Fluoride Action Network


This study was planned to determine the molecular basis and causes of damage to the kidney and the liver, which are the most affected tissues in sheep exposed to chronic fluoride. For this purpose, liver and kidney tissues were obtained from sheep with signs of fluorosis in the age range of 4-6 years. The control group consisted of clinically healthy sheep without fluorosis. The apoptotic and oxidative genes expression of target genes was determined using the real qRT-PCR method. According to the control gene (Gapdh) that was detected that in the liver, the apoptotic genes caspase-8, caspase-9, and Bim increased and caspase-3, Bcl-2, and Bak decreased, while in the kidney, caspase-3 and Bax and caspase-8, Bcl-2, Bcl2l-1, Bim, and Bak decreased. According to the 2-?Ct values of the oxidative stress genes, it was determined that Cygb, Gstp1, and Ncf1 genes increased significantly in the fluorosis group and Gpx1, sod1, and sod2 genes decreased significantly. In the kidney tissue, Cygb and Gpx1 increased in the fluorosis group, while sod1, sod2, Gstp1, Ncf1 and Ccs, and Nos2 were found to decrease significantly. As a result, it was shown that apoptosis and oxidative mechanisms are activated in the liver and the kidney tissues of sheep with fluorosis and these parameters have an important role in understanding the molecular basis of tissue damage in fluorosis.

*Original abstract online at https://link.springer.com/article/10.1007/s12011-020-02121-y


  1. Agalakova NI, Gusev GP (2012) Molecular mechanisms of cytotoxicity and apoptosis induced by inorganic fluoride. ISRN Cell Biol:403835

  2. Akinrinade ID, Memudu AE, Ogundele OM (2015) Fluoride and aluminum disturb neuronal morphology, transport functions, cholinesterase, lysosomal and cell cycle activities. Pathophysiology 22(2):105–115

  3. Alt?nta? A, Fidanc? UR, Sel T, Duru Ö, Ba?satan A (2000) Do?al ve endüstriyel florozisli koyunlarda böbrek fonksiyonu ve serum protein elektroforezi. Vet J Ankara Univ 47:105–114

  4. Ayd?n N, Dede S, Tanr?tan?r P (2014) The distribution of minerals in some tissues of sheep with fluorosis. Fluoride 47(1):43–48

  5. Barbier O, Arreola-Mendoza L, Del Razo LM (2010) Molecular mechanisms of fluoride toxicity. Chem Biol Interact 188(2):319–333

  6. Blaszczyk I, Grucka-Mamczar E, Kasperczyk S, Birkner E (2008) Influence of fluoride on rat kidney antioxidant system: effects of methionine and vitamin E. Biol Trace Elem Res 121:51–59

  7. Çetin S, Yur F (2019) Levels of trace elements in muscle and kidney tissues of sheep with fluorosis. Biol Trace Elem Res 174(1):82–84

  8. Chomczynski P, Mackey K (1995) Modification of the TRI reagent procedure for isolation of RNA from polysaccharide- and proteoglycan-rich sources. Biotechniques 19(6):942–945

  9. Choubisa SL (1999) Some observations on endemic fluorosis in domestic animals in Southern Rajasthan (India). Vet Res Commun 23:457–465

  10. Ersan Y, T?ra?o?lu T, Koç E (2015) Farede (Mus musculus) Kronik flor toksikasyonuna kar?? C vitamininin iyile?tirici etkilerinin histopatolojik ve elektroforetik yöntemlerle ara?t?r?lmas?. Ins Nat Appl Sci J 8(2):23–33

  11. Gao J, Song G, Liu M, Wang Y, Yang X (2014) Study on the relationship between renal apoptosis and expression of caspase protein in fluoride induced rat. Wei Sheng Yan Jiu 43(1):96–100

  12. Hassan HA, Yousef MI (2009) Mitigating effects of antioxidant properties of black berry juice on sodium fluoride induced hepatotoxicity and oxidative stress in rats. Food Chem Toxicol 47:2332–2337

  13. Kanagaraj VV, Panneerselvam L, Govindarajan V, Ameeramja J, Perumal E (2015) Caffeic acid, a phyto polyphenol mitigates fluoride induced hepatotoxicity in rats: a possible mechanism. Biofactors 41(2):90–100

