Research Studies
Study Tracker
Distribution of Fluoride in Plasma, Brain, and Bones and Associated Oxidative Damage After Induced Chronic Fluorosis in Wistar Rats.Abstract
The study was aimed to determine fluoride levels in plasma, brain, and bones of Wistar rats following chronic administration of fluoride at different dose levels and the consequent oxidative damage inflicted in these tissues. Brain histomorphology and bone radiographs were also evaluated to assess the extent of damage in these organs. Eighteen rats were randomly divided into three groups with six animals in each group. Group I served as control and groups II and III received 50 and 100 ppm fluoride in tap water, respectively for 180 days. A dose-dependent rise in the levels of fluoride in plasma, brain, and bones was observed in rats. Significant (P < 0.05) alterations in levels of total thiols, glutathione peroxidase, glutathione reductase, acetylcholinesterase, catalase, superoxide dismutase, lipids, as well as protein peroxidation in blood and brain were observed as compared to control in a dose-dependent manner. Radiological examination of bone revealed thinning of bone cortex with haphazard ossification, reduced bone density, and widening of marrow cavity indicating occurrence of flawed bone remodeling upon chronic fluoride exposure. Improper mineralization in bones of intoxicated rats indirectly reflected reduced bone tensile strength. Moreover, alterations in plasma Ca:P ratio and high levels of fluoride in bone ash indicated that chronic fluoride exposure leads to alterations in the bone matrix further corroborating the radio-graphical findings. Additionally, severe microscopic alterations were recorded in the cerebrum and cerebellum of treated rats which included neuronal necrosis, gliosis, spongiosis, perivascular cuffing, congestion, and hemorrhage which correlated well with oxidative changes induced by fluoride intoxication in the brain tissue of rats.
*Original abstract online at https://link.springer.com/article/10.1007%2Fs12011-021-02782-3
References
1.Ullah R, Zafar MS, Shahani N (2017) Potential fluoride toxicity from oral medicaments: a review. Iran J Basic Med Sci 20:841–848. PubMed PubMed Central Google Scholar
2. Maurya J, Pradhan SN, Seema, Ghosh AK (2020) Evaluation of ground water quality and health risk assessment due to nitrate and fluoride in the Middle Indo-Gangetic plains of India. Hum Ecol Risk Assess An Int J 1–17, https://doi.org/10.1080/10807039.2020.1844559
3. Jha SK, Mishra VK, Sharma DK, Damodaran T (2011) Fluoride in the environment and its metabolism in humans. In: Reviews of Environmental Contamination and Toxicology. Rev Environ Contam Toxicol, pp 121–142
4. Hanse A, Chabukdhara M, GohainBaruah S et al (2019) Fluoride contamination in groundwater and associated health risks in Karbi Anglong District, Assam. Northeast India Environ Monit Assess 191:782. https://doi.org/10.1007/s10661-019-7970-6
5. Johnston NR, Strobel SA (2020) Principles of fluoride toxicity and the cellular response: a review. Arch Toxicol 94:1051–1069
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
7. Strunecka A, Strunecky O (2020) Mechanisms of fluoride toxicity: from enzymes to underlying integrative networks. Appl Sci 10:1–24
8. De Carvalho JG, De Oliveira RC, Buzalaf MAR (2006) Plasmaas an indicator of bone fluoride levels in rats chronically exposed to fluoride. J Appl Oral Sci 14:238–241. https://doi.org/10.1590/s1678-77572006000400005
9. 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
10 Barbier O, Arreola-Mendoza L, Del Razo LM (2010) Molecular mechanisms of fluoride toxicity. Chem Biol Interact 188:319–333
11. Gao Q, Liu YJ, Guan ZZ (2009) Decreased learning and memory ability in rats with fluorosis: increased oxidative stress and reduced cholinesterase activity in the brain. Fluoride 42:277–285
12. 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
13. Baba NA, Raina R, Verma PK, Sultana M (2014) Alterations in plasma and tissue acetylcholinesterase activity following repeated oral exposure of chlorpyrifos alone and in conjunction with fluoride in Wistar rats. Proc Natl Acad Sci India Sect B – Biol Sci 84:969–972. https://doi.org/10.1007/s40011-013-0286-3
14. Mesram N, Nagapuri K, Banala RR et al (2017) Quercetin treatment against NaF induced oxidative stress related neuronal and learning changes in developing rats Quercetin treatment against neuronal and learning changes in rats. J King Saud Univ – Sci 29:221–229. https://doi.org/10.1016/j.jksus.2016.04.002
15. 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
16. 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
17. Basha PM, Rai P, Begum S (2011) Evaluation of fluoride-induced oxidative stress in rat brain: a multigeneration study. Biol Trace Elem Res 142:623–637. https://doi.org/10.1007/s12011-010-8780-4
18. Shivarajashankara YM, Shivashankara AR, Hanumanth Rao S, Gopalakrishna Bhat P (2001) Oxidative stress in children with endemic skeletal fluorosis. Fluoride 34:103–107
19. Tsunoda M, Aizawa Y, Nakano K et al (2005) Changes in fluoride levels in the liver, kidney, and brain and in neurotransmitters of mice after subacute administration of fluoride. Fluoride 38:284–292
