Sodium Fluoride, another form of fluorine, is orally bioavailable and can accumulate in reproductive organs and interfere with hormonal regulation and oxidative stress pathways, contributing to reproductive toxicity[1]. Sodium Fluoride is extensively used for the prevention of dental caries and tooth decay in the form of fluorinated drinking water, salts, or milk, tooth pastes, mouth washes, and fluo-ride tablets[2]. The acute Fluoride toxicosis usually occurs by soluble forms of Sodium Fluoride upon ingestion in large doses[3].
In vitro, bone mesenchymal stem cells (BMSCs) grew well in media containing 0-240μM Sodium Fluoride, whereas exposure to 480μM or 1200μM Sodium Fluoride caused a decline in cell viability—first evident at day 7 for 480μM and from day 3 onward for 1200μM—accompanied by reduced cell density and a marked rise in reactive oxygen species (ROS) on day 7[4]. After 12h of exposure to 0, 0.5, 5 or 10mM Sodium Fluoride, OCCM-30 cells treated with 5 or 10mM Sodium Fluoride exhibited apoptotic morphological changes and DNA fragmentation; 5mM Sodium Fluoride up-regulated Fas-L mRNA, whereas 10mM Sodium Fluoride induced the expression of cleaved caspase-3, -8, -9 and cleaved Poly (ADP-ribose) polymerase (PARP) and provoked a significant rise in intracellular ROS[5].
In vivo, oral administration of Sodium Fluoride to ICR mice at 12, 24, and 48mg/kg body weight for 42 consecutive days elicited dose- and time-dependent histopathological lesions in the liver, and dose-dependent elevate of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AKP) activities, and total bilirubin (TBIL) contents on days 21 and 42[6]. Intragastric administration of 0, 12, 24 and 48mg/kg Sodium Fluoride to ICR mice, Sodium Fluoride in excess of 12mg/kg activated the mitogen-activated protein kinases (MAPKs) signaling pathway by markedly increasing mRNA and protein levels of apoptosis signal-regulating kinase 1 (ASK1), mitogen-activated protein kinase kinases 1/2 (MEK1/2), extracellular signal-regulated protein kinases 1/2 (Erk1/2), mitogen-activated protein kinase kinases 4/7 (MEK4/7), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38) and mitogen-activated protein kinase kinases 3/6 (MEK3/6), and the nuclear factor-kappa B (NF-κB) signaling pathway by increasing the production of NF-κB and inhibitor of nuclear factor kappa-B kinase subunit beta (IKK-β) and reducing the production of the inhibitory kappa B (IκB)[7].
References:
[1] Talebi SF, Seify M, Bhandari RK, et al. Fluoride-induced testicular and ovarian toxicity: evidence from animal studies. Biol Res. 2025;58(1):6.
[2] A.A. Oyagbemi, T.O. Omobowale, O.E. Ola-Davies, et al. Luteolin-mediated Kim-1/NF-kB/Nrf2 signaling pathways protects sodium fluoride-induced hypertension and cardiovascular complications. BioFactors. 2018;44(6):518-531.
[3] Giri D K, Ghosh R C, Mondal M, et al. Pathology of acute oral toxicity of sodium fluoride in Wistar rats. Indian Journal of Veterinary Pathology. 2014;38(1):33-38.
[4] Wu S, Xia B, Mai S, et al. Sodium Fluoride under Dose Range of 2.4-24 μM, a Promising Osteoimmunomodulatory Agent for Vascularized Bone Formation. ACS Biomater Sci Eng. 2019;5(2):817-830.
[5] Ni J, Li Y, Zhang W, et al. Sodium fluoride causes oxidative stress and apoptosis in cementoblasts. Chem Biol Interact. 2018;294:34-39.
[6] Lu Y, Luo Q, Cui H, et al. Sodium fluoride causes oxidative stress and apoptosis in the mouse liver. Aging (Albany NY). 2017;9(6):1623-1639.
[7] Chen L, Kuang P, Liu H, et al. Sodium Fluoride (NaF) Induces Inflammatory Responses Via Activating MAPKs/NF-κB Signaling Pathway and Reducing Anti-inflammatory Cytokine Expression in the Mouse Liver. Biol Trace Elem Res. 2019;189(1):157-171.
Sodium Fluoride作为氟的另一种形式，经口服后可蓄积于生殖器官，干扰激素调控并激活氧化应激通路，从而导致生殖毒性[1]。Sodium Fluoride被广泛用于预防龋齿和牙釉质脱矿，常以氟化饮水、食盐、牛奶、牙膏、漱口水及含氟片剂等形式存在[2]。急性氟中毒通常由大剂量摄入可溶性Sodium Fluoride引起[3]。
在体外，骨髓间充质干细胞（BMSCs）在含0-240μM的Sodium Fluoride的培养基中生长良好；而暴露于480μM或1200μM的Sodium Fluoride时，细胞活力从第7天（480μM）或第3天（1200μM）开始下降，细胞密度减少，并于第7天出现活性氧（ROS）显著升高[4]。0、0.5、5或10mM的Sodium Fluoride处理OCCM-30细胞12h后，5mM与10mM的Sodium Fluoride组出现凋亡形态学改变及DNA片段化；5mM的Sodium Fluoride上调Fas-L mRNA表达，而10mM的Sodium Fluoride诱导cleaved caspase-3、-8、-9及cleaved聚ADP核糖聚合酶（PARP）表达，并显著增加胞内ROS水平[5]。
在体内，以12、24和48mg/kg的Sodium Fluoride连续灌胃ICR小鼠42天，可诱发肝脏呈剂量和时间依赖性组织病理学损伤，并于第21和42天剂量依赖性地升高丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、碱性磷酸酶（AKP）活性及总胆红素（TBIL）含量[6]。对ICR小鼠灌胃0、12、24和48mg/kg的Sodium Fluoride后，≥12mg/kg的Sodium Fluoride通过显著升高凋亡信号调节激酶1（ASK1）、丝裂原活化蛋白激酶激酶1/2（MEK1/2）、胞外信号调节蛋白激酶1/2（Erk1/2）、丝裂原活化蛋白激酶激酶4/7（MEK4/7）、c-Jun N-末端激酶（JNK）、p38丝裂原活化蛋白激酶（p38）及丝裂原活化蛋白激酶激酶3/6（MEK3/6）的mRNA和蛋白水平，激活MAPKs信号通路；同时通过升高 NF-κB和核因子κB抑制激酶β（IKK-β）的表达并降低抑制性κB（IκB）的表达，激活NF-κB信号通路[7]。