title: Perfluorooctane sulfonate mediates microglial activation and secretion of TNF-α through Ca²⁺-dependent PKC-NF-кB signaling.
abstract: Perfluorooctane sulfonate (PFOS), a ubiquitous pollutant widely found in the environment and biota, can cause numerous adverse effects on human health. In recent years, PFOS's toxic effects on the central nervous system (CNS) have been shown. However, we still have a lot to study in the underlying molecular mechanism of PFOS's neurotoxicity. Microglia, the innate immune cells of CNS, are critically implicated in various neurological diseases caused by pro-inflammatory mediators. In our research, we found that HAPI microglia secreted tumor necrosis factor-alpha (TNF-α) after PFOS exposure in time-dependent and dose-dependent way. We also discovered that intracellular concentration of free Ca(2+) ([Ca(2+)]i) significantly increased after PFOS treatments. It was noteworthy here the secretion of TNF-α mediated by PFOS was blocked by Ca(2+) inhibitor and protein kinase C (PKC) inhibitor. Besides these, we had learned as well that PFOS brought about the up-regulation of phosphorylated nuclear factor kappa B (NF-кB) p65 expression and accelerated degradation of NF-κB inhibitor alpha (IкBα), however, these effects could be attenuated or blocked by Ca(2+) inhibitor and PKC inhibitor. Finally, through treating SH-SY5Y cells with PFOS-treated microglial conditioned medium, we demonstrated that TNF-α mediated neuronal apoptosis. To sum up, our research had shown, for the first time, that the distinct TNF-α secretion brought by PFOS in HAPI microglia, was achieved through the Ca(2+)-dependent PKC-NF-кB signaling, subsequently participating in neuronal loss.
authors.affiliation: Department of Public Health, the Second People's Hospital of Nan Tong, Nantong, Jiangsu 226001, People's Republic of China.
authors.forename: Jianbin
authors.initials: J
authors.lastname: Yang
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 Disease Control and Prevention, the Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu 212002, People's Republic of China.
authors.forename: Shangshi
authors.initials: S
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 Labor and Environmental Hygiene, School of Public Health, Nantong University, Nantong, Jiangsu 226001, People's Republic of China.
authors.forename: Xia
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Labor and Environmental Hygiene, School of Public Health, Nantong University, Nantong, Jiangsu 226001, People's Republic of China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Dong
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: Jingling
authors.initials: J
authors.lastname: Han
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 Labor and Environmental Hygiene, 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 Nutrition and Food Hygiene, School of Public Health, Nantong University, Nantong, Jiangsu 226001, People's Republic of China. Electronic address: zhaojianya@ntu.edu.cn.
authors.forename: Jianya
authors.initials: J
authors.lastname: Zhao
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*; D020013:Calcium Signaling / Q000187:drug effects*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D005466:Fluorocarbons / Q000633:toxicity*; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors; D008262:Macrophage Activation / Q000187:drug effects*; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism*; D016328:NF-kappa B / Q000187:drug effects*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D051996:Transcription Factor RelA / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D017738:Alkanesulfonic Acids; D004785:Environmental Pollutants; D005466:Fluorocarbons; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; C076994:perfluorooctane sulfonic acid; D051550:I-kappa B Kinase; D011493:Protein Kinase C
keywords: Ca(2+); Microglia; NF-кB; PFOS; PKC; TNF-α