title: Dibutyltin promotes oxidative stress and increases inflammatory mediators in BV-2 microglia cells.
abstract: The organotin dibutyltin (DBT) is used as biocide and as stabilizer in the manufacture of silicones, polyvinyl chloride plastics, polyurethanes and polyester systems. Although the immuno- and neurotoxicity of DBT has been recognized, the underlying mechanisms remained unclear and the impact of DBT on microglia cells has not yet been established. We now used cultured mouse BV-2 cells as a model of activated microglia to investigate the impact of DBT on oxidative stress and pro-inflammatory cytokines. DBT, at subcytotoxic concentrations, increased intracellular reactive oxygen species (ROS), mitochondrial mass, mitochondrial ROS, and the mRNA expression of inducible nitric oxide synthase (iNOS) and NADPH-dependent oxidase-2 (NOX-2). ATP levels were decreased by DBT, followed by activation of AMP-activated protein kinase (AMPK). Moreover, DBT potentiated the expression of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Inhibition of NOX-2 diminished both ROS production and induction of IL-6 expression. The DBT-mediated increase in NF-κB activity and subsequent up regulation of IL-6 was abolished by co-treatment with a NF-κB inhibitor. Treatment of cells with pharmacological inhibitors indicated a role for mitogen-activated protein kinases (MAPKs), PI3K/Akt, protein kinase C (PKC) and phospholipase C (PLC) in the DBT-induced toxicity. Finally, the calcium chelator BAPTA-AM diminished oxidative stress and induction of IL-6 expression, indicating the involvement of increased intracellular calcium in the enhanced microglia activity upon exposure to DBT. Together, the results suggest that a potentiation of oxidative stress and pro-inflammatory cytokine expression in microglia cells contribute to the toxicity of DBT in the CNS.
authors.affiliation: Swiss Center for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. Electronic address: boonrat.chantong@unibas.ch.
authors.forename: Boonrat
authors.initials: B
authors.lastname: Chantong
authors.affiliation: Swiss Center for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. Electronic address: denise.kratschmar@unibas.ch.
authors.forename: Denise V
authors.initials: DV
authors.lastname: Kratschmar
authors.affiliation: Swiss Center for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. Electronic address: adam.lister@unibas.ch.
authors.forename: Adam
authors.initials: A
authors.lastname: Lister
authors.affiliation: Swiss Center for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. Electronic address: alex.odermatt@unibas.ch.
authors.forename: Alex
authors.initials: A
authors.lastname: Odermatt
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D018836:Inflammation Mediators / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology; D009947:Organotin Compounds / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011493:Protein Kinase C / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D018836:Inflammation Mediators; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D009947:Organotin Compounds; D017382:Reactive Oxygen Species; C056189:di-n-butyltin; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium
keywords: Dibutyltin; Inflammation; Microglia; Neurotoxicity; Organotin; Oxidative stress