References 1. Ludlow M, Luxton G, Mathew T (2007) Effects of fluoridation of community water supplies for people with chronic kidney disease. Nephrol Dial Transplant 22:2763–2767. https://doi.org/10.1093/ndt/gfm477 Article  PubMed  Google Scholar 2. Council NR (2006) Fluoride in drinking water. National Academies Press, Washington, D.C. Google Scholar 3. Ahmed KM, Bhattacharya P, Hasan MA et al (2004) Arsenic enrichment in groundwater of the alluvial aquifers in

Abstract

The study was designed to determine the fluoride distribution after its oral exposure in drinking water and its associated impact on biochemical, antioxidant markers and histology in the liver, kidney, and heart of male Wistar rats. On 100 ppm exposure, the highest accretion of fluoride occurred in the liver followed by the kidney and heart. Fluoride exposure significantly (p?0.05) increased the plasma levels of dehydrogenase, aminotransferases, kidney injury molecule-1 (KIM-1), and other plasma renal biomarkers but decreased the levels of total plasma proteins and albumin in a dose-dependent manner. Reduction (p?0.05) in the activities of antioxidant enzymes viz. acetylcholinesterase, arylesterase, superoxide dismutase, catalase, glutathione peroxidase, and reductase with increased levels of protein and lipid peroxidation was recorded in the liver, kidney, and heart of fluoride-administered rats. Fluoride exposure (100 ppm) induced lipid peroxidation was highest in kidney (4.4 times) followed by liver (2.6 times) and heart (2.5 times) and as compared to their respective control. The percent rise in protein oxidation at 30% was almost equal in the kidney and liver but was 21.5% in the heart as compared to control. The histopathological alterations observed included congestion and hemorrhage along with degeneration and necrosis of parenchymal cells in hepato-renal tissues and myocardium, severity of which varied in a dose-dependent manner. Taken together, fluoride distribution in the liver, heart, and kidney after chronic fluoride intake correlated well with fluoride-induced hepatic and cardio-renal toxicity in a concentration-dependent manner. These results draw attention that chronic fluoride intake pose a significant health risk for human and animal residents of fluoride endemic areas.


*Original abstract online at https://link.springer.com/article/10.1007%2Fs12011-022-03113-w

References

  1. 1.

    Ludlow M, Luxton G, Mathew T (2007) Effects of fluoridation of community water supplies for people with chronic kidney disease. Nephrol Dial Transplant 22:2763–2767. https://doi.org/10.1093/ndt/gfm477

    Article  PubMed  Google Scholar

  2. 2.

    Council NR (2006) Fluoride in drinking water. National Academies Press, Washington, D.C.

    Google Scholar

  3. 3.

    Ahmed KM, Bhattacharya P, Hasan MA et al (2004) Arsenic enrichment in groundwater of the alluvial aquifers in Bangladesh: an overview. Appl Geochemistry 19:181–200. https://doi.org/10.1016/j.apgeochem.2003.09.006

    CAS  Article  Google Scholar

  4. 4.

    Brahman KD, Kazi TG, Afridi HI et al (2013) Evaluation of high levels of fluoride, arsenic species and other physicochemical parameters in underground water of two sub districts of Tharparkar, Pakistan: a multivariate study. Water Res 47:1005–1020. https://doi.org/10.1016/j.watres.2012.10.042

    CAS  Article  PubMed  Google Scholar

  5. 5.

    ATSDR (2003) Public health statement: toxicological profile for fluorides, hydrogen fluoride, and fluorine Atlanta. U.S. Department of Health and Human Services, Public Health Service, GA

    Google Scholar

  6. 6.

    Srivastava S, Flora SJS (2020) Fluoride in drinking water and skeletal fluorosis: a review of the global impact. Curr Environ Heal reports 7:140–146. https://doi.org/10.1007/s40572-020-00270-9

    CAS  Article  Google Scholar

  7. 7.

    Samal AC, Bhattacharya P, Mallick A et al (2015) A study to investigate fluoride contamination and fluoride exposure dose assessment in lateritic zones of West Bengal, India. Environ Sci Pollut Res 22:6220–6229. https://doi.org/10.1007/s11356-014-3817-4

    CAS  Article  Google Scholar

  8. 8.

    Bhattacharya P, Samal AC, Banerjee S et al (2017) Assessment of potential health risk of fluoride consumption through rice, pulses, and vegetables in addition to consumption of fluoride-contaminated drinking water of West Bengal, India. Environ Sci Pollut Res 24:20300–20314. https://doi.org/10.1007/s11356-017-9649-2

    CAS  Article  Google Scholar

  9. 9.

