Abstract
Appropriate doses of fluoride (F) have therapeutic action against dental caries, but higher levels can cause disturbances in soft and mineralized tissues. Interestingly, the susceptibility to the toxic effects of F is genetically determined. This study evaluated the effects of F on the liver proteome of mice susceptible (A/J) or resistant (129P3/J) to the effects of F. Weanling male A/J (n = 12) and 129P3/J (n = 12) mice were housed in pairs and assigned to two groups given low-F food and drinking water containing 15 or 50 ppm F for 6 weeks. Liver proteome profiles were examined using nano-LC-ESI-MS/MS. Difference in expression among the groups was determined using the PLGS software. Treatment with the lower F concentration provoked more pronounced alterations in fold change in liver proteins in comparison to the treatment with the higher F concentration. Interestingly, most of the proteins with fold change upon treatment with 15 ppm F were increased in the A/J mice compared with their 129P3/J counterparts, suggesting an attempt of the former to fight the deleterious effects of F. However, upon treatment with 50 ppm F, most proteins with fold change were decreased in the A/J mice compared with their 129P3/J counterparts, especially proteins related to oxidative stress and protein folding, which might be related to the higher susceptibility of the A/J animals to the deleterious effects of F. Our findings add light into the mechanisms underlying genetic susceptibility to fluorosis.
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References
Buzalaf MA, Levy SM (2011) Fluoride intake of children: considerations for dental caries and dental fluorosis. Monogr Oral Sci 22:1–19
Rugg-Gunn AJ, Villa AE, Buzalaf MR (2011) Contemporary biological markers of exposure to fluoride. Monogr Oral Sci 22:37–51
Buzalaf MA, Whitford GM (2011) Fluoride metabolism. Monogr Oral Sci 22:20–36
Aoba T, Fejerskov O (2002) Dental fluorosis: chemistry and biology. Crit Rev Oral Biol Med 13:155–170
Krishnamachari KA (1986) Skeletal fluorosis in humans: a review of recent progress in the understanding of the disease. Prog Food Nutr Sci 10:279–314
Pushpalatha T, Srinivas M, Sreenivasula Reddy P (2005) Exposure to high fluoride concentration in drinking water will affect spermatogenesis and steroidogenesis in male albino rats. Biometals 18:207–212
Zhang S, Jiang C, Liu H, Guan Z, Zeng Q, Zhang C, Lei R, Xia T, Gao H, Yang L, Chen Y, Wu X, Zhang X, Cui Y, Yu L, Wang Z, Wang A (2013) Fluoride-elicited developmental testicular toxicity in rats: roles of endoplasmic reticulum stress and inflammatory response. Toxicol Appl Pharmacol 271:206–215
Ge YM, Ning HM, Wang SL, Wang JD (2005) DNA damage in thyroid gland cells of rats exposed to longterm intake of high fluoride and low iodine. Fluoride 38:318–323
Susheela AK, Bhatnagar M, Vig K, Mondal NK (2005) Excess fluoride ingestion and thyroid hormone derangements in children living in Delhi, India. Fluoride 38:98–108
Chen T, Cui HM, Cui Y, Bai CM, Gong T (2011) Decreased antioxidase activities and oxidative stress in the spleen of chickens fed on high-fluorine diets. Hum Exp Toxicol 30:1282–1286
Podder S, Chattopadhyay A, Bhattacharya S, Ray MR (2010) Histopathology and cell cycle alteration in the spleen of mice from low and high doses of sodium fluoride. Fluoride 43:237–245
Pereira HABD, Leite AD, Charone S, Lobo JGVM, Cestari TM, Peres-Buzalaf C et al (2013) Proteomic analysis of liver in rats chronically exposed to fluoride. PLoS One 8
Kobayashi CAN, Leite AL, Silva TL, Santos LD, Nogueira FCS, Oliveiraa RC et al (2009) Proteomic analysis of kidney in rats chronically exposed to fluoride. Chem Biol Interact 180:305–311
