Flouride induces endoplasmic reticulum stress and inhibits protein synthesis and secretion

Ramaswamy Sharma, Masahiro Tsuchiya, John D. Bartlett

研究成果: Article査読

102 被引用数 (Scopus)


Background: Exposure to excessive amounts of fluoride (F-) causes dental fluorosis in susceptible individuals; however, the mechanism of F-induced toxicity is unclear. Previously, we have shown that high-dose F- activates the unfolded protein response (UPR) in ameloblasts that are responsible for dental enamel formation. The UPR is a signaling pathway responsible for either alleviating endoplasmic reticulum (ER) stress or for inducing apoptosis of the stressed cells. Objectives: In this study we determined if low-dose F- causes ER stress and activates the UPR, and we also determined whether F- interferes with the secretion of proteins from the ER. Methods: We stably transfected the ameloblast-derived LS8 cell line with secreted alkaline phosphatase (SEAP) and determined activity and localization of SEAP and F-mediated induction of UPR proteins. Also, incisors from mice given drinking water containing various concentrations of F- were examined for eucaryotic initiation factor-2, subunit alpha (elf2α) phosphorylation. Results: We found that F- decreases the extracellular secretion of SEAP in a linear, dose-dependent manner. We also found a corresponding increase in the intracellular accumulation of SEAP after exposure to F-. These changes are associated with the induction of UPR proteins such as the molecular chaperone BiP and phosphorylation of the UPR sensor PKR-like ER kinase, and its substrate, eIF2α. Importantly, F- -induced phosphorylation of eIF2α was confirmed in vivo. Conclusions: These data suggest that F- initiates an ER stress response in ameloblasts that interferes with protein synthesis and secretion. Consequently, ameloblast ftinction during enamel development may be impaired, and this may culminate in dental fluorosis.

ジャーナルEnvironmental health perspectives
出版ステータスPublished - 2008 9月

ASJC Scopus subject areas

  • 公衆衛生学、環境および労働衛生
  • 健康、毒物学および変異誘発


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