Perfluorooctane sulfonate induces apoptosis of cerebellar granule cells via a ROS-dependent protein kinase C signaling pathway

• Published in: Neurotoxicology (Park Forest South) Vol. 33; no. 3; pp. 314 - 320
• Main Authors: Lee, Hyun-Gyo, Lee, Youn Ju, Yang, Jae-Ho
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01.06.2012; Elsevier
• Subjects: Acetylcysteine; Alkanesulfonic Acids - toxicity; Animals; Antioxidants - pharmacology; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; Brain; Caspase 3 - metabolism; Caspase-3; Cell culture; Cell Survival - drug effects; Cells, Cultured; Cerebellar granule cell; Cerebellum; Cerebellum - drug effects; Cerebellum - enzymology; Cerebellum - pathology; Chemical and industrial products toxicology. Toxic occupational diseases; Consumers; DNA Fragmentation; Dose-Response Relationship, Drug; Enzyme Activation; Fluorocarbons - toxicity; Granule cells; In Situ Nick-End Labeling; Isoenzymes; Learning; Medical sciences; Memory; Motor activity; Neurons - drug effects; Neurons - enzymology; Neurons - pathology; Neurotoxicity; Neurotoxicity Syndromes - enzymology; Neurotoxicity Syndromes - etiology; Neurotoxicity Syndromes - genetics; Neurotoxicity Syndromes - pathology; Neurotoxicity Syndromes - prevention & control; Oxidative Stress - drug effects; Perfluorooctane sulfonate; Protein kinase C; Protein Kinase C - genetics; Protein Kinase C - metabolism; Protein Transport; Rats; Rats, Sprague-Dawley; Reactive oxygen species; Reactive Oxygen Species - metabolism; RNA Interference; ROS; Signal transduction; Signal Transduction - drug effects; siRNA; Toxicology; Transfection; Translocation; Various organic compounds; Protein kinase C; Perfluorooctane sulfonate; Cerebellar granule cell; ROS; Apoptosis; Cerebellum; Granule neuron; Enzyme; Organic perhalocompound; Transferases; Central nervous system; In vitro; Encephalon; Signal transduction; Signaling pathway; Cell death; Fluorine Organic compounds
• ISSN: 0161-813X; 1872-9711
• DOI: 10.1016/j.neuro.2012.01.017

► We examined toxic effects of PFOS on cerebellar granule cells (CGC) from SD rats. ► PFOS increased ROS production and selectively translocated PKC isozymes. ► PKC activation was dampened by pretreatment of ROS inhibitor. ► PFOS induced apoptosis of CGC, which was blocked by siRNA of PKC isozymes. ► Thus, PFOS induces apoptosis of CGC in a ROS-dependent PKC activation. Perfluorinated chemicals (PFCs) have been widely used in a variety of industry and consumer products. Perfluorooctane sulfonate (PFOS), a prominent member of perfluoroalkyls, is known as a neurotoxicant in developing brain and affects behavior and motor activity. However, mechanism of neurotoxicity still remains unknown. In this study, we attempted to analyze apoptotic effects of PFOS on developing neuron. Cerebellar granule cells derived from 7-day old SD rats and grown in culture for additional 7 days were used to mimic postnatal day (PND)-14 conditions. PFOS exposure increased ROS production, which was blocked by ROS inhibitor, N-acetylcysteine (NAC). PFOS selectively induced dose-dependent translocations of PKC-α, -βII and -ɛ among PKC isozymes tested. The translocation of these specific PKC isozymes was blocked by NAC. A panel of different approaches was utilized to detect apoptotic effects. PFOS induced caspase-3 activity and nucleosomal DNA fragmentation in a dose-dependent manner, which were blocked by pretreatment of NAC. These apoptotic effects were further confirmed by TUNEL staining. Increases of caspase-3 activity and nucleosomal DNA fragmentation were dampened by the inhibition of PKC isozymes using siRNA technique. Taken together, our results suggest that PFOS may induce apoptosis of cerebellar granule cells via a ROS-mediated PKC signaling pathway. PKC signal transduction pathway is pivotal in learning and memory and apoptosis of neuronal cells is a critical event in neurotoxicity. Thus, this study may contribute to understand a new mechanistic aspect of PFOS-induced neurotoxicities.