Carvalho JG, Leite AD, Peres-Buzalaf C, Salvato F, Labate CA, Everett ET et al (2013) Renal proteome in mice with different susceptibilities to fluorosis. PLoS One 8
Mullenix PJ, Denbesten PK, Schunior A, Kernan WJ (1995) Neurotoxicity of sodium-fluoride in rats. Neurotoxicol Teratol 17:169–177
Niu RY, Zhang YL, Liu SL, Liu FY, Sun ZL, Wang JD (2015) Proteome alterations in cortex of mice exposed to fluoride and lead. Biol Trace Elem Res 164:99–105
Manji F, Baelum V, Fejerskov O (1986) Dental fluorosis in an area of Kenya with 2 ppm fluoride in the drinking-water. J Dent Res 65:659–662
Manji F, Baelum V, Fejerskov O, Gemert W (1986) Enamel changes in 2 low-fluoride areas of Kenya. Caries Res 20:371–380
Yoder KM, Mabelya L, Robison VA, Dunipace AJ, Brizendine EJ, Stookey GK (1998) Severe dental fluorosis in a Tanzanian population consuming water with negligible fluoride concentration. Community Dent Oral Epidemiol 26:382–393
Everett ET, McHenry MAK, Reynolds N, Eggertsson H, Sullivan J, Kantmann C et al (2002) Dental fluorosis: variability among different inbred mouse strains. J Dent Res 81:794–798
Carvalho JG, Leite AL, Yan D, Everett ET, Whitford GM, Buzalaf MAR (2009) Influence of genetic background on fluoride metabolism in mice. J Dent Res 88:1054–1058
Khan ZN, Leite AL, Charone S, IT Sabino TM, Pereira HABS et al (2016) Liver proteome of mice with different genetic susceptibilities to the effects of fluoride. J Appl Oral Sci:250–257
Taves DR (1968) Separation of fluoride by rapid diffusion using hexamethyldisiloxane. Talanta 15:969–96&
Lobo JGVM, Leite AL, Pereira HABS, Fernandes MS, Peres-Buzalaf C, Sumida DH et al (2015) Low-level fluoride exposure increases insulin sensitivity in experimental diabetes. J Dent Res 94:990–997
Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254
Leite AL, Lobo JGVM, Pereira HABD, Fernandes MS, Martini T, Zucki F et al (2014) Proteomic analysis of gastrocnemius muscle in rats with streptozotocin-induced diabetes and chronically exposed to fluoride. PLoS One 9
Bauer-Mehren A (2013) Integration of genomic information with biological networks using Cytoscape. Methods Mol Biol 1021:37–61
Orchard S (2012) Molecular interaction databases. Proteomics 12:1656–1662
Millan PP (2013) Visualization and analysis of biological networks. Methods Mol Biol 1021:63–88
Lima Leite A, Gualiume Vaz J, Lobo M, Barbosa HA, da Silva Pereira M, Silva Fernandes T, Martini FZ et al (2014) Proteomic analysis of gastrocnemius muscle in rats with streptozotocin-induced diabetes and chronically exposed to fluoride. PLoS One 9:e106646
Buzalaf MA, Caroselli EE, Cardoso de Oliveira R, Granjeiro JM, Whitford GM (2004) Nail and bone surface as biomarkers for acute fluoride exposure in rats. J Anal Toxicol 28:249–252
Buzalaf MA, Caroselli EE, de Carvalho JG, de Oliveira RC, da Silva Cardoso VE, Whitford GM (2005) Bone surface and whole bone as biomarkers for acute fluoride exposure. J Anal Toxicol 29:810–813
Kobayashi CA, Leite AL, Silva TL, Santos LD, Nogueira FC, Oliveira RC et al (2009) Proteomic analysis of kidney in rats chronically exposed to fluoride. Chem Biol Interact 180:305–311
Pereira HA, Leite Ade L, Charone S, Lobo JG, Cestari TM, Peres-Buzalaf C et al (2013) Proteomic analysis of liver in rats chronically exposed to fluoride. PLoS One 8:e75343
Lobo JG, Leite AL, Pereira HA, Fernandes MS, Peres-Buzalaf C, Sumida DH et al (2015) Low-level fluoride exposure increases insulin sensitivity in experimental diabetes. J Dent Res 94(7):990
