PMID- 26745386 OWN - NLM STAT- MEDLINE DCOM- 20161018 LR - 20161230 IS - 1872-7077 (Electronic) IS - 1382-6689 (Linking) VI - 41 DP - 2016 Jan TI - Tetrachlorobenzoquinone exhibits neurotoxicity by inducing inflammatory responses through ROS-mediated IKK/IkappaB/NF-kappaB signaling. PG - 241-50 LID - S1382-6689(15)30152-6 [pii] LID - 10.1016/j.etap.2015.12.012 [doi] AB - Tetrachlorobenzoquinone (TCBQ) is a joint metabolite of persistent organic pollutants (POPs), hexachlorobenzene (HCB) and pentachlorophenol (PCP). Previous studies have been reported that TCBQ contributes to acute hepatic damage due to its pro-oxidative nature. In the current study, TCBQ showed the highest capacity on the cytotoxicity, ROS formation and inflammatory cytokines release among four compounds, i.e., HCB, PCP, tetrachlorohydroquinone (TCHQ, reduced form of TCBQ) and TCBQ, in PC 12 cells. Further mechanistic study illustrated TCBQ activates nuclear factor-kappa B (NF-kappaB) signaling. The activation of NF-kappaB was identified by measuring the protein expressions of inhibitor of nuclear factor kappa-B kinase (IKK) alpha/beta, p-IKKalpha/beta, an inhibitor of NF-kappaB (IkappaB) alpha, p-IkappaBalpha, NF-kappaB (p65) and p-p65. The translocation of NF-kappaB was assessed by Western blotting of p65 in nuclear/cytosolic fractions, electrophoretic mobility shift assay (EMSA) and luciferase reporter gene assay. In addition, TCBQ significantly induced protein and mRNA expressions of inflammatory cytokines and mediators, such as interleukin-1 beta (IL-1beta), IL-6, tumor necrosis factor-alpha (TNF-alpha), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and the production of nitric oxide (NO) and prostaglandin E2 (PGE2). Pyrrolidine dithiocarbamate (PDTC), a specific NF-kappaB inhibitor inhibited these effects efficiently, further suggested TCBQ-induced inflammatory responses involve NF-kappaB signaling. Moreover, antioxidants, i.e., N-acetyl-l-cysteine (NAC), Vitamin E and curcumin, ameliorated TCBQ-induced ROS generation as well as the activation of NF-kappaB, which implied that ROS serve as the upstream molecule of NF-kappaB signaling. In summary, TCBQ exhibits a neurotoxic effect by inducing oxidative stress-mediated inflammatory responses via the activation of IKK/IkappaB/NF-kappaB pathway in PC12 cells. CI - Copyright (c) 2015 Elsevier B.V. All rights reserved. FAU - Fu, Juanli AU - Fu J AD - Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Beibei, Chongqing 400715, People's Republic of China. FAU - Shi, Qiong AU - Shi Q AD - Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Beibei, Chongqing 400715, People's Republic of China. FAU - Song, Xiufang AU - Song X AD - Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Beibei, Chongqing 400715, People's Republic of China. FAU - Xia, Xiaomin AU - Xia X AD - Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Beibei, Chongqing 400715, People's Republic of China. FAU - Su, Chuanyang AU - Su C AD - Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Beibei, Chongqing 400715, People's Republic of China. FAU - Liu, Zixuan AU - Liu Z AD - Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Beibei, Chongqing 400715, People's Republic of China. FAU - Song, Erqun AU - Song E AD - Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Beibei, Chongqing 400715, People's Republic of China. FAU - Song, Yang AU - Song Y AD - Key Laboratory of Luminescence and Real-Time Analytical Chemistry (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Beibei, Chongqing 400715, People's Republic of China. Electronic address: songyangwenrong@hotmail.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20151221 PL - Netherlands TA - Environ Toxicol Pharmacol JT - Environmental toxicology and pharmacology JID - 9612020 RN - 0 (Benzoquinones) RN - 0 (Cytokines) RN - 0 (Hydrocarbons, Chlorinated) RN - 0 (I-kappa B Proteins) RN - 0 (NF-kappa B) RN - 0 (Reactive Oxygen Species) RN - 0 (tetrachlorobenzoquinone) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type II) RN - EC 1.14.13.39 (Nos2 protein, rat) RN - EC 2.7.11.10 (I-kappa B Kinase) SB - IM MH - Animals MH - Benzoquinones/*toxicity MH - Cell Survival/drug effects MH - Cytokines/*genetics MH - Gene Expression Regulation/drug effects MH - Hydrocarbons, Chlorinated/*toxicity MH - I-kappa B Kinase/genetics/metabolism MH - I-kappa B Proteins/genetics/metabolism MH - Inflammation/chemically induced/*genetics/immunology MH - NF-kappa B/genetics/metabolism MH - Nitric Oxide Synthase Type II/genetics/metabolism MH - PC12 Cells MH - Rats MH - Reactive Oxygen Species/*metabolism MH - Signal Transduction/*drug effects OTO - NOTNLM OT - Antioxidant OT - Inflammatory OT - NF-kappaB OT - Neurotoxicity OT - ROS OT - TCBQ EDAT- 2016/01/09 06:00 MHDA- 2016/10/19 06:00 CRDT- 2016/01/09 06:00 PHST- 2015/10/11 00:00 [received] PHST- 2015/12/17 00:00 [revised] PHST- 2015/12/18 00:00 [accepted] PHST- 2016/01/09 06:00 [entrez] PHST- 2016/01/09 06:00 [pubmed] PHST- 2016/10/19 06:00 [medline] AID - S1382-6689(15)30152-6 [pii] AID - 10.1016/j.etap.2015.12.012 [doi] PST - ppublish SO - Environ Toxicol Pharmacol. 2016 Jan;41:241-50. doi: 10.1016/j.etap.2015.12.012. Epub 2015 Dec 21.