Skip to main content

Advertisement

SpringerLink
Log in

Calcium and Vitamin D Supplementation Effectively Alleviates Dental and Skeletal Fluorosis and Retain Elemental Homeostasis in Mice

  • Published:
Biological Trace Element Research Aims and scope Submit manuscript

Abstract

Fluoride (F) is an essential trace element, but chronic exposure beyond the permissible limit (1.5 ppm) effectuates dental and skeletal fluorosis. Although 200 million people across the world are suffering from toxic manifestations of F, till now proper treatment is not available. In this study, we assessed the effectiveness of calcium and vitamin D supplementation for alleviation of fluorosis. Swiss albino mice were divided into 6 groups; group I—control group (received drinking water ˂ 0.5 ppm F; within the permissible limit), group II—treated with 15 ppm of sodium fluoride (NaF) for 4 months, group III—treated with 15 ppm of NaF for 8 months through drinking water. Group IV—orally treated with 15 ppm NaF for 4 months, thereafter received only drinking water for next 4 months, group V—orally treated with 15 ppm NaF for 4 months, thereafter received drinking water supplemented with calcium and vitamin D (2.5-g calcium kg−1 diet and 1000 IU vitamin D kg−1 diet) for next 4 months, and group VI was treated with 15 ppm of NaF through drinking water as well as supplemented with calcium and vitamin D for 4 months. NaF treatment caused dental fluorosis, skeletal fluorosis, and alteration of bone’s metal profile. Substitution of NaF-containing water with normal drinking water reduced the severity of fluorosis but supplementation of calcium and vitamin D effectively alleviated dental and skeletal fluorosis, reduced F deposition, and retained elemental homeostasis of the bone. Our findings strongly support that calcium and vitamin D act as redeemer of fluorosis.

Graphical Abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Hem JD (1985) Study and interpretation of the chemical characteristic of natural water, Department of the Interior, US Geological Survey, USA, vol 2254

  2. Dey Bhowmik A, Shaw P, Mondal P et al (2019) Incidence of fluorosis and urinary fluoride concentration are not always positively correlated with drinking water fluoride level. Curr Sci 116:1551–1554

    Google Scholar 

  3. Handa BK (1975) Geochemistry and genesis of fluoride-containing ground waters in India. GROUNDWATER 13:275–281

    CAS  Google Scholar 

  4. Johnston NR, Strobel SA (2020) Principles of fluoride toxicity and the cellular response: a review. Arch Toxicol:1–19

  5. 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

    CAS  PubMed  Google Scholar 

  6. World Health Organization. Guidelines for drinking-water quality: recommendations (Vol. 1) WHO 2004

  7. Yamaguchi M (2007) Fluoride and bone metabolism. Clin Calcium 17:217–223

    CAS  PubMed  Google Scholar 

  8. Lyaruu DM, Vermeulen L, Stienen N, Bervoets TJM, DenBesten PK, Bronckers ALJJ (2012) Enamel pits in hamster molars, formed by a single high fluoride dose, are associated with a perturbation of transitional stage ameloblasts. Caries Res 46:575–580

    CAS  PubMed  Google Scholar 

  9. Wen X, Paine ML (2013) Iron deposition and ferritin heavy chain (Fth) localization in rodent teeth. BMC Res Notes 6:1–11

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Dey Bhowmik A, Chattopadhyay A (2019) A review on fluoride induced organotoxicity and genotoxicity in mammals and zebrafish. The nucleus 1-9

  11. Teotia SPS, Teotia M, Singh KP (2004) Highlights of forty years of research on endemic skeletal fluorosis in India. In 4th international workshop on fluorosis prevention and Defluoridation of water 107-125

  12. Wei Y, Zeng B, Zhang H (2018) Comparative proteomic analysis of fluoride treated rat bone provides new insights into the molecular mechanisms of fluoride toxicity. Toxicol Lett 291:39–50