Zhou BH, Zhao J, Liu J, Zhang JL, Li J, Wang HW (2015) Fluoride-induced oxidative stress is involved in the morphological damage and dysfunction of liver in female mice. Chemosphere 139:504–511
Mukhopadhyay D, Chattopadhyay A (2014) Induction of oxidative stress and related transcriptional effects of sodium fluoride in female zebrafish liver. Bull Environ Contam Toxicol 93:64–70
Sun K, Eriksson SE, Tan Y, Zhang L, Arner ES, Zhang J (2014) Serum thioredoxin reductase levels increase in response to chemically induced acute liver injury. Biochim Biophys Acta 1840:2105–2111
Wang X, Jiang Z, M Xing JF, Su Y, Sun L et al (2014) Interleukin-17 mediates triptolide-induced liver injury in mice. Food Chem Toxicol 71:33–41
Wang ZJ, Lee J, YX Si WW, Yang JM, Yin SJ et al (2014) A folding study of Antarctic krill (Euphausia superba) alkaline phosphatase using denaturants. Int J Biol Macromol 70:266–274
Xiong X, Liu J, He W, Xia T, He P, Chen X, Yang KD, Wang AG (2007) Dose-effect relationship between drinking water fluoride levels and damage to liver and kidney functions in children. Environ Res 103:112–116
Cao J, Chen J, Wang J, Jia R, Xue W, Luo Y, Gan X (2013) Effects of fluoride on liver apoptosis and Bcl-2, Bax protein expression in freshwater teleost, Cyprinus carpio. Chemosphere 91:1203–1212
Zlatkovic J, Todorovic N, Tomanovic N, Boskovic M, Djordjevic S, Lazarevic-Pasti T et al (2014) Chronic administration of fluoxetine or clozapine induces oxidative stress in rat liver: a histopathological study. Eur J Pharm Sci 59:20–30
Carvalho JG, Leite AL, Yan D, Everett ET, Whitford GM, Buzalaf MA (2009) Influence of genetic background on fluoride metabolism in mice. J Dent Res 88:1054–1058
Kobayashi CA, Leite AL, Peres-Buzalaf C, Carvalho JG, Whitford GM, Everett ET et al (2014) Bone response to fluoride exposure is influenced by genetics. PLoS One 9:e114343
Charone S, De Lima Leite A, Peres-Buzalaf C, Silva Fernandes M, Ferreira de Almeida L, Zardin Graeff MS et al (2016) Proteomics of secretory-stage and maturation-stage enamel of genetically distinct mice. Caries Res 50:24–31
Arguelles S, Garcia S, Maldonado M, Machado A, Ayala A (2004) Do the serum oxidative stress biomarkers provide a reasonable index of the general oxidative stress status? Biochim Biophys Acta 1674:251–259
Inkielewicz-Stepniak I, Czarnowski W (2010) Oxidative stress parameters in rats exposed to fluoride and caffeine. Food Chem Toxicol 48:1607–1611
Nabavia SM, Suredac A, Nabavia SF, Latifia AM, Moghaddam AH, Hellioe C (2012) Neuroprotective effects of silymarin on sodium fluoride-induced oxidative stress. J Fluor Chem 1425:79–82
Atmaca N, Atmaca HT, Kanici A, Anteplioglu T (2014) Protective effect of resveratrol on sodium fluoride-induced oxidative stress, hepatotoxicity and neurotoxicity in rats. Food Chem Toxicol 70:191–197
Ekstrand J, Ericsson Y, Rosell S (1977) Absence of protein-bound fluoride from human and blood plasma. Arch Oral Biol 22:229–232
Everett ET, McHenry MA, Reynolds N, Eggertsson H, Sullivan J, Kantmann C et al (2002) Dental fluorosis: variability among different inbred mouse strains. J Dent Res 81:794–798
Iano FG, Ferreira MC, Quaggio GB, Mileni Silva Fernandes MS, Oliveira RC, Ximenes VF et al (2014) Effects of chronic fluoride intake on the antioxidant systems of the liver and kidney in rats. J Fluor Chem 168:212–217
Pereira HA, Dionizio AS, Fernandes MS, Araujo TT, Cestari TM, Buzalaf CP et al (2016) Fluoride intensifies hypercaloric diet-induced ER oxidative stress and alters lipid metabolism. PLoS One 11:e0158121
Dabrowska E, Letko R, Balunowska M (2006) Effect of sodium fluoride on the morphological picture of the rat liver exposed to NaF in drinking water. Adv Med Sci 51(Suppl 1):91–95
