title: 2,4,6-Trichlorophenol cytotoxicity involves oxidative stress, endoplasmic reticulum stress, and apoptosis.
abstract: This study aims to evaluate the cytotoxicity and potential mechanisms of 2,4,6-trichlorophenol (2,4,6-TCP) in mouse embryonic fibroblasts. Our results show that 2,4,6-TCP causes morphological changes and reduces cell viability. The overproduction of reactive oxygen species, the upregulation of nuclear factor-E2-related factor 2 (Nrf2) and heme oxygenase 1 (HMOX1) messenger RNA (mRNA) expressions, and the nuclear translocation of Nrf2 protein demonstrate that 2,4,6-TCP induces oxidative stress, and the Nrf2/HMOX1 pathway might be involved in 2,4,6-TCP-induced antioxidative response. Simultaneously, our data also demonstrate that 2,4,6-TCP upregulates the expressions of binding immunoglobulin protein, inositol-requiring enzyme/endonuclease 1α, and C/EBP homologous protein; stimulates α subunit of eukaryotic translation initiation factor 2 phosphorylation; and induces the splicing of Xbp1 mRNA, suggesting that endoplasmic reticulum (ER) stress is triggered. Moreover, 2,4,6-TCP alters the mitochondrial membrane potential and increases the apoptosis rate, the caspase 3 activity, and the Bax/Bcl-2 ratio, demonstrating that the mitochondrial pathway is involved in the 2,4,6-TCP-induced apoptosis. Thus, these results show that 2,4,6-TCP induces oxidative stress, ER stress, and apoptosis, which together contribute to its cytotoxicity in vitro.
authors.affiliation: Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, Lanzhou, China.
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, Lanzhou, China.
authors.forename: Xiaona
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, Lanzhou, China.
authors.forename: Zhidan
authors.initials: Z
authors.lastname: Niu
authors.affiliation: Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, Lanzhou, China.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Qi
authors.affiliation: Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, Lanzhou, China huangdj@lzu.edu.cn ymzhang@lzu.edu.cn.
authors.forename: Dejun
authors.initials: D
authors.lastname: Huang
authors.affiliation: Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, Lanzhou, China.
authors.forename: Yingmei
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002733:Chlorophenols / Q000633:toxicity*; D004268:DNA-Binding Proteins / Q000235:genetics; D004622:Embryo, Mammalian; D000091342:Endoplasmic Reticulum Chaperone BiP; D004722:Endoribonucleases / Q000235:genetics; D004785:Environmental Pollutants / Q000633:toxicity*; D005347:Fibroblasts; D006360:Heat-Shock Proteins / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D051742:Transcription Factor CHOP / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D000071717:X-Box Binding Protein 1; D051028:bcl-2-Associated X Protein / Q000235:genetics
chemical_list: C494827:Bax protein, mouse; D002733:Chlorophenols; D004268:DNA-Binding Proteins; C497250:Ddit3 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; D004785:Environmental Pollutants; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; D051028:bcl-2-Associated X Protein; D051742:Transcription Factor CHOP; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; C024564:2,4,6-trichlorophenol
keywords: 2,4,6-trichlorophenol; apoptosis; cytotoxicity; endoplasmic reticulum stress; oxidative stress