    CAS  PubMed  Google Scholar 

  13. Gupta N, Gupta N, Chhabra P (2016) Image diagnosis: dental and skeletal fluorosis. Perm J 20:105–106

    Google Scholar 

  14. Wang Y, Yin Y, Gilula LA, Wilson AJ (1994) Endemic fluorosis of the skeleton: radiographic features in 127 patients. AJR Am J Roentgenol 162:93–98

    CAS  PubMed  Google Scholar 

  15. Qin X, Wang S, Yu M, Zhang L, Li X, Zuo Z, Zhang X, Wang L (2009) Child skeletal fluorosis from indoor burning of coal in southwestern China. J Environ Public Health 2009:1–7

    Google Scholar 

  16. Cao J, Liu JW, Tang LL et al (2005) Dental and early-stage skeletal fluorosis in children induced by fluoride in brick-tea. Fluoride 38:44–47

    Google Scholar 

  17. Mumtaz N, Pandey G, Labhasetwar PK (2015) Global fluoride occurrence, available technologies for fluoride removal, and electrolytic defluoridation: a review. Crit Rev Environ Sci Technol 45:2357–2389

    CAS  Google Scholar 

  18. Kabir H, Gupta AK, Tripathy S (2020) Fluoride and human health: systematic appraisal of sources, exposures, metabolism, and toxicity. Crit Rev Environ Sci Technol 50:1116–1193

    CAS  Google Scholar 

  19. Mondal P, Chattopadhyay A (2020) Environmental exposure of arsenic and fluoride and their combined toxicity: a recent update. J Appl Toxicol 40:552–566

    CAS  PubMed  Google Scholar 

  20. Narsimha A, Sudarshan V (2017) Contamination of fluoride in groundwater and its effect on human health: a case study in hard rock aquifers of Siddipet, Telangana State, India. Appl Water Sci 7:2501–2512

    CAS  Google Scholar 

  21. Mondal P, Shaw P, Bandyopadhyay A, Dey Bhowmik A, Chakraborty A, Sudarshan M, Chattopadhyay A (2019) Mixture effect of arsenic and fluoride at environmentally relevant concentrations in zebrafish (Danio rerio) liver: expression pattern of Nrf2 and related xenobiotic metabolizing enzymes. Aquat Toxicol 213:105219

    CAS  PubMed  Google Scholar 

  22. Mukhopadhyay D, Priya P, Chattopadhyay A (2015) Sodium fluoride affects zebrafish behaviour and alters mRNA expressions of biomarker genes in the brain: role of Nrf2/Keap1. Environ Toxicol Pharmacol 40:352–359

    CAS  PubMed  Google Scholar 

  23. Manivannan J, Sinha S, Ghosh M et al (2013) Evaluation of multi-endpoint assay to detect genotoxicity and oxidative stress in mice exposed to sodium fluoride. Mutat Res Genet Toxicol Environ Mutagen 751:59–65

    Google Scholar 

  24. Chattopadhyay A, Podder S, Agarwal S et al (2010) Fluoride- induced histopathology and synthesis of stress protein in liver and kidney of mice. Arch Toxicol 85:327–335

    PubMed  Google Scholar 

  25. Podder S, Chattopadhyay A, Bhattacharya S (2010) Histopathology and cell cycle alteration in the spleen of mice from low and high doses of sodium fluoride. FLUORIDE 43:237–245

    CAS  Google Scholar 

  26. Chouhan S, Lomash V, Flora SJS (2010) Fluoride induced changes in haem biosynthesis pathway, neurological variables and tissue histopathology of rats. J Appl Toxicol 30:63–73

    CAS  PubMed  Google Scholar 

  27. Zhu K, Prince RL (2012) Calcium and bone. Clin Biochem 45:936–942

    CAS  PubMed  Google Scholar 

  28. Sasano Y, Nakamura M, Henmi A, Okata H, Suzuki O, Kayaba A, Mayanagi M (2019) Degradation of extracellular matrices propagates calcification during development and healing in bones and teeth. J Oral Biosci 61:149–156

