Fluoride (F) is ubiquitous natural substance and widespread industrial pollutant. Although low fluoride concentrations are beneficial for normal tooth and bone development, acute or chronic exposure to high fluoride doses results in adverse health effects. The molecular mechanisms underlying fluoride toxicity are different by nature. Fluoride is able to stimulate G-proteins with subsequent activation of downstream signal transduction pathways such as PKA-, PKC-, PI3-kinase-, Ca2+-, and MAPK-dependent systems. G-protein-independent routes include tyrosine phosphorylation and protein phosphatase inhibition. Along with other toxic effects, fluoride was shown to induce oxidative stress leading to excessive generation of ROS, lipid peroxidation, decrease in the GSH/GSSH ratio, and alterations in activities of antioxidant enzymes, as well as to inhibit glycolysis thus causing the depletion of cellular ATP and disturbances in cellular metabolism. Fluoride triggers the disruption of mitochondria outer membrane and release of cytochrome c into cytosol, what activates caspases-9 and -3 (intrinsic) apoptotic pathway. Extrinsic (death receptor) Fas/FasL-caspase-8 and -3 pathway was also described to be implicated in fluoride-induced apoptosis. Fluoride decreases the ratio of antiapoptotic/proapoptotic Bcl-2 family proteins and upregulates the expression of p53 protein. Finally, fluoride changes the expression profile of apoptosis-related genes and causes endoplasmic reticulum stress leading to inhibition of protein synthesis. 1. Introduction Fluorine (F), a member of the halogen family, is the most electronegative and reactive of all the elements of Periodic table. Elemental fluorine does not exist in nature but forms inorganic and organic compounds called fluorides representing approximately 0.06–0.09% of the Earth’s crust. Fluorides are released into environment through a combination of natural and anthropogenic processes; therefore, their concentrations in the environment are highly variable. Natural processes include the weathering and dissolution of fluoride-rich minerals, emissions from volcanoes, geothermal activity, and marine aerosols [1, 2]. Fluoride levels in surface waters depend on geographical location and proximity to emission sources but are generally low, ranging from 0.01 to 0.3?mg/L in freshwater and from 1.2 to 1.5?mg/L in seawater. However, high fluoride concentrations (3?mg/L and greater) are common in the groundwaters at many geographical areas rich with fluoride-containing rocks. These regions include East African Rift system (from Jordan in
References
[1]
R. Fuge, “Sources of halogens in the environment, influences on human and animal health,” Environmental Geochemistry and Health, vol. 10, no. 2, pp. 51–61, 1988.
[2]
R. B. Symonds, W. I. Rose, and M. H. Reed, “Contribution of Cl- and F-bearing gases to the atmosphere by volcanoes,” Nature, vol. 334, no. 6181, pp. 415–418, 1988.
[3]
WHO (World Health Organization), K. Bailey, J. Chilton et al., Eds., Fluoride in Drinking Water, WHO Press, Geneva, Switzerland, 2006.
[4]
Environmental Health Criteria (EHC) 227, Fluorides, World Health Organization, Geneva, Switzerland, 2002.
[5]
F. M. Fordyce, K. Vrana, E. Zhovinsky et al., “A health risk assessment for fluoride in Central Europe,” Environmental Geochemistry and Health, vol. 29, no. 2, pp. 83–102, 2007.
[6]
M. H. Wong, K. F. Fung, and H. P. Carr, “Aluminium and fluoride contents of tea, with emphasis on brick tea and their health implications,” Toxicology Letters, vol. 137, no. 1-2, pp. 111–120, 2003.
[7]
G. Pizzo, M. R. Piscopo, I. Pizzo, and G. Giuliana, “Community water fluoridation and caries prevention: a critical review,” Clinical Oral Investigations, vol. 11, no. 3, pp. 189–193, 2007.
[8]
V. Dhar and M. Bhatnagar, “Physiology and toxicity of fluoride,” Indian Journal of Dental Research, vol. 20, no. 3, pp. 350–355, 2009.
[9]
T. Aoba and O. Fejerskov, “Dental fluorosis: chemistry and biology,” Critical Reviews in Oral Biology and Medicine, vol. 13, no. 2, pp. 155–170, 2002.
[10]
Q. Q. Tang, J. Du, H. H. Ma, S. J. Jiang, and X. J. Zhou, “Fluoride and children's intelligence: a meta-analysis,” Biological Trace Element Research, vol. 126, no. 1–3, pp. 115–120, 2008.
[11]
A. L. J. J. Bronckers, D. M. Lyaruu, and P. K. Denbesten, “The impact of fluoride on ameloblasts and the mechanisms of enamel fluorosis,” Journal of Dental Research, vol. 88, pp. 877–893, 2009.
[12]
D. Raja Reddy, “Neurology of endemic skeletal fluorosis,” Neurology India, vol. 57, no. 1, pp. 7–12, 2009.
[13]
K. A. V. R. Krishnamachari, “Skeletal fluorosis in humans: a review of recent progress in the understanding of the disease,” Progress in Food and Nutrition Science, vol. 10, no. 3-4, pp. 279–314, 1986.
[14]
G. M. Whitford, “Intake and metabolism of fluoride,” Advances in Dental Research, vol. 8, no. 1, pp. 5–14, 1994.
[15]
J. Gutknecht and A. Walter, “Hydrofluoric and nitric acid transport through lipid bilayer membranes,” Biochimica et Biophysica Acta, vol. 644, no. 1, pp. 153–156, 1981.
