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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 1 mM reduced viability and DNA synthesis in mESCs and induced cell cycle arrest in the G{sub 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 suggestmore » that NaF affects viability of mESCs in a concentration-dependent manner, where more than 1 mM NaF causes apoptosis through hydroxyl radical-dependent and caspase- and JNK-mediated pathways. -- Highlights: ► The mode of NaF-induced cell death and the mechanisms involved were examined. ► NaF induced mainly apoptotic death of mouse embryonic stem cells (mESCs). ► NaF induced mitochondrial-mediated and caspase-dependent apoptosis. ► JNK- and p53-mediated pathways are involved in NaF-mediated apoptosis in the cells. ► ROS are the up-stream effector in NaF-mediated activation of JNK and p53 in mESCs.« less

Authors:
 [1];  [2];  [1];  [3];  [2];  [1];  [4];  [1];  [1];  [1];  [5];  [3]
  1. Institute of Oral Biosciences and School of Dentistry (BK21 Program), Chonbuk National University, Jeonju 561-756 (Korea, Republic of)
  2. Graduate Center for Toxicology, School of Medicine, University of Kentucky, Lexington, KY 40536-0305 (United States)
  3. (Korea, Republic of)
  4. Department of Maxillofacial Biomedical Engineering and Institute of Oral Biology, School of Dentistry, Kyung Hee University, Seoul 130-701 (Korea, Republic of)
  5. (United States)
Publication Date:
OSTI Identifier:
22215269
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 259; Journal Issue: 3; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ADP; APOPTOSIS; CALCIUM IONS; CATALASE; CATS; ELECTRON SPIN RESONANCE; IODIDES; MICE; MITOCHONDRIA; OXYGEN; RIBOSE; SODIUM FLUORIDES; STEM CELLS; SUPEROXIDE DISMUTASE; TETRAZOLIUM

Citation Formats

Nguyen Ngoc, Tam Dan, Son, Young-Ok, Lim, Shin-Saeng, Department of Bioactive Material Sciences and Research Center of Bioactive Materials, Chonbuk National University, Jeonju 561-756, Shi, Xianglin, Kim, Jong-Ghee, Heo, Jung Sun, Choe, Youngji, Jeon, Young-Mi, E-mail: young@jbnu.ac.kr, Lee, Jeong-Chae, E-mail: leejc88@jbnu.ac.kr, Graduate Center for Toxicology, School of Medicine, University of Kentucky, Lexington, KY 40536-0305, and Department of Bioactive Material Sciences and Research Center of Bioactive Materials, Chonbuk National University, Jeonju 561-756. Sodium fluoride induces apoptosis in mouse embryonic stem cells through ROS-dependent and caspase- and JNK-mediated pathways. United States: N. p., 2012. Web. doi:10.1016/J.TAAP.2012.01.010.
Nguyen Ngoc, Tam Dan, Son, Young-Ok, Lim, Shin-Saeng, Department of Bioactive Material Sciences and Research Center of Bioactive Materials, Chonbuk National University, Jeonju 561-756, Shi, Xianglin, Kim, Jong-Ghee, Heo, Jung Sun, Choe, Youngji, Jeon, Young-Mi, E-mail: young@jbnu.ac.kr, Lee, Jeong-Chae, E-mail: leejc88@jbnu.ac.kr, Graduate Center for Toxicology, School of Medicine, University of Kentucky, Lexington, KY 40536-0305, & Department of Bioactive Material Sciences and Research Center of Bioactive Materials, Chonbuk National University, Jeonju 561-756. Sodium fluoride induces apoptosis in mouse embryonic stem cells through ROS-dependent and caspase- and JNK-mediated pathways. United States. doi:10.1016/J.TAAP.2012.01.010.
Nguyen Ngoc, Tam Dan, Son, Young-Ok, Lim, Shin-Saeng, Department of Bioactive Material Sciences and Research Center of Bioactive Materials, Chonbuk National University, Jeonju 561-756, Shi, Xianglin, Kim, Jong-Ghee, Heo, Jung Sun, Choe, Youngji, Jeon, Young-Mi, E-mail: young@jbnu.ac.kr, Lee, Jeong-Chae, E-mail: leejc88@jbnu.ac.kr, Graduate Center for Toxicology, School of Medicine, University of Kentucky, Lexington, KY 40536-0305, and Department of Bioactive Material Sciences and Research Center of Bioactive Materials, Chonbuk National University, Jeonju 561-756. Thu . "Sodium fluoride induces apoptosis in mouse embryonic stem cells through ROS-dependent and caspase- and JNK-mediated pathways". United States. doi:10.1016/J.TAAP.2012.01.010.
@article{osti_22215269,
title = {Sodium fluoride induces apoptosis in mouse embryonic stem cells through ROS-dependent and caspase- and JNK-mediated pathways},
author = {Nguyen Ngoc, Tam Dan and Son, Young-Ok and Lim, Shin-Saeng and Department of Bioactive Material Sciences and Research Center of Bioactive Materials, Chonbuk National University, Jeonju 561-756 and Shi, Xianglin and Kim, Jong-Ghee and Heo, Jung Sun and Choe, Youngji and Jeon, Young-Mi, E-mail: young@jbnu.ac.kr and Lee, Jeong-Chae, E-mail: leejc88@jbnu.ac.kr and Graduate Center for Toxicology, School of Medicine, University of Kentucky, Lexington, KY 40536-0305 and Department of Bioactive Material Sciences and Research Center of Bioactive Materials, Chonbuk National University, Jeonju 561-756},
abstractNote = {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 1 mM reduced viability and DNA synthesis in mESCs and induced cell cycle arrest in the G{sub 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 1 mM NaF causes apoptosis through hydroxyl radical-dependent and caspase- and JNK-mediated pathways. -- Highlights: ► The mode of NaF-induced cell death and the mechanisms involved were examined. ► NaF induced mainly apoptotic death of mouse embryonic stem cells (mESCs). ► NaF induced mitochondrial-mediated and caspase-dependent apoptosis. ► JNK- and p53-mediated pathways are involved in NaF-mediated apoptosis in the cells. ► ROS are the up-stream effector in NaF-mediated activation of JNK and p53 in mESCs.},
doi = {10.1016/J.TAAP.2012.01.010},
journal = {Toxicology and Applied Pharmacology},
number = 3,
volume = 259,
place = {United States},
year = {Thu Mar 15 00:00:00 EDT 2012},
month = {Thu Mar 15 00:00:00 EDT 2012}
}
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