title: Reactive oxygen species mediate nitric oxide production through ERK/JNK MAPK signaling in HAPI microglia after PFOS exposure.
abstract: Perfluorooctane sulfonate (PFOS), an emerging persistent contaminant that is commonly encountered during daily life, has been shown to exert toxic effects on the central nervous system (CNS). However, the molecular mechanisms underlying the neurotoxicity of PFOS remain largely unknown. It has been widely acknowledged that the inflammatory mediators released by hyper-activated microglia play vital roles in the pathogenesis of various neurological diseases. In the present study, we examined the impact of PFOS exposure on microglial activation and the release of proinflammatory mediators, including nitric oxide (NO) and reactive oxidative species (ROS). We found that PFOS exposure led to concentration-dependent NO and ROS production by rat HAPI microglia. We also discovered that there was rapid activation of the ERK/JNK MAPK signaling pathway in the HAPI microglia following PFOS treatment. Moreover, the PFOS-induced iNOS expression and NO production were attenuated after the inhibition of ERK or JNK MAPK by their corresponding inhibitors, PD98059 and SP600125. Interestingly, NAC, a ROS inhibitor, blocked iNOS expression, NO production, and activation of ERK and JNK MAPKs, which suggested that PFOS-mediated microglial NO production occurs via a ROS/ERK/JNK MAPK signaling pathway. Finally, by exposing SH-SY5Y cells to PFOS-treated microglia-conditioned medium, we demonstrated that NO was responsible for PFOS-mediated neuronal apoptosis.
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong, Jiangsu 226001, People's Republic of China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong, Jiangsu 226001, People's Republic of China.
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Nie
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong, Jiangsu 226001, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Labor and Environmental Hygiene, School of Public Health, Nantong University, Nantong, Jiangsu 226001, People's Republic of China.
authors.forename: Ting
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Labor and Environmental Hygiene, School of Public Health, Nantong University, Nantong, Jiangsu 226001, People's Republic of China.
authors.forename: Jiamin
authors.initials: J
authors.lastname: Mao
authors.affiliation: Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, Nantong, Jiangsu 226001, People's Republic of China.
authors.forename: Xinhang
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Labor and Environmental Hygiene, School of Public Health, Nantong University, Nantong, Jiangsu 226001, People's Republic of China.
authors.forename: Yiyang
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Department of Labor and Environmental Hygiene, School of Public Health, Nantong University, Nantong, Jiangsu 226001, People's Republic of China.
authors.forename: Jiyun
authors.initials: J
authors.lastname: Shi
authors.affiliation: Department of Occupational Medicine and Environmental Toxicology, School of Public Health, Nantong University, Nantong, Jiangsu 226001, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong, Jiangsu 226001, People's Republic of China.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Wan
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong, Jiangsu 226001, People's Republic of China. Electronic address: wqy@ntu.edu.cn.
authors.forename: Qiyun
authors.initials: Q
authors.lastname: Wu
mesh_terms: D017738:Alkanesulfonic Acids / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005466:Fluorocarbons / Q000633:toxicity*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017628:Microglia / Q000187:drug effects* / Q000201:enzymology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D019899:Paracrine Communication / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors
chemical_list: D017738:Alkanesulfonic Acids; D000975:Antioxidants; D004785:Environmental Pollutants; D005466:Fluorocarbons; D018836:Inflammation Mediators; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; C076994:perfluorooctane sulfonic acid; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases
keywords: ERK/JNK MAPK; Microglia; NO; PFOS; ROS; iNOS