title: PFHxS induces apoptosis of neuronal cells via ERK1/2-mediated pathway.
abstract: Perfluorohexanesulfonate (PFHxS) is one of the most widely distributed perfluoroalkyl compounds (PFCs) and its possible neurotoxicity has been suggested. However, the effects of PFHxS on neuronal function remain to be elucidated. In this study, the effects of PFHxS on neuronal cell death and the underlying mechanisms were examined. Cerebellar granule cells (CGCs) were isolated from 7-day old rat pups and maintained in culture for additional 7d. The apoptotic effects of PFHxS were determined by caspase-3 activity and TUNEL staining. PFHxS increased the apoptotic death of CGC in concentration-dependent manner. It also increased the activation of ERK1/2, JNK and p38 MAPK with different temporal activation. PD98059, an inhibitor of ERK1/2 pathway, completely blocked PFHxS-induced apoptosis whereas SP600125, a JNK inhibitor, significantly increased the apoptosis, showing their opposite roles in the apoptosis of CGCs. Treatment of antioxidants, Trolox or N-acetylcysteine (NAC), completely blocked ROS generation by PFHxS but neither of these antioxidants prevented PFHxS-induced apoptosis, suggesting that ROS may not play a key role in the process of apoptosis. PD98059 prevented ROS accumulation by PFHxS but the ERK1/2 activation was not affected by Trolox or NAC. These results indicate that ROS is one of downstream targets of ERK1/2, not vice versa. Taken together, PFHxS increased apoptosis of CGC in ERK1/2-dependent manner, where downstream pathway other than ROS may play a major role. This is a first report that PFHxS induces apoptosis of CGC isolated from the developing brain and its possible mode of action is associated with ERK1/2 pathway.
authors.affiliation: Department of Pharmacology/Toxicology, School of Medicine, Catholic University of Daegu, Daegu, Republic of Korea.
authors.forename: Youn Ju
authors.initials: YJ
authors.lastname: Lee
authors.forename: So-Young
authors.initials: SY
authors.lastname: Choi
authors.forename: Jae-Ho
authors.initials: JH
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D005466:Fluorocarbons; D015386:Hazardous Substances / Q000633:toxicity*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013451:Sulfonic Acids / Q000633:toxicity*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D005466:Fluorocarbons; D015386:Hazardous Substances; D017382:Reactive Oxygen Species; D013451:Sulfonic Acids; C471071:perfluorohexanesulfonic acid; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3
keywords: Apoptosis; Cerebellar granule cell; Mitogen-activated protein kinase; Perfluorohexane sulfonate; Reactive oxygen species