    Bhattacharya P, Adhikari S, Samal AC et al (2020) Health risk assessment of co-occurrence of toxic fluoride and arsenic in groundwater of Dharmanagar region, North Tripura (India). Groundw Sustain Dev 11:100430. https://doi.org/10.1016/j.gsd.2020.100430

    Article  Google Scholar

  10. 10.

    Demelash H, Beyene A, Abebe Z, Melese A (2019) Fluoride concentration in ground water and prevalence of dental fluorosis in Ethiopian Rift Valley: systematic review and meta-analysis. BMC Public Health 19:1298. https://doi.org/10.1186/s12889-019-7646-8

    Article  PubMed  PubMed Central  Google Scholar

  11. 11.

    García-Pérez A, Pérez-Pérez NG, Flores-Rojas AI et al (2020) Marginalization and fluorosis its relationship with dental caries in rural children in Mexico: a cross-sectional study. Community Dent Health 37:216–222. https://doi.org/10.1922/CDH_00017Perez07

    Article  PubMed  Google Scholar

  12. 12.

    Nopakun J, Messer HH, Voller V (1989) Fluoride absorption from the gastrointestinal tract of rats. J Nutr 119:1411–1417. https://doi.org/10.1093/jn/119.10.1411

    CAS  Article  PubMed  Google Scholar

  13. 13.

    Buzalaf MAR, Whitford GM (2011) Fluoride metabolism. In: Monographs in Oral Science. Karger Publishers, pp 20–36

  14. 14.

    Dharmaratne RW (2019) Exploring the role of excess fluoride in chronic kidney disease: a review. Hum Exp Toxicol 38:269–279. https://doi.org/10.1177/0960327118814161

    CAS  Article  PubMed  Google Scholar

  15. 15.

    Perera T, Ranasinghe S, Alles N, Waduge R (2018) Effect of fluoride on major organs with the different time of exposure in rats. Environ Health Prev Med 23:17. https://doi.org/10.1186/s12199-018-0707-2

    CAS  Article  PubMed  PubMed Central  Google Scholar

  16. 16.

    Santoyo-Sanchez MP, Del Carmen S-L, Arreola-Mendoza L, Barbier OC (2013) Effects of acute sodium fluoride exposure on kidney function, water homeostasis, and renal handling of calcium and inorganic phosphate. Biol Trace Elem Res 152:367–372. https://doi.org/10.1007/s12011-013-9622-y

    CAS  Article  PubMed  Google Scholar

  17. 17.

    Malin AJ, Lesseur C, Busgang SA, et al (2019) Fluoride exposure and kidney and liver function among adolescents in the United States: NHANES, 2013–2016. Environ Int 132: https://doi.org/10.1016/j.envint.2019.105012

  18. 18.

    Basha M, Sujitha N (2011) Chronic fluoride toxicity and myocardial damage: antioxidant offered protection in second generation rats. Toxicol Int 18:99. https://doi.org/10.4103/0971-6580.84260

    Article  PubMed  PubMed Central  Google Scholar

  19. 19.

    Varol E, Varol S (2012) Effect of fluoride toxicity on cardiovascular systems: role of oxidative stress. Arch Toxicol 86:1627–1627. https://doi.org/10.1007/s00204-012-0862-y

    CAS  Article  PubMed  Google Scholar

  20. 20.

    Lopes GO, Ferreira MKM, Davis L et al (2020) Effects of fluoride long-term exposure over the cerebellum: global proteomic profile, oxidative biochemistry, cell density, and motor behavior evaluation. Int J Mol Sci 21:1–20. https://doi.org/10.3390/ijms21197297

    CAS  Article  Google Scholar

  21. 21.

    Chattopadhyay A, Podder S, Agarwal S, Bhattacharya S (2011) Fluoride-induced histopathology and synthesis of stress protein in liver and kidney of mice. Arch Toxicol 85:327–335. https://doi.org/10.1007/s00204-010-0588-7

    CAS  Article  PubMed  Google Scholar

  22. 22.

    Kazory A, Ronco C (2019) Hepatorenal syndrome or hepatocardiorenal syndrome: revisiting basic concepts in view of emerging data. Cardiorenal Med 9:1–7. https://doi.org/10.1159/000492791

    Article  PubMed  Google Scholar

  23. 23.

    Karaoz E, Oncu M, Gulle K et al (2004) Effect of chronic fluorosis on lipid peroxidation and histology of kidney tissues in first- and second-generation rats. Biol Trace Elem Res 102:199–208. https://doi.org/10.1385/BTER:102:1-3:199

    CAS  Article  PubMed  Google Scholar

  24. 24.