[16]
R. C. Baselt, Disposition of Toxic Drugs and Chemicals in Man, Biomedical Publications, Foster City, Calif, USA, 7th edition, 2004.
[17]
O. Barbier, L. Arreola-Mendoza, and L. M. Del Razo, “Molecular mechanisms of fluoride toxicity,” Chemico-Biological Interactions, vol. 188, no. 2, pp. 319–333, 2010.
[18]
K. Kubota, D. H. Lee, M. Tsuchiya et al., “Fluoride induces endoplasmic reticulum stress in ameloblasts responsible for dental enamel formation,” The Journal of Biological Chemistry, vol. 280, no. 24, pp. 23194–23202, 2005.
[19]
Q. Yan, Y. Zhang, W. Li, and P. K. DenBesten, “Micromolar fluoride alters ameloblast lineage cells in vitro,” Journal of Dental Research, vol. 86, no. 4, pp. 336–340, 2007.
[20]
L. F. Jacinto-Alemán, J. C. Hernández-Guerrero, C. Trejo-Solís, M. D. Jiménez-Farfán, and A. M. Fernández-Presas, “In vitro effect of sodium fluoride on antioxidative enzymes and apoptosis during murine odontogenesis,” Journal of Oral Pathology and Medicine, vol. 39, no. 9, pp. 709–714, 2010.
[21]
H. Karube, G. Nishitai, K. Inageda, H. Kurosu, and M. Matsuoka, “NaF activates MAPKs and induces apoptosis in odontoblast-like cells,” Journal of Dental Research, vol. 88, no. 5, pp. 461–465, 2009.
[22]
W. J. Qu, D. B. Zhong, P. F. Wu, J. F. Wang, and B. Han, “Sodium fluoride modulates caprine osteoblast proliferation and differentiation,” Journal of Bone and Mineral Metabolism, vol. 26, no. 4, pp. 328–334, 2008.
[23]
X. Yan, C. Feng, Q. Chen et al., “Effects of sodium fluoride treatment in vitro on cell proliferation, apoptosis and caspase-3 and caspase-9 mRNA expression by neonatal rat osteoblasts,” Archives of Toxicology, vol. 83, no. 5, pp. 451–458, 2009.
[24]
S. Yang, Z. Wang, C. Farquharson et al., “Sodium fluoride induces apoptosis and alters bcl-2 family protein expression in MC3T3-E1 osteoblastic cells,” Biochemical and Biophysical Research Communications, vol. 410, no. 4, pp. 910–915, 2011.
[25]
E. V. Thrane, M. Refsnes, G. H. Thoresen, M. L?g, and P. E. Schwarze, “Fluoride-induced apoptosis in epithelial lung cells involves activation of MAP kinases p38 and possibly JNK,” Toxicological Sciences, vol. 61, no. 1, pp. 83–91, 2001.
[26]
M. Refsnes, P. E. Schwarze, J. A. Holme, and M. L?g, “Fluoride-induced apoptosis in human epithelial lung cells (A549 cells): role of different G protein-linked signal systems,” Human and Experimental Toxicology, vol. 22, no. 3, pp. 111–123, 2003.
[27]
H. Xu, X. Q. Jin, L. Jing, and G. S. Li, “Effect of sodium fluoride on the expression of Bcl-2 family and osteopontin in rat renal tubular cells,” Biological Trace Element Research, vol. 109, no. 1, pp. 55–60, 2006.
[28]
C. Bai, T. Chen, Y. Cui, T. Gong, X. Peng, and H. M. Cui, “Effect of high fluorine on the cell cycle and apoptosis of renal cells in chickens,” Biological Trace Element Research, vol. 138, no. 1–3, pp. 173–180, 2010.
[29]
A. G. Wang, T. Xia, Q. L. Chu et al., “Effects of fluoride on lipid peroxidation, DNA damage and apoptosis in human embryo hepatocytes,” Biomedical and Environmental Sciences, vol. 17, no. 2, pp. 217–222, 2004.
[30]
X. A. Zhan, M. Wang, Z. R. Xu, W. F. Li, and J. X. Li, “Evaluation of caspase-dependent apoptosis during fluoride-induced liver lesion in pigs,” Archives of Toxicology, vol. 80, no. 2, pp. 74–80, 2006.
[31]
L. F. He and J. G. Chen, “DNA damage, apoptosis and cell cycle changes induced by fluoride in rat oral mucosal cells and hepatocytes,” World Journal of Gastroenterology, vol. 12, no. 7, pp. 1144–1148, 2006.
[32]
Y. Ge, H. Ning, C. Feng et al., “Apoptosis in brain cells of offspring rats exposed to high fluoride and low iodine,” Fluoride, vol. 39, no. 3, pp. 173–178, 2006.
[33]
M. Zhang, A. Wang, T. Xia, and P. He, “Effects of fluoride on DNA damage, S-phase cell-cycle arrest and the expression of NF-κB in primary cultured rat hippocampal neurons,” Toxicology Letters, vol. 179, no. 1, pp. 1–5, 2008.
[34]
Y.-J. Liu, Z.-Z. Guan, Q. Gao, and J.-J. Pei, “Increased level of apoptosis in rat brains and SH-SY5Y cells exposed to excessive fluoride—a mechanism connected with activating JNK phosphorylation,” Toxicology Letters, vol. 204, no. 2-3, pp. 183–189, 2011.
