title: Acute exposure to 3-methylcholanthrene induces hepatic oxidative stress via activation of the Nrf2/ARE signaling pathway in mice.
abstract: Polycyclic aromatic hydrocarbons (PAHs) are the most common contaminants in the environment. The primary focus on the toxicity of PAHs is their ability to activate the aryl hydrocarbon receptor (AhR)-mediated pathway and lead to carcinogenesis in different organisms. However, the influence of PAHs on the antioxidant system in mammalian systems has received only limited attention. In the present study, we observed that the intraperitoneal injection of 100 mg/kg 3-methylcholanthrene (3MC) into mice significantly increased reactive oxygen species (ROS) levels and malondialdehyde (MDA) contents and decreased glutathione (GSH) contents and the activity of total antioxidant capacity (T-AOC), indicating that serious oxidative stress had been induced in the liver of mice. Then, the oxidative stress signal activated the nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) pathway by enhancing the mRNA levels of Nrf2, p38, and Erk2. Moreover, the mRNA levels of Nrf2/ARE target genes, including glutathione peroxidase (Gpx), glutathione reductase (GR), glutathione synthetase (GS), NAD(P)H: quinone oxidoreductase 1 (Nqo1), superoxide dismutase 1 (Sod1), and Sod2, increased significantly after treatment with 3MC for 24 hours. The hepatic levels of NQO1 and the activities of GR and GS were also significantly enhanced at 24 hours after 3MC treatment. Because the expression of NQO1 is co-regulated by Nrf2/ARE and AhR/XRE in mammalian tissues, NQO1 may play an important role in protecting against the oxidative stress induced by 3MC. Taken together, our findings suggested that acute exposure to 3MC altered the cellular redox balance in hepatocytes to trigger Nrf2-regulated antioxidant responses, which may represent an adaptive cell defense mechanism against the oxidative stress induced by PAHs.
authors.affiliation: Department of Biotechnology, College of Biological and Environmental Engineering, Zhejiang University of Technology, Hangzhou, 310032, China.
authors.forename: Yuanxiang
authors.initials: Y
authors.lastname: Jin
authors.forename: Wenyu
authors.initials: W
authors.lastname: Miao
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Lin
authors.forename: Xiuhong
authors.initials: X
authors.lastname: Pan
authors.forename: Yang
authors.initials: Y
authors.lastname: Ye
authors.forename: Minjie
authors.initials: M
authors.lastname: Xu
authors.forename: Zhengwei
authors.initials: Z
authors.lastname: Fu
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008748:Methylcholanthrene / Q000633:toxicity*; D051379:Mice; D008813:Mice, Inbred ICR; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D020218:Response Elements; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D018336:Receptors, Aryl Hydrocarbon; D008315:Malondialdehyde; D008748:Methylcholanthrene; D005978:Glutathione
keywords: 3-methylcholanthrene; ICR mice; NQO1; Nrf2 pathway; oxidative stress