    Council NR (1993) Health effects of ingested fluoride. National Academies Press, Washington, D.C.

    Google Scholar

  25. 25.

    Ahmad KR, Noor S, Jabeen S et al (2017) Amelioration by jambul fruit extract of fluoride-induced hepato-nephronal histopathologies and impaired neuromotor capacity in mice. Fluoride 50:2–14

    CAS  Google Scholar

  26. 26.

    Inkielewicz I, Krechniak J (2003) Fluoride content in soft tissues and urine of rats exposed to sodium fluoride in drinking water. Fluoride 36:263–266

    CAS  Google Scholar

  27. 27.

    Inkielewicz I, Czarnowski W, Krechniak J (2003) Determination of fluoride in soft tissues. Fluoride 36:16–20

    CAS  Google Scholar

  28. 28.

    Mochnik PA, Frei B, Ames BN (1994) [23] Measurement of antioxidants in human blood plasma. In: Methods in Enzymology. Methods Enzymol, pp 269–279

  29. 29.

    Aebi H (1974) Catalase. In: Methods of Enzymatic Analysis. Elsevier, pp 673–684

  30. 30.

    Marklund S, Marklund G (1974) Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur J Biochem 47:469–474. https://doi.org/10.1111/j.1432-1033.1974.tb03714.x

    CAS  Article  PubMed  PubMed Central  Google Scholar

  31. 31.

    Hafeman DG, Sunde RA, Hoekstra WG (1974) Effect of dietary selenium on erythrocyte and liver glutathione peroxidase in the rat. J Nutr 104:580–587. https://doi.org/10.1093/jn/104.5.580

    CAS  Article  PubMed  Google Scholar

  32. 32.

    Carlberg I, Mannervik B (1985) [59] Glutathione reductase. Methods Enzymol 113:484–490. https://doi.org/10.1016/S0076-6879(85)13062-4

    CAS  Article  PubMed  Google Scholar

  33. 33.

    Voss G, Sachsse K (1970) Red cell and plasma cholinesterase activities in microsamples of human and animal blood determined simultaneously by a modified acetylthiocholine/DTNB procedure. Toxicol Appl Pharmacol 16:764–772. https://doi.org/10.1016/0041-008X(70)90082-7

    CAS  Article  PubMed  Google Scholar

  34. 34.

    Burlina A, Michielin E, Galzigna L (1977) Characteristics and behaviour of arylesterase in human serum and liver. Eur J Clin Invest 7:17–20. https://doi.org/10.1111/j.1365-2362.1977.tb01564.x

    CAS  Article  PubMed  Google Scholar

  35. 35.

    Shafiq-Ur-Rehman (1984) Lead-induced regional lipid peroxidation in brain. Toxicol Lett 21:333–7

  36. 36.

    Witko-Sarsat V, Friedlander M, Capeillère-Blandin C et al (1996) Advanced oxidation protein products as a novel marker of oxidative stress in uremia. Kidney Int 49:1304–1313. https://doi.org/10.1038/ki.1996.186

    CAS  Article  PubMed  Google Scholar

  37. 37.

    Drury, R.A.B WEA (1980) Carleton’s histological technique. (1980 edition) | Open Library

  38. 38.

    Strunecka A, Strunecky O (2020) Mechanisms of fluoride toxicity: from enzymes to underlying integrative networks. Appl Sci 10:1–24

    Article  Google Scholar

  39. 39.

    Bharti VK, Srivastava RS (2009) Fluoride-induced oxidative stress in rat’s brain and its amelioration by buffalo (bubalus bubalis) pineal proteins and melatonin. Biol Trace Elem Res 130:131–140. https://doi.org/10.1007/s12011-009-8320-2

    CAS  Article  PubMed  Google Scholar

  40. 40.

    Jothiramajayam M, Sinha S, Ghosh M et al (2014) Sodium fluoride promotes apoptosis by generation of reactive oxygen species in human lymphocytes. J Toxicol Environ Heal – Part A Curr Issues 77:1269–1280. https://doi.org/10.1080/15287394.2014.928658

    CAS  Article  Google Scholar

  41. 41.

    Agalakova NI, Gusev GP (2012) Molecular mechanisms of cytotoxicity and apoptosis induced by inorganic fluoride. ISRN Cell Biol 2012:1–16. https://doi.org/10.5402/2012/403835

    CAS  Article  Google Scholar

  42. 42.