[35]
A. C. Loweth, G. T. Williams, J. H. B. Scarpello, and N. G. Morgan, “Heterotrimeric G-proteins are implicated in the regulation of apoptosis in pancreatic β-cells,” Experimental Cell Research, vol. 229, no. 1, pp. 69–76, 1996.
[36]
J. Elliott, J. H. B. Scarpello, and N. G. Morgan, “Effects of tyrosine kinase inhibitors on cell death induced by sodium fluoride and pertussis toxin in the pancreatic β-cell line, RINm5F,” British Journal of Pharmacology, vol. 132, no. 1, pp. 119–126, 2001.
[37]
H. Wang, B. Zhou, J. Cao, X. Gu, C. Cao, and J. Wang, “Effects of dietary protein and calcium on thymus apoptosis induced by fluoride in female rats (wistar rats),” Environmental Toxicology, vol. 24, no. 3, pp. 218–224, 2009.
[38]
M. Guney, B. Oral, G. Take, S. G. Giray, and T. Mungan, “Effect of fluoride intoxication on endometrial apoptosis and lipid peroxidation in rats: role of vitamins E and C,” Toxicology, vol. 231, no. 2-3, pp. 215–223, 2007.
[39]
M. Guney, B. Oral, H. Demirin, N. Karahan, T. Mungan, and N. Delibas, “Protective effects of vitamins C and E against endometrial damage and oxidative stress in fluoride intoxication,” Clinical and Experimental Pharmacology and Physiology, vol. 34, no. 5-6, pp. 467–474, 2007.
[40]
A. Machalinska, A. Machoy-Mokrzynska, W. Marlicz, I. Stecewicz, and B. Machalinski, “NaF- induced apoptosis in human bone marrow and cord blood CD34 positive cells,” Fluoride, vol. 34, no. 4, pp. 258–263, 2001.
[41]
Z. H. Wang, X. L. Li, Z. Q. Yang, and M. Xu, “Fluorine-induced apoptosis and lipid peroxidation in human hair follicles in vitro,” Biological Trace Element Research, vol. 137, no. 3, pp. 280–288, 2010.
[42]
S. Chouhan and S. J. S. Flora, “Effects of fluoride on the tissue oxidative stress and apoptosis in rats: biochemical assays supported by IR spectroscopy data,” Toxicology, vol. 254, no. 1-2, pp. 61–67, 2008.
[43]
S. Chouhan, V. Lomash, and S. J. S. Flora, “Fluoride-induced changes in haem biosynthesis pathway, neurological variables and tissue histopathology of rats,” Journal of Applied Toxicology, vol. 30, no. 1, pp. 63–73, 2010.
[44]
N. I. Agalakova and G. P. Gusev, “Fluoride-induced death of rat erythrocytes in vitro,” Toxicology in Vitro, vol. 25, no. 8, pp. 1609–1618, 2011.
[45]
C. D. Anuradha, S. Kanno, and S. Hirano, “Oxidative damage to mitochondria is a preliminary step to caspase-3 activation in fluoride-induced apoptosis in HL-60 cells,” Free Radical Biology and Medicine, vol. 31, no. 3, pp. 367–373, 2001.
[46]
J. S. Song, H. Y. Lee, E. Lee, H. J. Hwang, and J. H. Kim, “Cytotoxicity and apoptosis induction of sodium fluoride in human promyelocytic leukemia (HL-60) cells,” Environmental Toxicology and Pharmacology, vol. 11, no. 2, pp. 85–91, 2002.
[47]
S. Otsuki, S. R. M. Morshed, S. A. Chowdhury et al., “Possible link between glycolysis and apoptosis induced by sodium fluoride,” Journal of Dental Research, vol. 84, no. 10, pp. 919–923, 2005.
[48]
A. H. Wyllie, “"where, o death, is thy sting?" A brief review of apoptosis biology,” Molecular Neurobiology, vol. 42, no. 1, pp. 4–9, 2010.
[49]
M. S. Ola, M. Nawaz, and H. Ahsan, “Role of Bcl-2 family proteins and caspases in the regulation of apoptosis,” Molecular and Cellular Biochemistry, vol. 351, pp. 41–58, 2011.
[50]
E. F. Mason and J. C. Rathmell, “Cell metabolism: an essential link between cell growth and apoptosis,” Biochimica et Biophysica Acta, vol. 1813, no. 4, pp. 645–654, 2011.
[51]
L. Li, “The biochemistry and physiology of metallic fluoride: action, mechanism, and implications,” Critical Reviews in Oral Biology and Medicine, vol. 14, no. 2, pp. 100–114, 2003.
[52]
P. C. Sternweis and A. G. Gilman, “Aluminum: a requirement for activation of the regulatory component of adenylate cyclase by fluoride,” Proceedings of the National Academy of Sciences of the United States of America, vol. 79, no. 16 I, pp. 4888–4891, 1982.
[53]
J. Bigay, P. Deterre, C. Pfister, and M. Chabre, “Fluoride complexes of aluminium or beryllium act on G-proteins as reversibly bound analogues of the gamma phosphate of GTP,” The EMBO Journal, vol. 6, no. 10, pp. 2907–2913, 1987.
[54]
T. Higashijima, K. M. Ferguson, P. C. Sternweis, E. M. Ross, M. D. Smigel, and A. G. Gilman, “The effect of activating ligands on the intrinsic fluorescence of guanine nucleotide-binding regulatory proteins,” The Journal of Biological Chemistry, vol. 262, no. 2, pp. 752–756, 1987.