  14. Küçüke?men Ç, Sönmez H (2008) Di? hekimli?inde florun, insan vücudu ve di?ler üzerindeki etkilerinin de?erlendirilmesi. Med J SDU 15(3):43–53

  15. Kurtdede E, Pekcan M, Karagül H (2017) Türkiye’de florozis sorunu ve florun biyokimyasal etkile?imi. Ataturk Univ J Vet Sci 12(3):320–326

  16. Lee JH, Jung JY, Jeong YJ, Park JH, Yang KH, Choi NK, Kim SH, Kim WJ (2008) 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 243(3):340–347

  17. Liu J, Cui H, Peng X, Fang J, Zuo Z, Wang H, Wu B, Deng Y, Wang K (2013) Dietary high fluoride induces apoptosis and alters Bcl-2, Bax, and caspase-3 protein expression in the cecal tonsil lymphocytes of broilers. Biol Trace Elem Res 152:25–30

  18. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2???CT method. Methods 25(4):402–408

  19. Luo Q, Cui H, Deng H, Kuang P, Liu H, Lu Y, Fang J, Zuo Z, Deng J, Li Y, Wang X, Zhao L (2017) Histopathological findings of renal tissue induced by oxidative stress due to different concentrations of fluoride. Oncotarget 8(31):50430–50446

  20. Ni J, Li Y, Zhang W, Shu R, Zhong Z (2018) Sodium fluoride causes oxidative stress and apoptosis in cementoblasts. Chem Biol Interact 294:34–39

  21. Quadri JA, Sarwar S, Sinha A, Kalaivani M, Dinda AK, Bagga A et al (2018) Fluoride associated ultrastructural changes and apoptosis in human renal tubule: a pilot study. Hum Exp Toxicol 37(11):1199–1206

  22. ?endil Ç, Bay?u N (1973) ?nsan ve hayvanlarda A?r? ili Do?ubeyaz?t ilçesi köylerinde görülen flor zehirlenmesi ve bunun Van ?li Muradiye ilçesi köylerinde de saptamam?zla ilgili ilk tebli?. Vet J Ankara Univ 10:474–489

  23. Song GH, Gao JP, Chun FW, Chen CY, Yan XY, Guo M et al (2014) Sodium fluoride induces apoptosis in the kidney of rats through caspase-mediated pathways and DNA damage. J Physiol Biochem 70(3):857–868

  24. Tiwari BS, Belenghi B, Levine A (2002) Oxidative stress increased respiration and generation of reactive oxygen species, resulting in ATP depletion, opening of mitochondrial permeability transition, and programmed cell death. Plant Physiol 128(4):1271–1281

  25. TRIZOL RNA isolation protocol—Yale School of Medicine. https://medicine.yale.edu/keck/ycga/Images/TRIZOLRNAIsolation_092107_tcm240-21453.pdf

  26. Yan X, Wang L, Yang X, Qiu Y, Tian X, Lv Y, Tian F, Song G, Wang T (2017) Fluoride induces apoptosis in H9c2 cardiomyocytes via the mitochondrial pathway. Chemosphere 182:159–165

  27. Yüksek V, Dede, S, Ta?p?nar M, Çetin S (2017) The effects of vitamins A, D, E, and C on apoptosis and DNA damage in sodium fluoride-treated renal and osteoblast cell lines. Fluoride 50(3)30: 300–13

  28. Yur F, Mert N, Dede S, De?er Y, Ertekin A, Mert H, Ya?ar S, Do?an I, I??k A (2013) Evaluation of serum lipid fractions and tissue antioxidant levels in sheep with fluorosis. Fluoride 46(2):90–96

  29. Zhao L, Li J, Su J, Snead ML, Ruan J (2016) LS8 cell apoptosis induced by NaF through p-ERK and p-JNK—a mechanism study of dental fluorosis. Acta Odontol Scand 74(7):539–549

  30. 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

  31. Zuo H, Chen L, Kong M, Qiu L, Lu P, Wu P et al (2018) Toxic effects of fluoride on organisms. Life Sci 198:18–24