    Yan X, Yang X, Hao X et al (2015) Sodium fluoride induces apoptosis in H9c2 cardiomyocytes by altering mitochondrial membrane potential and intracellular ROS level. Biol Trace Elem Res 166:210–215. https://doi.org/10.1007/s12011-015-0273-z

    CAS  Article  PubMed  Google Scholar

  43. 43.

    Sharma P, Verma PK, Sood S, et al (2021) Distribution of fluoride in plasma, brain, and bones and associated oxidative damage after induced chronic fluorosis in Wistar rats. Biol Trace Elem Res 1–12. https://doi.org/10.1007/s12011-021-02782-3

  44. 44.

    Arulkumar M, Vijayan R, Penislusshiyan S et al (2017) Alteration of paraoxonase, arylesterase and lactonase activities in people around fluoride endemic area of Tamil Nadu, India. Clin Chim Acta 471:206–215. https://doi.org/10.1016/j.cca.2017.05.036

    CAS  Article  PubMed  Google Scholar

  45. 45.

    Kant V, Srivastava AK, Verma PK, Raina R (2009) Alterations in biochemical parameters during subacute toxicity of fluoride alone and in conjunction with aluminum sulfate in goats. Biol Trace Elem Res 130:20–30. https://doi.org/10.1007/s12011-008-8311-8

    CAS  Article  PubMed  Google Scholar

  46. 46.

    Raina R, Baba NA, Verma PK et al (2015) Hepatotoxicity induced by subchronic exposure of fluoride and chlorpyrifos in Wistar rats: mitigating effect of ascorbic acid. Biol Trace Elem Res 166:157–162. https://doi.org/10.1007/s12011-015-0263-1

    CAS  Article  PubMed  Google Scholar

  47. 47.

    Adali MK, Varol E, Aksoy F et al (2013) Impaired heart rate recovery in patients with endemic fluorosis. Biol Trace Elem Res 152:310–315. https://doi.org/10.1007/s12011-013-9627-6

    CAS  Article  PubMed  Google Scholar

  48. 48.

    O’Toole TE, Conklin DJ, Bhatnagar A (2008) Environmental risk factors for heart disease. Rev Environ Health 23:167–202. https://doi.org/10.1515/REVEH.2008.23.3.167

    Article  PubMed  Google Scholar

  49. 49.

    Parveen A, Babbar R, Agarwal S et al (2011) Mechanistic clues in the cardioprotective effect of terminalia arjuna bark extract in isoproterenol-induced chronic heart failure in rats. Cardiovasc Toxicol 11:48–57. https://doi.org/10.1007/s12012-010-9099-2

    Article  PubMed  Google Scholar

  50. 50.

    Wang J, Yang J, Cheng X et al (2019) Calcium alleviates fluoride-induced bone damage by inhibiting endoplasmic reticulum stress and mitochondrial dysfunction. J Agric Food Chem 67:10832–10843. https://doi.org/10.1021/acs.jafc.9b04295

    CAS  Article  PubMed  Google Scholar

  51. 51.

    Zhou B Hua, Zhao J, Liu J, et al (2015) Fluoride-induced oxidative stress is involved in the morphological damage and dysfunction of liver in female mice. Chemosphere 139:504–511. https://doi.org/10.1016/j.chemosphere.2015.08.030

  52. 52.

    Ma Y, Niu R, Sun Z et al (2012) Inflammatory responses induced by fluoride and arsenic at toxic concentration in rabbit aorta. Arch Toxicol 86:849–856. https://doi.org/10.1007/s00204-012-0803-9

    CAS  Article  PubMed  Google Scholar

  53. 53.

    Li Y, Berenji GR, Shaba WF et al (2012) Association of vascular fluoride uptake with vascular calcification and coronary artery disease. Nucl Med Commun 33:14–20. https://doi.org/10.1097/MNM.0b013e32834c187e

    CAS  Article  PubMed  Google Scholar

  54. 54.

    Mujahid M, Ramaswamy C, Shanthi Naidu K, Shobha M (2015) Effect of fluoride induced toxicity on cardiac tissue: possible role of oxidative stress in degenerative changes of cardiac tissue. Res J Pharm Biol Chem Sci 6:333–338

    CAS  Google Scholar

  55. 55.

    Akinrinde AS, Tijani M, Awodele OA, Oyagbemi AA (2021) Fluoride-induced hepatotoxicity is prevented by L-arginine supplementation via suppression of oxidative stress and stimulation of nitric oxide production in rats. Toxicol Environ Health Sci 13:57–64. https://doi.org/10.1007/s13530-020-00070-6

    Article  Google Scholar

  56. 56.