[55]
R. Mittal, M. R. Ahmadian, R. S. Goody, and A. Wittinghofer, “Formation of a transition-state analog of the Ras GTPase reaction by Ras·Gdp, tetrafluoroaluminate, and GTPase-activating proteins,” Science, vol. 273, no. 5271, pp. 115–117, 1996.
[56]
A. Wittinghofer, “Signal transduction via Ras,” Biological Chemistry, vol. 379, no. 8-9, pp. 933–937, 1998.
[57]
P. F. Blackmore, S. B. Bocckino, L. E. Waynick, and J. H. Exton, “Role of a guanine nucleotide-binding regulatory protein in the hydrolysis of hepatocyte phosphatidylinositol 4,5-bisphosphate by calcium-mobilizing hormones and the control of cell calcium,” The Journal of Biological Chemistry, vol. 260, no. 27, pp. 14477–14483, 1985.
[58]
J. Elliott, J. H. B. Scarpello, and N. G. Morgan, “Differential effects of genistein on apoptosis induced by fluoride and pertussis toxin in human and rat pancreatic islets and RINm5F cells,” Journal of Endocrinology, vol. 172, no. 1, pp. 137–143, 2002.
[59]
J. H. Dominguez, J. G.N. Garcia, J. K. Rothrock, D. English, and C. Mann, “Fluoride mobilizes intracellular calcium and promotes Ca2+ influx in rat proximal tubules,” American Journal of Physiology, vol. 261, no. 2, pp. F318–F327, 1991.
[60]
J. G. Garcia, J. Dominguez, and D. English, “Sodium fluoride induces phosphoinositide hydrolysis, Ca2+ mobilization, and prostacyclin synthesis in cultured human endothelium: further evidence for regulation by a pertussis toxin-insensitive guanine nucleotide-binding protein,” American Journal of Respiratory Cell and Molecular Biology, vol. 5, no. 2, pp. 113–124, 1991.
[61]
M. ?u?a, G. J. R. Standke, M. Jeschke, and D. Rohner, “Fluoroaluminate induces pertussis toxin-sensitive protein phosphorylation: differences in MC3T3-E1 osteoblastic and NIH3T3 fibroblastic cells,” Biochemical and Biophysical Research Communications, vol. 235, no. 3, pp. 680–684, 1997.
[62]
M. Susa, “Heterotrimeric G proteins as fluoride targets in bone (review),” International Journal of Molecular Medicine, vol. 3, no. 2, pp. 115–126, 1999.
[63]
P. Wang, A. D. Verin, A. Birukova, L. I. Gilbert-McClain, K. Jacobs, and J. G. N. Garcia, “Mechanisms of sodium fluoride-induced endothelial cell barrier dysfunction: role of MLC phosphorylation,” American Journal of Physiology, vol. 281, no. 6, pp. L1472–L1483, 2001.
[64]
N. V. Bogatcheva, P. Wang, A. A. Birukova, A. D. Verin, and J. G. N. Garcia, “Mechanism of fluoride-induced MAP kinase activation in pulmonary artery endothelial cells,” American Journal of Physiology, vol. 290, no. 6, pp. L1139–L1145, 2006.
[65]
M. Refsnes, H. Kersten, P. E. Schwarze, and M. L?g, “Involvement of protein kinase C in fluoride-induced apoptosis in different types of lung cells,” Annals of the New York Academy of Sciences, vol. 973, pp. 218–220, 2002.
[66]
J. G. Garcia, J. Stasek, V. Natarajan, C. E. Patterson, and J. Dominguez, “Role of protein kinase C in the regulation of prostaglandin synthesis in human endothelium,” American Journal of Respiratory Cell and Molecular Biology, vol. 6, no. 3, pp. 315–325, 1992.
[67]
M. E. Reyland and A. P. Bradford, “PKC and the control of apoptosis, Protein kinase C in cancer signaling and therapy,” in Current Cancer Research, M. G. Kazanietz, Ed., vol. 2, pp. 189–222, 2010.
[68]
G. E. N. Kass and S. Orrenius, “Calcium signaling and cytotoxicity,” Environmental Health Perspectives, vol. 107, no. 1, pp. 25–35, 1999.
[69]
M. J. Berridge, P. Lipp, and M. D. Bootman, “The versatility and universality of calcium signalling,” Nature Reviews Molecular Cell Biology, vol. 1, no. 1, pp. 11–21, 2000.
[70]
C. C. Cummings and M. E. McIvor, “Fluoride-induced hyperkalemia: the role of Ca2+-dependent K+ channels,” American Journal of Emergency Medicine, vol. 6, no. 1, pp. 1–3, 1988.
[71]
J. E. Zerwekh, A. C. Morris, P. K. Padalino, F. Gottschalk, and C. Y. C. Pak, “Fluoride rapidly and transiently raises intracellular calcium in human osteoblasts,” Journal of Bone and Mineral Research, vol. 5, no. 1, pp. S131–S136, 1990.
[72]
Z. Xu, B. Xu, T. Xia et al., “Relationship between intracellular Ca2+ and ROS during fluoride-induced injury in SH-SY5Y cells,” Environmental Toxicology. In press.
[73]
H. Murao, N. Sakagami, T. Iguchi, T. Murakami, and Y. Suketa, “Sodium fluoride increases intracellular calcium in rat renal epithelial cell line NRK-52E,” Biological and Pharmaceutical Bulletin, vol. 23, no. 5, pp. 581–584, 2000.
