title: The pentachlorophenol metabolite tetrachlorohydroquinone induces massive ROS and prolonged p-ERK expression in splenocytes, leading to inhibition of apoptosis and necrotic cell death.
abstract: Pentachlorophenol (PCP) has been used extensively as a biocide and a wood preservative and has been reported to be immunosuppressive in rodents and humans. Tetrachlorohydroquinone (TCHQ) is a major metabolite of PCP. TCHQ has been identified as the main cause of PCP-induced genotoxicity due to reactive oxidant stress (ROS). However, the precise mechanisms associated with the immunotoxic effects of PCP and TCHQ remain unclear. The aim of this study was to examine the effects of PCP and TCHQ on the induction of ROS and injury to primary mouse splenocytes. Our results shown that TCHQ was more toxic than PCP and that a high dose of TCHQ led to necrotic cell death of the splenocytes through induction of massive and sudden ROS and prolonged ROS-triggered ERK activation. Inhibition of ROS production by N-acetyl-cysteine (NAC) partially restored the mitochondrial membrane potential, inhibited ERK activity, elevated caspase-3 activity and PARP cleavage, and, eventually, switched the TCHQ-induced necrosis to apoptosis. We suggest that prolonged ERK activation is essential for TCHQ-induced necrosis, and that ROS play a pivotal role in the different TCHQ-induced cell death mechanisms.
authors.affiliation: Department of Environmental and Occupational Health, National Cheng Kung University, Medical College, Tainan, Taiwan.
authors.forename: Hsiu-Min
authors.initials: HM
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China.
authors.forename: Ben-Zhan
authors.initials: BZ
authors.lastname: Zhu
authors.affiliation: Department of Environmental and Occupational Health, National Cheng Kung University, Medical College, Tainan, Taiwan.
authors.forename: Rong-Jane
authors.initials: RJ
authors.lastname: Chen
authors.affiliation: Department of Occupational and Environmental Medicine, National Cheng Kung University Hospital, Tainan, Taiwan ; Department of Cosmetic Science and Institute of Cosmetic Science, Chia Nan University of Pharmacy and Science, Tainan, Taiwan.
authors.forename: Bour-Jr
authors.initials: BJ
authors.lastname: Wang
authors.affiliation: Department of Environmental and Occupational Health, National Cheng Kung University, Medical College, Tainan, Taiwan.
authors.forename: Ying-Jan
authors.initials: YJ
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005434:Flow Cytometry; D006873:Hydroquinones / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009336:Necrosis; D010416:Pentachlorophenol / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013154:Spleen / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism
chemical_list: D006873:Hydroquinones; D017382:Reactive Oxygen Species; C044578:2,3,5,6-tetrachlorohydroquinone; D010416:Pentachlorophenol; D048049:Extracellular Signal-Regulated MAP Kinases