    Verma PK, Raina R, Sultana M et al (2016) Acetaminophen induced oxidative and histopathological alterations in hepatic tissue: protective effects of Alstonia scholaris leaf extracts. Pharmacogn J 8:385–391. https://doi.org/10.5530/pj.2016.4.12

    CAS  Article  Google Scholar

  57. 57.

    Xiong X, Liu J, He W et al (2007) Dose–effect relationship between drinking water fluoride levels and damage to liver and kidney functions in children. Environ Res 103:112–116. https://doi.org/10.1016/j.envres.2006.05.008

    CAS  Article  PubMed  Google Scholar

  58. 58.

    Liu Y, O?flaherty C (2017) In vivo oxidative stress alters thiol redox status of peroxiredoxin 1 and 6 and impairs rat sperm quality. Asian J Androl 19:73–79. https://doi.org/10.4103/1008-682X.170863

  59. 59.

    Zhang Z, Zhou B, Wang H et al (2014) Maize purple plant pigment protects against fluoride-induced oxidative damage of liver and kidney in rats. Int J Environ Res Public Health 11:1020–1033. https://doi.org/10.3390/ijerph110101020

    CAS  Article  PubMed  PubMed Central  Google Scholar

  60. 60.

    Lu Y, Luo Q, Cui H, et al (2017) Sodium fluoride causes oxidative stress and apoptosis in the mouse liver. Aging (Albany NY) 9:1623–1639. https://doi.org/10.18632/aging.101257

  61. 61.

    Guo X, ying, Sun G fan, Sun Y chun, (2003) Erratum: Oxidative stress from fluoride-induced hepatotoxicity in rats (Flouride (2003) 36:1 (25–29)). Fluoride 36:83

    Google Scholar

  62. 62.

    Khan AM, Raina R, Dubey N, Verma PK (2018) Effect of deltamethrin and fluoride co-exposure on the brain antioxidant status and cholinesterase activity in Wistar rats. Drug Chem Toxicol 41:123–127. https://doi.org/10.1080/01480545.2017.1321009

    CAS  Article  PubMed  Google Scholar

  63. 63.

    Bonventre JV (2008) Kidney injury molecule-1 (KIM-1): a specific and sensitive biomarker of kidney injury. Scand J Clin Lab Invest 68:78–83. https://doi.org/10.1080/00365510802145059

    CAS  Article  Google Scholar

  64. 64.

    Song C, Fu B, Zhang J et al (2017) Sodium fluoride induces nephrotoxicity via oxidative stress-regulated mitochondrial SIRT3 signaling pathway. Sci Rep 7:672. https://doi.org/10.1038/s41598-017-00796-3

    CAS  Article  PubMed  PubMed Central  Google Scholar

  65. 65.

    Zhan XA, Li JX, Wang M, Xu ZR (2006) Effects of fluoride on growth and thyroid function in young pigs. Fluoride 39:95–100

    CAS  Google Scholar

  66. 66.

    Waikar SS, Sabbisetti V, Ärnlöv J et al (2016) Relationship of proximal tubular injury to chronic kidney disease as assessed by urinary kidney injury molecule-1 in five cohort studies. Nephrol Dial Transplant 31:1460–1470. https://doi.org/10.1093/ndt/gfw203

    CAS  Article  PubMed  PubMed Central  Google Scholar

  67. 67.

    Cárdenas-González MC, Del Razo LM, Barrera-Chimal J et al (2013) Proximal renal tubular injury in rats sub-chronically exposed to low fluoride concentrations. Toxicol Appl Pharmacol 272:888–894. https://doi.org/10.1016/j.taap.2013.07.026

    CAS  Article  PubMed  Google Scholar

Download references

Acknowledgements

The authors thank the Dean, Faculty of Veterinary Science and Animal Husbandry, R S Pura, Jammu, for providing necessary facilities for conducting the research.

Author information

Affiliations

Contributions

All authors contributed to the study conception and design. Dr Priyanka Sharma and Dr Pawan Kumar Verma contributed to the conception, design, and execution of the research work to generate the basic data. Dr Shilpa Sood carried out histopathological work and final editing of the manuscript. Dr Maninder Singh and Ms Deepika contributed to the statistical analysis of data.

Corresponding author

Correspondence to Pawan Kumar Verma.

Ethics declarations

Ethics Approval

The experimental protocol was duly approved by Institutional Animal Ethics Committee (IAEC) vide letter no. 09/IAEC/2020 dated 22/10/2020.