The acid test of fluoride: how pH modulates toxicity.
The acid test of fluoride: how pH modulates toxicity.
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DOI：
10.1371/journal.pone.0010895
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发表时间：
2010-05-28
期刊：
影响因子：
3.7
通讯作者：
Bartlett JD
中科院分区：
文献类型：
--
作者：
Sharma R;Tsuchiya M;Skobe Z;Tannous BA;Bartlett JD
目前尚不清楚为什么负责牙釉质形成的成釉细胞对氟化物（F-）特别敏感。在这里，我们提出了一个新的理论与支持数据表明，低pH环境的成熟阶段成釉细胞增强其敏感性，以一个给定的剂量的F −。牙釉质的形成是在中性pH环境中开始的（分泌阶段）;然而，随着大多数矿物质沉淀，pH可以下降到6.0以下（成熟阶段）。低pH值可以促进F −进入细胞。在这里，我们询问F −在低pH值下是否更具毒性，这是通过增加细胞应激和降低细胞功能来衡量的。在低pH下用F-处理成釉细胞衍生的LS 8细胞降低了磷酸化应激相关蛋白PERK、eIF2 α、JNK和c-jun所需的F-阈值剂量。荧光素酶分泌在低pH下与F-处理后2小时内显著降低，中性pH，表明功能毒性增加。与分泌期成釉细胞（pH <7.2）相比，饮用100 ppm F −的大鼠在成熟期成釉细胞（pH <6.0）中表现出应激介导的eIF2 α磷酸化增加。有趣的是，F −处理的大鼠表现出在釉质发育成熟阶段表达的转录物（Klk 4和Amtn）显著减少。相反，分泌期基因AmelX、Ambn、Enam和Mmp20的表达不受影响。成熟阶段成釉细胞的低pH环境促进F −的摄取，导致细胞应激增加，损害成釉细胞功能，导致氟斑牙。
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. 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. 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.
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影响因子：
3.7
作者：
Badr CE;Hewett JW;Breakefield XO;Tannous BA
通讯作者：
Tannous BA
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