The Acid Test of Fluoride: How pH Modulates Toxicity

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The Acid Test of Fluoride: How pH Modulates Toxicity

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dc.contributor.author Tsuchiya, Masahiro
dc.contributor.author Skobe, Ziedonis
dc.contributor.author Sharma, Ramaswamy Narayanaswamy
dc.contributor.author Tannous, Bakhos A.
dc.contributor.author Bartlett, John D.
dc.date.accessioned 2011-12-21T21:55:08Z
dc.date.issued 2010
dc.identifier.citation Sharma, Ramaswamy, Masahiro Tsuchiya, Ziedonis Skobe, Bakhos A. Tannous, and John D. Bartlett. 2010. The Acid Test of Fluoride: How pH Modulates Toxicity. PLoS ONE 5(5): e10895. en_US
dc.identifier.issn 1932-6203 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:5692485
dc.description.abstract Background: It is not known why the ameloblasts responsible for dental enamel formation are uniquely sensitive to fluoride (\(F^−\)). Herein, we present a novel theory with supporting data to show that the low pH environment of maturating stage ameloblasts enhances their sensitivity to a given dose of \(F^−\). Enamel formation is initiated in a neutral pH environment (secretory stage); however, the pH can fall to below 6.0 as most of the mineral precipitates (maturation stage). Low pH can facilitate entry of \(F^−\) into cells. Here, we asked if \(F^−\) was more toxic at low pH, as measured by increased cell stress and decreased cell function. Methodology/Principal Findings: Treatment of ameloblast-derived LS8 cells with \(F^−\) at low pH reduced the threshold dose of \(F^−\) required to phosphorylate stress-related proteins, PERK, eIF2α, JNK and c-jun. To assess protein secretion, LS8 cells were stably transduced with a secreted reporter, Gaussia luciferase, and secretion was quantified as a function of \(F^−\) dose and pH. Luciferase secretion significantly decreased within 2 hr of \(F^−\) treatment at low pH versus neutral pH, indicating increased functional toxicity. Rats given 100 ppm \(F^−\) in their drinking water exhibited increased stress-mediated phosphorylation of eIF2α in maturation stage ameloblasts (pH<6.0) as compared to secretory stage ameloblasts (pH∼7.2). Intriguingly, \(F^−\)-treated rats demonstrated a striking decrease in transcripts expressed during the maturation stage of enamel development (Klk4 and Amtn). In contrast, the expression of secretory stage genes, AmelX, Ambn, Enam and Mmp20, was unaffected. Conclusions: The low pH environment of maturation stage ameloblasts facilitates the uptake of \(F^−\), causing increased cell stress that compromises ameloblast function, resulting in dental fluorosis. en_US
dc.language.iso en_US en_US
dc.publisher Public Library of Science en_US
dc.relation.isversionof doi:10.1371/journal.pone.0010895 en_US
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2878349/pdf/ en_US
dash.license LAA
dc.subject cell biology en_US
dc.subject cell signaling en_US
dc.subject cellular death and stress responses en_US
dc.subject gene expression en_US
dc.subject pediatrics and child health en_US
dc.subject child development en_US
dc.subject public health and epidemiology en_US
dc.subject environmental health en_US
dc.title The Acid Test of Fluoride: How pH Modulates Toxicity en_US
dc.type Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal PLoS ONE en_US
dash.depositing.author Tannous, Bakhos A.
dc.date.available 2011-12-21T21:55:08Z
dash.affiliation.other HMS^Neurology-Massachusetts General Hospital en_US

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