[74]
A. Kagaya, Y. Uchitomi, A. Kugaya et al., “Differential regulation of intracellular signaling systems by sodium fluoride in rat glioma cells,” Journal of Neurochemistry, vol. 66, no. 4, pp. 1483–1488, 1996.
[75]
H. Matsui, M. Morimoto, K. Horimoto, and Y. Nishimura, “Some characteristics of fluoride-induced cell death in rat thymocytes: cytotoxicity of sodium fluoride,” Toxicology in Vitro, vol. 21, no. 6, pp. 1113–1120, 2007.
[76]
H. Xu, Y. L. Zhou, J. M. Zhang, H. Liu, L. Jing, and G. S. Li, “Effects of fluoride on the intracellular free Ca2+ and Ca2+-ATPase of kidney,” Biological Trace Element Research, vol. 116, no. 3, pp. 279–287, 2007.
[77]
Z. Sun, R. Niu, K. Su et al., “Effects of sodium fluoride on hyperactivation and Ca2+ signaling pathway in sperm from mice: an in vivo study,” Archives of Toxicology, vol. 84, no. 5, pp. 353–361, 2010.
[78]
M. Los, S. Maddika, B. Erb, and K. Schulze-Osthoff, “Switching Akt: from survival signaling to deadly response,” BioEssays, vol. 35, pp. 492–495, 2009.
[79]
N. Wettschureck and S. Offermanns, “Rho/Rho-kinase mediated signaling in physiology and pathophysiology,” Journal of Molecular Medicine, vol. 80, no. 10, pp. 629–638, 2002.
[80]
E. Yang, S. B. Jeon, I. Baek, M. J. Song, Y. R. Yoon, and I. K. Kim, “Fluoride induces vascular contraction through activation of RhoA/Rho kinase pathway in isolated rat aortas,” Environmental Toxicology and Pharmacology, vol. 29, no. 3, pp. 290–296, 2010.
[81]
M. A. Lemmon and J. Schlessinger, “Cell signaling by receptor tyrosine kinases,” Cell, vol. 141, no. 7, pp. 1117–1134, 2010.
[82]
F. Vinals, X. Testar, M. Palacin, and A. Zorzano, “Inhibitory effect of fluoride on insulin receptor autophosphorylation and tyrosine kinase activity,” Biochemical Journal, vol. 291, no. 2, pp. 615–622, 1993.
[83]
A. Plotnikov, E. Zehorai, S. Procaccia, and R. Seger, “The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation,” Biochimica et Biophysica Acta, vol. 1813, pp. 1619–1633, 2011.
[84]
L. W. Wu, H. K. Yoon, D. J. Baylink, L. M. Graves, and K. H. W. Lau, “Fluoride at mitogenic doses induces a sustained activation of p44(mapk), but not p42(mapk), in human TE85 osteosarcoma cells,” Journal of Clinical Endocrinology and Metabolism, vol. 82, no. 4, pp. 1126–1135, 1997.
[85]
Y. Zhang, W. Li, H. S. Chi, J. Chen, and P. K. DenBesten, “JNK/c-Jun signaling pathway mediates the fluoride-induced down-regulation of MMP-20 in vitro,” Matrix Biology, vol. 26, no. 8, pp. 633–641, 2007.
[86]
Q. Chen, Z. Wang, Y. Xiong, X. Zou, and Z. Liu, “Comparative study of p38 MAPK signal transduction pathway of peripheral blood mononuclear cells from patients with coal-combustion-type fluorosis with and without high hair selenium levels,” International Journal of Hygiene and Environmental Health, vol. 213, no. 5, pp. 381–386, 2010.
[87]
G. Gloire, E. Charlier, and J. Piette, “Regulation of CD95/APO-1/Fas-induced apoptosis by protein phosphatases,” Biochemical Pharmacology, vol. 76, no. 11, pp. 1451–1458, 2008.
[88]
M. R. Junttila, S. P. Li, and J. Westermarck, “Phosphatase-mediated crosstalk between MAPK signaling pathways in the regulation of cell survival,” The FASEB Journal, vol. 22, no. 4, pp. 954–965, 2008.
[89]
E. Shacter-Noiman and P. B. Chock, “Properties of a Mr = 38,000 phosphoprotein phosphatase. Modulation by divalent cations, ATP, and fluoride,” The Journal of Biological Chemistry, vol. 258, no. 7, pp. 4214–4219, 1983.
[90]
R. Franco, C. D. Bortner, and J. A. Cidlowski, “Potential roles of electrogenic ion transport and plasma membrane depolarization in apoptosis,” Journal of Membrane Biology, vol. 209, no. 1, pp. 43–58, 2006.
[91]
T. I. Ivanova, N. I. Agalakova, and G. P. Gusev, “Activation of sodium transport in rat erythrocytes by inhibition of protein phosphatases 1 and 2A,” Comparative Biochemistry and Physiology B, vol. 145, no. 1, pp. 60–67, 2006.
[92]
N. I. Agalakova and G. P. Gusev, “Diverse effects of fluoride on Na+ and K+ transport across the rat erythrocyte membrane,” Fluoride, vol. 41, pp. 28–39, 2008.
[93]
C. Lytle, “Activation of the avian erythrocyte Na-K-Cl cotransport protein by cell shrinkage, cAMP, fluoride, and calyculin-A involves phosphorylation at common sites,” The Journal of Biological Chemistry, vol. 272, no. 24, pp. 15069–15077, 1997.