20. AOAC (2012) Official methods of analysis, Association of official analytical chemist, 19th edn. Washington D.C, USA, pp 1–21
21. 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
22. Mochnik PA, Frei B, Ames BN (1994) [23] Measurement of antioxidants in human blood plasma. In: Methods in Enzymology. Methods Enzymol, pp 269–279
23. Beutler E (1975) Reduced glutathione (GSH). In Bergmeyen, H.V., Ed., Red blood cell metabolism a manual of biochemical methods, 2nd Edition, Grune and Stratton, New York, 112–114. – References – Scientific Research Publishing. In: book
24. Aebi H (1974) Catalase. In: Methods of enzymatic analysis. Elsevier, pp 673–684
25. 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
26. 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
27. Carlberg I, Mannervik B (1985) [59] Glutathione reductase. Methods Enzymol 113:484–490. https://doi.org/10.1016/S0076-6879(85)13062-4
29. 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
30. Shafiq-Ur-Rehman, (1984) Lead-induced regional lipid peroxidation in brain. Toxicol Lett 21:333–337
31. Drury, R.A.B WEA (1980) Carleton’s histological technique. (1980 edition) | Open Library
32. McPherson CA, Zhang G, Gilliam R et al (2018) An evaluation of neurotoxicity following fluoride exposure from gestational through adult ages in Long-Evans hooded rats. Neurotox Res 34:781–798. https://doi.org/10.1007/s12640-018-9870-x
33. 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
34. Samir D (2017) Study of fluoride-induced haematological alterations and liver oxidative stress in rats. World J Pharm Pharm Sci 211–221. https://doi.org/10.20959/wjpps20175-8989
35. Agalakova NI, Gusev GP (2012) Fluoride induces oxidative stress and ATP depletion in the rat erythrocytes in vitro. Environ Toxicol Pharmacol 34:334–337. https://doi.org/10.1016/j.etap.2012.05.006
36. Umarani V, Muvvala S, Ramesh A et al (2015) Rutin potentially attenuates fluoride-induced oxidative stress-mediated cardiotoxicity, blood toxicity and dyslipidemia in rats. Toxicol Mech Methods 25:143–149. https://doi.org/10.3109/15376516.2014.1003359
37. Prabu SM, Muthumani M (2012) Silibinin ameliorates arsenic induced nephrotoxicity by abrogation of oxidative stress, inflammation and apoptosis in rats. Mol Biol Rep. https://doi.org/10.1007/s11033-012-2029-6
38. Kalyanalakshmi P, Vijayabhaskar M, Dhananjaya Naidu M (2007) Lipid peroxidation and antioxidant enzyme status of adult males with skeletal fluorosis in Andhra Pradesh, India. Fluoride 40:42–45
39. Shanthakumari D, Srinivasalu S, Subramanian S (2004) Effect of fluoride intoxication on lipidperoxidation and antioxidant status in experimental rats. Toxicology 204:219–228. https://doi.org/10.1016/j.tox.2004.06.058
40. Spittle B (1994) Psychopharmacology of fluoride: a review. Int Clin Psychopharmacol 9:79–82. https://doi.org/10.1097/00004850-199400920-00002
41. 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
42. Hamza RZ, El-Shenawy NS, Ismail HAA (2014) Protective effects of blackberry and quercetin on sodium fluoride-induced oxidative stress and histological changes in the hepatic, renal, testis and brain tissue of male rat. J Basic Clin Physiol Pharmacol 26:237–251. https://doi.org/10.1515/jbcpp-2014-0065
43. Narayanaswamy M, Piler MB (2010) Effect of maternal exposure of fluoride on biometals and oxidative stress parameters in developing CNS of rat. Biol Trace Elem Res 133:71–82. https://doi.org/10.1007/s12011-009-8413-y
44. Nabavi SF, Habtemariam S, Jafari M et al (2012) Protective role of gallic acid on sodium fluoride induced oxidative stress in rat brain. Bull Environ Contam Toxicol 89:73–77. https://doi.org/10.1007/s00128-012-0645-4
45. Ge Y, ming, Ning H mei, Gu X li, et al (2013) Effects of high fluoride and low iodine on thyroid function in offspring rats. J Integr Agric 12:502–508. https://doi.org/10.1016/S2095-3119(13)60251-8
46. Shivarajashankara YM, Shivashankara AR, Gopalakrishna Bhat P et al (2002) Histological changes in the brain of young fluoride-intoxicated rats. Fluoride 35:12–21
47. Kakei M, Yoshikawa M (2015) Fluoride exposure may accelerate the osteoporotic change in postmenopausal women: animal model of fluoride-induced osteoporosis. Adv Tech Biol Med 04: https://doi.org/10.4172/2379-1764.1000170
48. Fina BL, Lombarte M, Rigalli JP, Rigalli A (2014) Fluoride increases superoxide production and impairs the respiratory chain in ROS 17/2.8 osteoblastic cells. PLoS One 9:e100768. https://doi.org/10.1371/journal.pone.0100768
49. Jin XQ, Xu H, Shi HY et al (2007) Fluoride-induced oxidative stress of osteoblasts and protective effects of baicalein against fluoride toxicity. Biol Trace Elem Res 116:81–89. https://doi.org/10.1007/BF02685921
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
51. Shanthakumari D, Subramanian DS (2007) Effect of fluoride intoxication on bone tissue of experimental rats. Res J Environ Sci 1:82–92. https://doi.org/10.3923/rjes.2007.82.92
52. Zang ZY, Fan JY, Yen W et al (1996) The effect of nutrition on the development of endemic osteomalacia in patients with skeletal fluorosis. Fluoride – Q Reports 29:20–24
Acknowledgements
The authors thank the Dean, Faculty of Veterinary Science and Animal Husbandry, R S Pura, Jammu, for providing the necessary facilities for conducting the research.