Barbier O, Arreola-Mendoza L, Del Razo LM (2010) Molecular mechanisms of fluoride toxicity. Chem Biol Interact 188:319–333
Dunipace AJ, Brizendine EJ, Zhang W, Wilson ME, Miller LL, Katz BP et al (1995) Effect of aging on animal response to chronic fluoride exposure. J Dent Res 74:358–368
Melo CGS, Perles J, Zanoni JN, Souza SRG, Santos EX, Leite AL et al (2017) Enteric innervation combined with proteomics for the evaluation of the effects of chronic fluoride exposure on the duodenum of rats. Sci Rep 7:1070
Bottari NB, Mendes RE, Baldissera MD, Bochi GV, Moresco RN, Leal ML et al (2016) Relation between iron metabolism and antioxidants enzymes and delta-ALA-D activity in rats experimentally infected by Fasciola hepatica. Exp Parasitol 165:58–63
Sassa S (1982) Delta-aminolevulinic acid dehydratase assay. Enzyme 28:133–145
Sassa S (1998) ALAD porphyria. Semin Liver Dis 18:95–101
Shanthakumari D, Srinivasalu S, Subramanian S (2004) Effect of fluoride intoxication on lipidperoxidation and antioxidant status in experimental rats. Toxicology 204:219–228
Wanders RJ, Waterham HR (2006) Biochemistry of mammalian peroxisomes revisited. Annu Rev Biochem 75:295–332
Xu H, Hu LS, Chang M, Jing L, Zhang XY, Li GS (2005) Proteomic analysis of kidney in fluoride-treated rat. Toxicol Lett 160:69–75
Warburg O, Chistian W (1941) Isohering und kristallisation des görungs ferments enolase. Biochem Zool 310:384–421
Hayes JD, Pulford DJ (1995) The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit Rev Biochem Mol Biol 30:445–600
Schroer KT, Gibson AM, Sivaprasad U, Bass SA, Ericksen MB, Wills-Karp M et al (2011) Downregulation of glutathione S-transferase pi in asthma contributes to enhanced oxidative stress. J Allergy Clin Immunol 128:539–548
Pappa A, Chen C, Koutalos Y, Townsend AJ, Vasiliou V (2003) Aldh3a1 protects human corneal epithelial cells from ultraviolet- and 4-hydroxy-2-nonenal-induced oxidative damage. Free Radic Biol Med 34:1178–1189
Lassen N, Pappa A, Black WJ, Jester JV, Day BJ, Min E et al (2006) Antioxidant function of corneal ALDH3A1 in cultured stromal fibroblasts. Free Radic Biol Med 41:1459–1469
Felipo V (2013) Hepatic encephalopathy: effects of liver failure on brain function. Nat Rev Neurosci 14:851–858
Stanley CA (2009) Regulation of glutamate metabolism and insulin secretion by glutamate dehydrogenase in hypoglycemic children. Am J Clin Nutr 90:862S–866S
McGill MR, Sharpe MR, Williams CD, Taha M, Curry SC, Jaeschke H (2012) The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation. J Clin Invest 122:1574–1583
Anuradha CD, Kanno S, Hirano S (2001) Oxidative damage to mitochondria is a preliminary step to caspase-3 activation in fluoride-induced apoptosis in HL-60 cells. Free Radic Biol Med 31:367–373
Chen R, Kang R, Fan XG, Tang D (2014) Release and activity of histone in diseases. Cell Death Dis 5:e1370
Jakubowski H (2006) Pathophysiological consequences of homocysteine excess. J Nutr 136:1741S–1749S
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The authors thank CNPq/TWAS for providing a scholarship to the first author (190145/2013-7).
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Khan, Z.N., Sabino, I.T., de Souza Melo, C.G. et al. Liver Proteome of Mice with Distinct Genetic Susceptibilities to Fluorosis Treated with Different Concentrations of F in the Drinking Water. Biol Trace Elem Res 187, 107–119 (2019). https://doi.org/10.1007/s12011-018-1344-8
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DOI: https://doi.org/10.1007/s12011-018-1344-8