[94]
G. P. Gusev and N. I. Agalakova, “Regulation of K-Cl cotransport in erythrocytes of frog Rana temporaria by commonly used protein kinase and protein phosphatase inhibitors,” Journal of Comparative Physiology B, vol. 180, no. 3, pp. 385–391, 2010.
[95]
R. Franco and J. A. Cidlowski, “Apoptosis and glutathione: beyond an antioxidant,” Cell Death and Differentiation, vol. 16, no. 10, pp. 1303–1314, 2009.
[96]
D. Chlubek, “Fluoride and oxidative stress,” Fluoride, vol. 36, no. 4, pp. 217–228, 2003.
[97]
G. B. Reddy, A. L. Khandare, P. Y. Reddy, G. S. Rao, N. Balakrishna, and I. Srivalli, “Antioxidant defense system and lipid peroxidation in patients with skeletal fluorosis and in fluoride-intoxicated rabbits,” Toxicological Sciences, vol. 72, no. 2, pp. 363–368, 2003.
[98]
J. H. Lee, J. Y. Jung, Y. J. Jeong et al., “Involvement of both mitochondrial- and death receptor-dependent apoptotic pathways regulated by Bcl-2 family in sodium fluoride-induced apoptosis of the human gingival fibroblasts,” Toxicology, vol. 243, no. 3, pp. 340–347, 2008.
[99]
J. A. Izquierdo-Vega, M. Sánchez-Gutiérrez, and L. M. Del Razo, “Decreased in vitro fertility in male rats exposed to fluoride-induced oxidative stress damage and mitochondrial transmembrane potential loss,” Toxicology and Applied Pharmacology, vol. 230, no. 3, pp. 352–357, 2008.
[100]
J. A. Izquierdo-Vega, M. Sánchez-Gutiérrez, and L. M. del Razo, “NADPH oxidase participates in the oxidative damage caused by fluoride in rat spermatozoa. Protective role of α-tocopherol,” Journal of Applied Toxicology, vol. 31, no. 6, pp. 579–588, 2011.
[101]
E. A. García-Montalvo, H. Reyes-Pérez, and L. M. Del Razo, “Fluoride exposure impairs glucose tolerance via decreased insulin expression and oxidative stress,” Toxicology, vol. 263, no. 2-3, pp. 75–83, 2009.
[102]
Y. Y. Wang, B. L. Zhao, X. J. Li, Z. Su, and W. J. Xi, “Spin trapping technique studies on active oxygen radicals from human polymorphonuclear leukocytes during fluoride-stimulated respiratory burst,” Fluoride, vol. 30, no. 1, pp. 5–15, 1997.
[103]
I. Gutowska, I. Baranowska-Bosiacka, M. Ba?kiewicz et al., “Fluoride as a pro-inflammatory factor and inhibitor of ATP bioavailability in differentiated human THP1 monocytic cells,” Toxicology Letters, vol. 196, no. 2, pp. 74–79, 2010.
[104]
J. Ghosh, J. Das, P. Manna, and P. C. Sil, “Cytoprotective effect of arjunolic acid in response to sodium fluoride mediated oxidative stress and cell death via necrotic pathway,” Toxicology in Vitro, vol. 22, no. 8, pp. 1918–1926, 2008.
[105]
Z. Sun, R. Niu, B. Wang et al., “Fluoride-induced apoptosis and gene expression profiling in mice sperm in vivo,” Archives of Toxicology, vol. 85, pp. 1441–1452, 2011.
[106]
Y. M. Shivarajashankara, A. R. Shivashankara, B. P. Gopalakrishna, and S. H. Rao, “Oxidative stress in children with endemic skeletal fluorosis,” Fluoride, vol. 34, pp. 108–113, 2001.
[107]
P. Kalyanalakshmi, M. Vijayabhaskar, and M. Dhananjaya Naidu, “Lipid peroxidation and antioxidant enzyme status of adult males with skeletal fluorosis in Andhra Pradesh, India,” Fluoride, vol. 40, no. 1, pp. 42–45, 2007.
[108]
Y. M. Shivarajashankara, A. R. Shivashankara, P. Gopalakrishna Bhat, and S. Hanumanth Rao, “Effect of fluoride intoxication on lipid peroxidation and antioxidant systems in rats,” Fluoride, vol. 34, no. 2, pp. 108–113, 2001.
[109]
Y. M. Shivarajashankara, A. R. Shivashankara, P. Gopalakrishna Bhat, and S. Hanumanth Rao, “Lipid peroxidation and antioxidant systems in the blood of young rats subjected to chronic fluoride toxicity,” Indian Journal of Experimental Biology, vol. 41, no. 8, pp. 857–860, 2003.
[110]
I. Inkielewicz and J. Krechniak, “Fluoride effects on glutathione peroxidase and lipid peroxidation in rats,” Fluoride, vol. 37, no. 1, pp. 7–12, 2004.
[111]
I. B?aszczyk, E. Grucka-Mamczar, S. Kasperczyk, and E. Birkner, “Influence of methionine upon the concentration of malondialdehyde in the tissues and blood of rats exposed to sodium fluoride,” Biological Trace Element Research, vol. 129, no. 1–3, pp. 229–238, 2009.
[112]
E. Karaoz, M. Oncu, K. Gulle et al., “Effect of chronic fluorosis on lipid peroxidation and histology of kidney tissues in first- and second-generation rats,” Biological Trace Element Research, vol. 102, no. 1–3, pp. 199–208, 2004.
