title: Tetrachlorobenzoquinone exhibits neurotoxicity by inducing inflammatory responses through ROS-mediated IKK/IκB/NF-κB signaling.
abstract: 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-κB) signaling. The activation of NF-κB was identified by measuring the protein expressions of inhibitor of nuclear factor kappa-B kinase (IKK) α/β, p-IKKα/β, an inhibitor of NF-κB (IκB) α, p-IκBα, NF-κB (p65) and p-p65. The translocation of NF-κB 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-1β), IL-6, tumor necrosis factor-alpha (TNF-α), 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-κB inhibitor inhibited these effects efficiently, further suggested TCBQ-induced inflammatory responses involve NF-κB 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-κB, which implied that ROS serve as the upstream molecule of NF-κB signaling. In summary, TCBQ exhibits a neurotoxic effect by inducing oxidative stress-mediated inflammatory responses via the activation of IKK/IκB/NF-κB pathway in PC12 cells.
authors.affiliation: 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.
authors.forename: Juanli
authors.initials: J
authors.lastname: Fu
authors.affiliation: 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.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Shi
authors.affiliation: 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.
authors.forename: Xiufang
authors.initials: X
authors.lastname: Song
authors.affiliation: 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.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Xia
authors.affiliation: 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.
authors.forename: Chuanyang
authors.initials: C
authors.lastname: Su
authors.affiliation: 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.
authors.forename: Zixuan
authors.initials: Z
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Erqun
authors.initials: E
authors.lastname: Song
authors.affiliation: 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.
authors.forename: Yang
authors.initials: Y
authors.lastname: Song
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D006843:Hydrocarbons, Chlorinated / Q000633:toxicity*; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D016716:PC12 Cells; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D016227:Benzoquinones; D016207:Cytokines; D006843:Hydrocarbons, Chlorinated; D020672:I-kappa B Proteins; D016328:NF-kappa B; D017382:Reactive Oxygen Species; C000591600:tetrachlorobenzoquinone; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051550:I-kappa B Kinase
keywords: Antioxidant; Inflammatory; NF-κB; Neurotoxicity; ROS; TCBQ