    PubMed  Google Scholar 

  29. Uwitonze AM, Rahman S, Ojeh N et al (2020) Oral manifestations of magnesium and vitamin D inadequacy. J Steroid Biochem Mol Biol 105636

  30. Christakos S, Dhawan P, Porta A, Mady LJ, Seth T (2011) Vitamin D and intestinal calcium absorption. Mol Cell Endocrinol 347:25–29

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Yumol JL, Wakefield CB, Sacco SM, Sullivan PJ, Comelli EM, Ward WE (2018) Bone development in growing female mice fed calcium and vitamin D at lower levels than is present in the AIN-93G reference diet. Bone Rep 8:229–238

    PubMed  PubMed Central  Google Scholar 

  32. Hunt JR, Hunt CD, Zito CA, Idso JP, Johnson LAK (2008) Calcium requirements of growing rats based on bone mass, structure, or biomechanical strength are similar. J Nutr 138:1462–1468

    CAS  PubMed  Google Scholar 

  33. Thylstrup A, Fejerskov O (1978) Clinical appearance of dental fluorosis in permanent teeth in relation to histologic changes. Community Dent Oral Epidemiol 6:315–328

    CAS  PubMed  Google Scholar 

  34. Mithal A, Trivedi N, Gupta SK, Kumar S, Gupta RK (1993) Radiological spectrum of endemic fluorosis: relationship with calcium intake. Skelet Radiol 22:257–261

    CAS  Google Scholar 

  35. de Menezes LMB, Volpato MC, Rosalen PL et al (2003) Bone as a biomarker of acute fluoride toxicity. Forensic Sci Int 137:209–214

    Google Scholar 

  36. Cetin S, Yur F, Taspinar M et al (2019) The effects of some minerals on apoptosis and DNA damage in sodium fluoride-administered renal and osteoblast cell lines. FLUORIDE 52:362–378

    CAS  Google Scholar 

  37. Richards A (1990) Nature and mechanisms of dental fluorosis in animals. J Dent Res 69:701–705

    PubMed  Google Scholar 

  38. Atchley WR, Fitch WM (1991) Gene trees and the origins of inbred strains of mice. Science 254:554–558

    CAS  PubMed  Google Scholar 

  39. Everett ET, McHenry MAK, Reynolds N et al (2002) Dental fluorosis: variability among different inbred mouse strains. J Dent Res 81:794–798

    CAS  PubMed  Google Scholar 

  40. An J, Leeuwenburgh S, Wolke J et al (2016) Mineralization processes in hard tissue: bone. In biomineralization and biomaterials 129-146 Woodhead publishing

  41. Saito M, Marumo KMSKM (2010) Collagen cross-links as a determinant of bone quality: a possible explanation for bone fragility in aging, osteoporosis, and diabetes mellitus. Osteoporos Int 21:195–214

    CAS  PubMed  Google Scholar 

  42. Robinson C (2009) Fluoride and the caries lesion: interactions and mechanism of action. Eur Arch Paediatr Dent 10:136–140

    CAS  PubMed  Google Scholar 

  43. Rezaee T, Bouxsein ML, Karim L (2020) Increasing fluoride content deteriorates rat bone mechanical properties. Bone 136:115369–115376

    CAS  PubMed  Google Scholar 

  44. Wergedal JE, Baylink DJ (1983) Fluoride directly stimulates proliferation and alkaline phosphatase activity of bone-forming cells. Science 222:330–332

    PubMed  Google Scholar 

  45. Khandare AL, Harikumar R, Sivakumar B (2005) Severe bone deformities in young children from vitamin D deficiency and fluorosis in Bihar-India. Calcif Tissue Int 76:412–418

    CAS  PubMed  Google Scholar 

  46. Krishnamachari KA (1986) Skeletal fluorosis in humans: a review of recent progress in the understanding of the disease. Prog Food Nutr Sci 10:279

    CAS  PubMed  Google Scholar 

  47. Chavassieux P (1990) Bone effects of fluoride in animal models in vivo. A review and a recent study. J Bone Miner Res 5:95–99