[113]
H. Xu, C. H. Wang, Z. T. Zhao, W. B. Zhang, and G. S. Li, “Role of oxidative stress in osteoblasts exposed to sodium fluoride,” Biological Trace Element Research, vol. 123, no. 1–3, pp. 109–115, 2008.
[114]
J. Jeji, R. Sharma, S. S. Jolly, and S. Pamnani, “Implication of glutathione in endemic fluorosis,” Fluoride, vol. 18, no. 2, pp. 117–119, 1985.
[115]
J. Li and S. Ca, “Recent studies on endemic fluorosis in China,” Fluoride, vol. 27, pp. 125–128, 1994.
[116]
M. Sinha, P. Manna, and P. C. Sil, “A 43?kD protein from the herb, Cajanus indicus L., protects against fluoride induced oxidative stress in mice erythrocytes,” Pathophysiology, vol. 14, no. 1, pp. 47–54, 2007.
[117]
D. Shanthakumari, S. Srinivasalu, and S. Subramanian, “Effect of fluoride intoxication on lipidperoxidation and antioxidant status in experimental rats,” Toxicology, vol. 204, no. 2-3, pp. 219–228, 2004.
[118]
H. A. Hassan and M. I. Yousef, “Mitigating effects of antioxidant properties of black berry juice on sodium fluoride induced hepatotoxicity and oxidative stress in rats,” Food and Chemical Toxicology, vol. 47, no. 9, pp. 2332–2337, 2009.
[119]
M. L. Vani and K. P. Reddy, “Effects of fluoride accumulation on some enzymes of brain and gastrocnemius muscle of mice,” Fluoride, vol. 33, no. 1, pp. 17–26, 2000.
[120]
G. Liu, C. Chai, and L. Cui, “Fluoride causing abnormally elevated serum nitric oxide levels in chicks,” Environmental Toxicology and Pharmacology, vol. 13, no. 3, pp. 199–204, 2003.
[121]
J. J. Lemasters, “Dying a thousand deaths: redundant pathways from different organelles to apoptosis and necrosis,” Gastroenterology, vol. 129, no. 1, pp. 351–360, 2005.
[122]
J. Qin, G. Chai, J. M. Brewer, L. L. Lovelace, and L. Lebioda, “Fluoride inhibition of enolase: crystal structure and thermodynamics,” Biochemistry, vol. 45, no. 3, pp. 793–800, 2006.
[123]
S. A. Feig, S. B. Shohet, and D. G. Nathan, “Energy metabolism in human erythrocytes. I. Effects of sodium fluoride,” Journal of Clinical Investigation, vol. 50, no. 8, pp. 1731–1737, 1971.
[124]
J. H. Jeng, C. C. Hsieh, W. H. Lan et al., “Cytotoxicity of sodium fluoride on human oral mucosal fibroblasts and its mechanisms,” Cell Biology and Toxicology, vol. 14, no. 6, pp. 383–389, 1998.
[125]
M. L. Coleman, E. A. Sahai, M. Yeo, M. Bosch, A. Dewar, and M. F. Olson, “Membrane blebbing during apoptosis results from caspase-mediated activation of ROCK I,” Nature Cell Biology, vol. 3, no. 4, pp. 339–345, 2001.
[126]
L. P. Wen, J. A. Fahrni, S. Troie, J. L. Guan, K. Orth, and G. D. Rosen, “Cleavage of focal adhesion kinase by caspases during apoptosis,” The Journal of Biological Chemistry, vol. 272, no. 41, pp. 26056–26061, 1997.
[127]
S. Nagata, “Apoptotic DNA fragmentation,” Experimental Cell Research, vol. 256, no. 1, pp. 12–18, 2000.
[128]
R. Kim, M. Emi, and K. Tanabe, “Role of mitochondria as the gardens of cell death,” Cancer Chemotherapy and Pharmacology, vol. 57, no. 5, pp. 545–553, 2006.
[129]
C. D. Anuradha, S. Kanno, and S. Hirano, “Fluoride induces apoptosis by caspase-3 activation in human leukemia HL-60 cells,” Archives of Toxicology, vol. 74, no. 4-5, pp. 226–230, 2000.
[130]
B. Xu, Z. Xu, T. Xia et al., “Effects of the Fas/Fas-L pathway on fluoride-induced apoptosis in SH-SY5Y cells,” Environmental Toxicology, vol. 26, no. 1, pp. 86–92, 2011.
[131]
J. Gutiérrez-Salinas, J. A. Morales-González, E. Madrigal-Santillán et al., “Exposure to sodium fluoride produces signs of apoptosis in rat leukocytes,” International Journal of Molecular Sciences, vol. 11, no. 9, pp. 3610–3622, 2010.
[132]
G. Ren, K. Wang, R. Chang et al., “Simultaneous administration of fluoride and selenite regulates proliferation and apoptosis in murine osteoblast-like MC3T3-E1 cells by altering osteoprotegerin,” Biological Trace Element Research, vol. 144, no. 1–3, pp. 1437–1448, 2011.
[133]
C.-H. Chien, H. Sakagami, M. Kouhara, A. Sasaki, K. Matsumoto, and H. Kanegae, “Effect of simulated orthodontic forces on flouride-induced cytotoxicity in MC3T3-E1 osteoblast-like cells,” In Vivo, vol. 23, no. 2, pp. 259–266, 2009.
