were also improved by 4-PBA cotreatment in cells. In vivo study demonstrated that PFOA-induced lipid metabolism perturbation and liver injury were partially ameliorated by 4-PBA in mice after 28 days of exposure. These findings demonstrated that PFOA-induced ER stress leading to UPR might play an important role in PFOA-induced hepatotoxic effects, and chemical chaperone 4-PBA could ameliorate the effects. [Display omitted] •Perfluorononanoic acid (PFOA) induces hepatic endoplasmic reticulum (ER) stress.•PFOA exposure disturbs the hepatic antioxidant defense system in mice.•Antioxidant pretreatment did not influence ER stress induced by PFOA in vitro.•Sodium 4-phenylbutyrate (4-PBA) ameliorates the hepatotoxic effects of PFOA.</description><subject>Animals</subject><subject>Apoptosis - drug effects</subject><subject>Caprylates - toxicity</subject><subject>Chemical and Drug Induced Liver Injury - drug therapy</subject><subject>Chemical and Drug Induced Liver Injury - metabolism</subject><subject>Chemical and Drug Induced Liver Injury - pathology</subject><subject>Endoplasmic Reticulum Stress - drug effects</subject><subject>Fluorocarbons - toxicity</subject><subject>Hep G2 Cells</subject><subject>Hepatotoxicity</subject><subject>Humans</subject><subject>Lipid metabolism</subject><subject>Lipid Metabolism - drug effects</subject><subject>Liver - drug effects</subject><subject>Liver - metabolism</subject><subject>Liver - pathology</subject><subject>Liver injury</subject><subject>Mice</subject><subject>Oxidative stress</subject><subject>Phenylbutyrates - administration &amp; 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As one of the most dominant PFAAs, perfluorooctanoic acid (PFOA) has been suggested to induce hepatotoxicity and several other toxicological effects. However, details on the mechanisms for PFOA-induced hepatotoxicity still need to be elucidated. In this study, we observed the occurrence of endoplasmic reticulum (ER) stress in mouse livers and HepG2 cells after PFOA exposure using several familiar markers for the unfolded protein response (UPR). ER stress in HepG2 cells after PFOA exposure was not significantly influenced by autophagy inhibition or stimulation. The antioxidant defense system was significantly disturbed in mouse livers after PFOA exposure, and reactive oxygen species (ROS) were increased in cells exposed to PFOA for 24 h. However, N-acetyl-L-cysteine (NAC) pretreatment did not satisfactorily alleviate the UPR in cells exposed to PFOA even though the increase of ROS was less evident. Furthermore, exposure of HepG2 cells to PFOA in the presence of sodium 4-phenylbutyrate (4-PBA), a chemical chaperone and ER stress inhibitor, suggested that 4-PBA alleviated the UPR and autophagosome accumulation induced by PFOA in cells. In addition, several toxicological effects attributed to PFOA exposure, including cell cycle arrest, proteolytic activity impairment, and neutral lipid accumulation, were also improved by 4-PBA cotreatment in cells. In vivo study demonstrated that PFOA-induced lipid metabolism perturbation and liver injury were partially ameliorated by 4-PBA in mice after 28 days of exposure. These findings demonstrated that PFOA-induced ER stress leading to UPR might play an important role in PFOA-induced hepatotoxic effects, and chemical chaperone 4-PBA could ameliorate the effects. [Display omitted] •Perfluorononanoic acid (PFOA) induces hepatic endoplasmic reticulum (ER) stress.•PFOA exposure disturbs the hepatic antioxidant defense system in mice.•Antioxidant pretreatment did not influence ER stress induced by PFOA in vitro.•Sodium 4-phenylbutyrate (4-PBA) ameliorates the hepatotoxic effects of PFOA.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>26159507</pmid><doi>10.1016/j.freeradbiomed.2015.06.043</doi><tpages>12</tpages></addata></record>
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subjects Animals
Apoptosis - drug effects
Caprylates - toxicity
Chemical and Drug Induced Liver Injury - drug therapy
Chemical and Drug Induced Liver Injury - metabolism
Chemical and Drug Induced Liver Injury - pathology
Endoplasmic Reticulum Stress - drug effects
Fluorocarbons - toxicity
Hep G2 Cells
Hepatotoxicity
Humans
Lipid metabolism
Lipid Metabolism - drug effects
Liver - drug effects
Liver - metabolism
Liver - pathology
Liver injury
Mice
Oxidative stress
Phenylbutyrates - administration & dosage
Reactive Oxygen Species - metabolism
Signal Transduction - drug effects
Sodium 4-phenylbutyrate
Unfolded Protein Response - drug effects
title Perfluorooctanoic acid exposure induces endoplasmic reticulum stress in the liver and its effects are ameliorated by 4-phenylbutyrate
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