    Google Scholar 

  48. Cashman KD (2002) Calcium intake, calcium bioavailability and bone health. Br J Nutr 87:169–177

    Google Scholar 

  49. Heidari B, Hajian-Tilaki K, Babaei M (2020) Effectiveness and safety of routine calcium supplementation in postmenopausal women. A narrative review. Diabetes Metab Syndr 14:435–442

    PubMed  Google Scholar 

  50. Bhan A, Rao AD, Rao DS (2010) Osteomalacia as a result of vitamin D deficiency. Endocrinol Metab Clin 39:321–331

    CAS  Google Scholar 

  51. Taylor HC, Elbadawy EH (2006) Renal tubular acidosis type 2 with Fanconi's syndrome, osteomalacia, osteoporosis, and secondary hyperaldosteronism in an adult consequent to vitamin D and calcium deficiency: effect of vitamin D and calcium citrate therapy. Endocr Pract 12:559–567

    PubMed  Google Scholar 

  52. Choudhury P, Gnanasundaram N, Bajoria AA (2018) Fluoride toxicity in rabbits and the role of calcium in prevention of fluoride toxicity. Biomed Pharmacol 11:445–452

    CAS  Google Scholar 

  53. Boink ABTJ, Wemer J, Meulenbelt J, Vaessen HAMG, de Wildt DJ (1994) The mechanism of fluoride-induced hypocalcaemia. Hum ExpToxicol 13:149–155

    CAS  Google Scholar 

  54. Thippeswamy HM, Devananda D, Kumar MN et al (2020) The association of fluoride in drinking water with serum calcium, vitamin D and parathyroid hormone in pregnant women and newborn infants. Eur J Clin Nutr:1–9

  55. Zeng XX, Deng J, Xiang J et al (2020) Protections against toxicity in the brains of rat with chronic fluorosis and primary neurons exposed to fluoride by resveratrol involves nicotinic acetylcholine receptors. J Trace Elem Med Biol:126475

  56. Patil Smita B, Pawar SS (2017) Effect of fluoride ingestion on trace elements on brain and liver of rat Rattus rattus (Wistar). Int J Life Sci 8:125–128

    Google Scholar 

  57. Ranjan R, Swarup D, Patrac RC (2011) Changes in levels of zinc, copper, cobalt, and manganese in soft tissues of fluoride-exposed rabbits. Fluoride 44:83–88

    CAS  Google Scholar 

  58. Karademir B (2010) Effects of fluoride ingestion on serum levels of the trace minerals Co, Mo, Cr, Mn, and Li in adult male mice. Fluoride 43:174–178

    CAS  Google Scholar 

  59. Koller M, Saleh HM (2018) Introductory chapter: an introduction to trace elements. In trace elements-human health and environment 1-7 IntechOpen

  60. Moll R, Davis B (2017) Iron, vitamin B12 and folate. Medicine 45:198–203

    Google Scholar 

  61. Fathima NN, Bose MC, Rao JR, Nair BU (2006) Stabilization of type I collagen against collagenases (type I) and thermal degradation using iron complex. J Inorg Biochem 100:1774–1780

    CAS  PubMed  Google Scholar 

  62. Bray TM, Bettger WJ (1990) The physiological role of zinc as an antioxidant. Free Radic Biol Med 8:281–291

    CAS  PubMed  Google Scholar 

  63. Seo HJ, Cho YE, Kim T, Shin HI, Kwun IS (2010) Zinc may increase bone formation through stimulating cell proliferation, alkaline phosphatase activity and collagen synthesis in osteoblastic MC3T3-E1 cells. Nutr Res Pract 4:356–361

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Lee J, Hosseindoust A, Kim M, Kim KY, Choi YH, Lee SH, Lee SY, Cho HJ, Kang WS, Chae BJ (2020) Biological evaluation of hot-melt extruded nano-selenium and the role of selenium on the expression profiles of selenium-dependent antioxidant enzymes in chickens. Biol Trace Elem Res 194:536–544