[134]
A. Burlacu, “Regulation of apoptosis by Bcl-2 family proteins,” Journal of Cellular and Molecular Medicine, vol. 7, no. 3, pp. 249–257, 2003.
[135]
S. Otsuki, K. Sugiyama, O. Amano, T. Yasui, and H. Sakagami, “Negative regulation of NaF-induced apoptosis by Bad-CAII complex,” Toxicology, vol. 287, no. 1–3, pp. 131–136, 2011.
[136]
C. L. Tsai, J. W. Lin, H. K. Kuo et al., “Induction of apoptosis in rabbit oral mucosa by 1.23% acidulated phosphate fluoride gel,” Archives of Toxicology, vol. 82, no. 2, pp. 81–87, 2008.
[137]
W. Sun and J. Yang, “Functional mechanisms for human tumor suppression,” Journal of Cancer, vol. 15, pp. 136–140, 2010.
[138]
O. D.K. Maddocks and K. H. Vousden, “Metabolic regulation by p53,” Journal of Molecular Medicine, vol. 89, no. 3, pp. 237–245, 2011.
[139]
A. G. Wang, Q. L. Chu, W. H. He et al., “Effects on protein and mRNA expression levels of p53 induced by fluoride in human embryonic hepatocytes,” Toxicology Letters, vol. 158, no. 2, pp. 158–163, 2005.
[140]
M. Salgado-Bustamante, M. D. Ortiz-Pérez, E. Calderón-Aranda et al., “Pattern of expression of apoptosis and inflammatory genes in humans exposed to arsenic and/or fluoride,” Science of the Total Environment, vol. 408, no. 4, pp. 760–767, 2010.
[141]
J. Lu, H. Chen, Q. Xu et al., “Comparative proteomics of kidney samples from puffer fish Takifugu rubripes exposed to excessive fluoride: an insight into molecular response to fluorosis,” Toxicology Mechanisms and Methods, vol. 20, no. 6, pp. 345–354, 2010.
[142]
J. Lu, J. Zheng, H. Liu, J. Li, Q. Xu, and K. Chen, “Proteomics analysis of liver samples from puffer fish Takifugu rubripes exposed to excessive fluoride: an insight into molecular response to fluorosis,” Journal of Biochemical and Molecular Toxicology, vol. 24, no. 1, pp. 21–28, 2010.
[143]
J. Lu, Q. Xu, J. Zheng, H. Liu, J. Li, and K. Chen, “Comparative proteomics analysis of cardiac muscle samples from pufferfish Takifugu rubripes exposed to excessive fluoride: initial molecular response to fluorosis,” Toxicology Mechanisms and Methods, vol. 19, no. 6-7, pp. 468–475, 2009.
[144]
H. Okudo, H. Kato, Y. Arakaki, and R. Urade, “Cooperation of ER-60 and BiP in the oxidative refolding of denatured proteins in vitro,” The Journal of Biological Chemistry, vol. 138, no. 6, pp. 773–780, 2005.
[145]
G. Giancarlo, “SMC3 knockdown triggers genomic instability and p53-dependent apoptosis in human and zebrafish cells,” Molecular Cancer, vol. 5, pp. 52–65, 2006.
[146]
F. Chen and V. Castranova, “Nuclear factor-κB, an unappreciated tumor suppressor,” Cancer Research, vol. 67, no. 23, pp. 11093–11098, 2007.
[147]
M. Fu, C. Wang, Z. Li, T. Sakamaki, and R. G. Pestell, “Minireview: cyclin D1: normal and abnormal functions,” Endocrinology, vol. 145, no. 12, pp. 5439–5447, 2004.
[148]
M. Zhang, A. Wang, W. He et al., “Effects of fluoride on the expression of NCAM, oxidative stress, and apoptosis in primary cultured hippocampal neurons,” Toxicology, vol. 236, no. 3, pp. 208–216, 2007.
[149]
C. Y. Liu and R. J. Kaufman, “The unfolded protein response,” Journal of Cell Science, vol. 116, no. 10, pp. 1861–1862, 2003.
[150]
R. Kim, M. Emi, K. Tanabe, and S. Murakami, “Role of the unfolded protein response in cell death,” Apoptosis, vol. 11, no. 1, pp. 5–13, 2006.
[151]
R. Sharma, M. Tsuchiya, and J. D. Bartlett, “Flouride induces endoplasmic reticulum stress and inhibits protein synthesis and secretion,” Environmental Health Perspectives, vol. 116, no. 9, pp. 1142–1146, 2008.
[152]
R. Sharma, M. Tsuchiya, Z. Skobe, B. A. Tannous, and J. D. Bartlett, “The acid test of fluoride: how pH modulates toxicity,” PloS One, vol. 5, no. 5, Article ID e10895, 2010.
[153]
S. Jin, T. Tong, W. Fan et al., “GADD45-induced cell cycle G2-M arrest associates with altered subcellular distribution of cyclin B1 and is independent of p38 kinase activity,” Oncogene, vol. 21, no. 57, pp. 8696–8704, 2002.
[154]
M. Ito, H. Nakagawa, T. Okada, S. Miyazaki, and S. Matsuo, “ER-stress caused by accumulated intracistanal granules activates autophagy through a different signal pathway from unfolded protein response in exocrine pancreas cells of rats exposed to fluoride,” Archives of Toxicology, vol. 83, no. 2, pp. 151–159, 2009.