title: Sodium fluoride induces apoptosis in mouse embryonic stem cells through ROS-dependent and caspase- and JNK-mediated pathways.
abstract: Sodium fluoride (NaF) is used as a source of fluoride ions in diverse applications. Fluoride salt is an effective prophylactic for dental caries and is an essential element required for bone health. However, fluoride is known to cause cytotoxicity in a concentration-dependent manner. Further, no information is available on the effects of NaF on mouse embryonic stem cells (mESCs). We investigated the mode of cell death induced by NaF and the mechanisms involved. NaF treatment greater than 1mM reduced viability and DNA synthesis in mESCs and induced cell cycle arrest in the G(2)/M phase. The addition of NaF induced cell death mainly by apoptosis rather than necrosis. Catalase (CAT) treatment significantly inhibited the NaF-mediated cell death and also suppressed the NaF-mediated increase in phospho-c-Jun N-terminal kinase (p-JNK) levels. Pre-treatment with SP600125 or z-VAD-fmk significantly attenuated the NaF-mediated reduction in cell viability. In contrast, intracellular free calcium chelator, but not of sodium or calcium ion channel blockers, facilitated NaF-induced toxicity in the cells. A JNK specific inhibitor (SP600125) prevented the NaF-induced increase in growth arrest and the DNA damage-inducible protein 45α. Further, NaF-mediated loss of mitochondrial membrane potential was apparently inhibited by pifithrin-α or CAT inhibitor. These findings suggest that NaF affects viability of mESCs in a concentration-dependent manner, where more than 1mM NaF causes apoptosis through hydroxyl radical-dependent and caspase- and JNK-mediated pathways.
authors.affiliation: Institute of Oral Biosciences and School of Dentistry (BK21 Program), Chonbuk National University, Jeonju 561-756, South Korea.
authors.forename: Tam Dan
authors.initials: TD
authors.lastname: Nguyen Ngoc
authors.forename: Young-Ok
authors.initials: YO
authors.lastname: Son
authors.forename: Shin-Saeng
authors.initials: SS
authors.lastname: Lim
authors.forename: Xianglin
authors.initials: X
authors.lastname: Shi
authors.forename: Jong-Ghee
authors.initials: JG
authors.lastname: Kim
authors.forename: Jung Sun
authors.initials: JS
authors.lastname: Heo
authors.forename: Youngji
authors.initials: Y
authors.lastname: Choe
authors.forename: Young-Mi
authors.initials: YM
authors.lastname: Jeon
authors.forename: Jeong-Chae
authors.initials: JC
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002327:Cariostatic Agents / Q000008:administration & dosage / Q000633:toxicity*; D002374:Catalase / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D053595:Embryonic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D017665:Hydroxyl Radical / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012969:Sodium Fluoride / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D002327:Cariostatic Agents; D017382:Reactive Oxygen Species; D017665:Hydroxyl Radical; D012969:Sodium Fluoride; D004247:DNA; D002374:Catalase; D048031:JNK Mitogen-Activated Protein Kinases