title: para-Phenylenediamine induces apoptosis through activation of reactive oxygen species-mediated mitochondrial pathway, and inhibition of the NF-κB, mTOR, and Wnt pathways in human urothelial cells.
abstract: para-Phenylenediamine (PPD) has long been used in two-thirds of permanent oxidative hair dye formulations. Epidemiological studies and in vivo studies have shown that hair dye is a suspected carcinogen of bladder cancer. However, the toxicity effects of PPD to human bladder remains elusive. In this study, the effects of PPD and its involvement in the apoptosis pathways in human urothelial cells (UROtsa) was investigated. It was demonstrated that PPD decreased cell viability and increased the number of sub-G1hypodiploid cells in UROtsa cells. Cell death due to apoptosis was detected using Annexin V binding assay. Further analysis showed PPD generated reactive oxygen species (ROS), induced mitochondrial dysfunction through the loss of mitochondrial membrane potential and increased caspase-3 level in UROtsa cells. Western blot analysis of PPD-treated UROtsa cells showed down-regulation of phosphorylated proteins from NF-κB, mTOR, and Wnt pathways. In conclusion, PPD induced apoptosis via activation of ROS-mediated mitochondrial pathway, and possibly through inhibition of NF-κB, mTOR, and Wnt pathways. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 265-277, 2017.
authors.affiliation: Department of Human Biology, School of Medicine, International Medical University, Kuala Lumpur, 57000, Malaysia.
authors.forename: Kasi
authors.initials: K
authors.lastname: Reena
authors.affiliation: Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Subang Jaya, Selangor, 47500, Malaysia.
authors.forename: Khuen Yen
authors.initials: KY
authors.lastname: Ng
authors.affiliation: Department of Human Biology, School of Medicine, International Medical University, Kuala Lumpur, 57000, Malaysia.
authors.forename: Rhun Yian
authors.initials: RY
authors.lastname: Koh
authors.affiliation: Department of Human Biology, School of Medicine, International Medical University, Kuala Lumpur, 57000, Malaysia.
authors.forename: Ponnudurai
authors.initials: P
authors.lastname: Gnanajothy
authors.affiliation: Department of Human Biology, School of Medicine, International Medical University, Kuala Lumpur, 57000, Malaysia.
authors.forename: Soi Moi
authors.initials: SM
authors.lastname: Chye
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010655:Phenylenediamines / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D010655:Phenylenediamines; D017382:Reactive Oxygen Species; D051153:Wnt Proteins; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D053148:Caspase 3; D020169:Caspases; C029728:4-phenylenediamine
keywords: NF-κB; apoptosis; human urothelial cells; mTOR; para-phenylenediamine