Sodium fluoride induces apoptosis in mouse embryonic stem cells through ROS-dependent and caspase- and JNK-mediated pathways

Tam Dan Nguyen Ngoc, Young Ok Son, Shin Saeng Lim, Xianglin Shi, Jong Ghee Kim, Jung Sun Heo, Youngji Choe, Young Mi Jeon, Jeong Chae Lee

Research output: Contribution to journalArticlepeer-review

66 Scopus citations


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.

Original languageEnglish
Pages (from-to)329-337
Number of pages9
JournalToxicology and Applied Pharmacology
Issue number3
StatePublished - Mar 15 2012

Bibliographical note

Funding Information:
This research was supported by Basic Science Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology ( 2011-0009123 ). Part of this research was supported by NIH grants ( R01ES015518-04 , R01CA116697-05 , and R01CA119028-05S1 ). Dr. J.-C. Lee was supported by the Chonbuk National University for his sabbatical leave of absence at the University of Kentucky to perform part of the experiments for this work.


  • Cell death
  • Cellular signaling
  • Mouse embryonic stem cells
  • ROS
  • Sodium fluoride

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology


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