    CAS  PubMed  Google Scholar 

  65. Rayman MP (2000) The importance of selenium to human health. Lancet 356:233–241

    CAS  PubMed  Google Scholar 

  66. Osredkar J, Sustar N (2011) Copper and zinc, biological role and significance of copper/zinc imbalance. J Clinic Toxicol S 3:0495–0513

    Google Scholar 

  67. Vincente AR, Manganaris GA, Ortiz CM et al (2014) Nutritional quality of fruits and vegetables. In postharvest handling 69-122 academic press

  68. Li L, Yang X (2018) The essential element manganese, oxidative stress, and metabolic diseases: links and interactions. Oxidative Med Cell Longev:1–12

  69. Gupta AK, Nicol K (2004) The use of sulfur in dermatology. J Drugs Dermatol 3:427–431

    PubMed  Google Scholar 

  70. Nimni ME, Han B, Cordoba F (2007) Are we getting enough sulfur in our diet? Nutr Metab 4:1–12

    Google Scholar 

  71. Kumar S, Trivedi AV (2016) A review on role of nickel in the biological system. Int J Curr Microbiol App Sci 5:719–727

    CAS  Google Scholar 

  72. Rodríguez J, Mandalunis PM (2018) A review of metal exposure and its effects on bone health. J Toxicol 2018:1–11

    Google Scholar 

  73. Gopalakrishnan SB, Viswanathan G (2012) Assessment of fluoride-induced changes on physicochemical and structural properties of bone and the impact of calcium on its control in rabbits. J Bone Miner Metab 30:154–163

    CAS  PubMed  Google Scholar 

  74. Kanwar KC, Singh M (1981) Zinc depletion following experimental fluorosis in mice. Sci Total Environ 22:79–83

    CAS  PubMed  Google Scholar 

  75. Bhatnagar M, Rao P, Bhatnagar C, Bhatnagar R (2003) Trace element concentration in various tissues following fluoride administration to female mice. Indian J Exp Biol 41:652–654

    CAS  PubMed  Google Scholar 

  76. Meireles SS, Andre Dde A, Leida FL, Bocangel JS, Demarco FF (2009) Surface roughness and enamel loss with two microabrasion techniques. J Contemp Dent Pract 10:58–65

    PubMed  Google Scholar 

  77. Train TE, McWhorter AG, Seale NS, Wilson CF, Guo IY (1996) Examination of esthetic improvement and surface alteration following microabrasion in fluorotic human incisors in vivo. Pediatr Dent 18:353–362

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors convey their sincere gratitude to the Centre for Advanced Studies (CAS)-Phase II programme of University Grants Commission (UGC), New Delhi. ADB is thankful to DST-INSPIRE fellowship. PS is grateful to Meritorious Fellowship, UGC. PM is thankful for Junior Research Fellowship, Council of Scientific & Industrial Research (CSIR), India.

Author information

Authors and Affiliations

  1. Department of Zoology, Visva-Bharati, Santiniketan, West Bengal, 731235, India

    Arpan Dey Bhowmik, Pallab Shaw, Paritosh Mondal & Ansuman Chattopadhyay

  2. UGC-DAE Consortium for Scientific Research, Kolkata Centre, 3/LB-8, Bidhan Nagar, Kolkata, 700098, India

    Anindita Chakraborty & Muthammal Sudarshan

Authors
  1. Arpan Dey Bhowmik
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pallab Shaw
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paritosh Mondal
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anindita Chakraborty
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Muthammal Sudarshan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ansuman Chattopadhyay
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ansuman Chattopadhyay.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dey Bhowmik, A., Shaw, P., Mondal, P. et al. Calcium and Vitamin D Supplementation Effectively Alleviates Dental and Skeletal Fluorosis and Retain Elemental Homeostasis in Mice. Biol Trace Elem Res 199, 3035–3044 (2021). https://doi.org/10.1007/s12011-020-02435-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12011-020-02435-x

Keywords

Search

Navigation