Fluoride Action Network

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Abstract

Fluoride is one of the major toxicants in the environment and is often found in drinking water at higher concentrations. Living organisms including humans exposed to high fluoride levels are found to develop mild-to-severe detrimental pathological conditions called fluorosis. Fluoride can cross the hematoencephalic barrier and settle in various brain regions. This accumulation affects the structure and function of both the central and peripheral nervous systems. The neural ultrastructure damages are reflected in metabolic and cognitive activities. Hindrances in synaptic plasticity and signal transmission, early neuronal apoptosis, functional alterations of the intercellular signaling pathway components, improper protein synthesis, dyshomeostasis of the transcriptional and neurotrophic factors, oxidative stress, and inflammatory responses are accounted for the fluoride neurotoxicity. Fluoride causes a decline in brain functions that directly influence the overall quality of life in both humans and animals. Animal studies are widely used to explore the etiology of fluoride-induced neurotoxicity. A good number of these studies support a positive correlation between fluoride intake and toxicity phenotypes closely associated with neurotoxicity. However, the experimental dosages highly surpass the normal environmental concentrations and are difficult to compare with human exposures. The treatment procedures are highly dependent on the dosage, duration of exposure, sex, and age of specimens among other factors which make it difficult to arrive at general conclusions. Our review aims to explore fluoride-induced neuronal damage along with associated histopathological, behavioral, and cognitive effects in experimental models. Furthermore, the correlation of various molecular mechanisms upon fluoride intoxication and associated neurobehavioral deficits has been discussed. Since there is no well-established mechanism to prevent fluorosis, phytochemical-based alleviation of its characteristic indications has been proposed as a possible remedial measure.

Keywords: Excitotoxicity; Experimental fluorosis; Learning and memory; Locomotor behavior; Neurotoxicity; Oxidative stress.

*Original study online at https://link.springer.com/article/10.1007/s12011-022-03242-2

Excerpt:

References

  1. García MG, Borgnino L (2015) Fluoride in the context of the environment. In: Fluorine: Chemistry, Analysis, Function and Effects, 2015, pp. 3–21. https://doi.org/10.1039/9781782628507-00003

  2. Seixas NS, Cohen M, Zevenbergen B et al (2010) Urinary fluoride as an exposure index in aluminum smelting. AIHAJ 61(1):89–94. https://doi.org/10.1080/15298660008984520

    Article  Google Scholar

  3. Choubisa SL, Choubisa D (2016) Status of industrial fluoride pollution and its diverse adverse health effects in man and domestic animals in India. Environ Sci Pollut Res 23(8):7244–7254. https://doi.org/10.1007/s11356-016-6319-8

    CAS  Article  Google Scholar

  4. Roy A, Sengupta S, Das P (2017) Integral approach of adsorption and chemical treatment of fluoride containing wastewater: batch and optimization using RSM. J Environ Chem Eng 5(1):274–282. https://doi.org/10.1016/j.jece.2016.12.003

    CAS  Article  Google Scholar

  5. Perumal E, Paul V, Govindarajan V et al (2013) A brief review on experimental fluorosis. Toxicol Lett 223(2):236–251. https://doi.org/10.1016/j.toxlet.2013.09.005

    CAS  Article  PubMed  Google Scholar

  6. Dhar V, Bhatnagar M (2009) Physiology and toxicity of fluoride. Indian J Dent Res 20(3):350

    Article  Google Scholar

  7. Mullane DM, Baez RJ, Jones S, et al (2016) Fluoride and oral health. Community Dental Health, 33 (2). pp. 69–99. ISSN 0265–539X https://doi.org/10.1922/CDH_3707O%E2%80%99Mullane31

  8. Chachra D, Turner CH, Dunipace AJ et al (1999) The effect of fluoride treatment on bone mineral in rabbits. Calcif Tissue Int 64(4):345–351. https://doi.org/10.1007/s002239900630

    CAS  Article  PubMed  Google Scholar

  9. Kanduti D, Sterbenk P, Artnik B (2016) Fluoride: a review of use and effects on health. Materia socio-medica 28(2):133. https://doi.org/10.5455/msm.2016.28.133-137

    Article  PubMed  PubMed Central  Google Scholar

  10. Ameeramja J, Perumal E (2018). Possible modulatory effect of tamarind seed coat extract on fluoride-induced pulmonary inflammation and fibrosis in rats. Inflammation. 886-95. https://doi.org/10.1007/s10753-018-0743-5

  11. Ameeramja J, Perumal E (2017). Pulmonary fluorosis: a review. Environ Sci Pollut Res 22119-32. https://doi.org/10.1007/s11356-017-9951-z

  12. Kanagaraj VV, Panneerselvam L, Govindarajan V et al (2015) Caffeic acid, a phyto polyphenol mitigates fluoride induced hepatotoxicity in rats: a possible mechanism. BioFactors 41(2):90–100. https://doi.org/10.1002/biof.1203

    CAS  Article  PubMed  Google Scholar

  13. Ekambaram P, Namitha T, Bhuvaneswari S et al (2010) Therapeutic efficacy of Tamarindus indica (L) to protect against fluoride-induced oxidative stress in the liver of female rats. Fluoride 43(2):134

    CAS  Google Scholar

  14. Panneerselvam L, Raghunath A, Perumal E (2017) Acute fluoride poisoning alters myocardial cytoskeletal and AMPK signaling proteins in rats. Int J Cardiol 229:96–101. https://doi.org/10.1016/j.ijcard.2016.11.221

    Article  PubMed  Google Scholar

  15. Panneerselvam L, Raghunath A, Sundarraj K, Perumal E (2019) Acute fluoride exposure alters myocardial redox and inflammatory markers in rats. Mol Biol Rep 46(6):6155–6164. https://doi.org/10.1007/s11033-019-05050-9

    CAS  Article  PubMed  Google Scholar

  16. Dharmaratne RW (2019) Exploring the role of excess fluoride in chronic kidney disease: a review. Hum Exper Toxicol 38(3):269–79

  17. Podder S, Chattopadhyay A, Bhattacharya S et al (2010) Histopathology and cell cycle alteration in the spleen of mice from low and high doses of sodium fluoride. Fluoride 43(4):237

    CAS  Google Scholar

  18. Paul V, Ekambaram P, Jayakumar AR (1998) Effects of sodium fluoride on locomotor behavior and a few biochemical parameters in rats. Environ Toxicol Pharmacol 6(3):187–191. https://doi.org/10.1016/S1382-6689(98)00033-7

    CAS  Article  PubMed  Google Scholar

  19. Ekambaram P, Paul V (2002) Modulation of fluoride toxicity in rats by calcium carbonate and by withdrawal of fluoride exposure. Pharmacol Toxicol 90(2):53–58. https://doi.org/10.1034/j.1600-0773.2002.900201.x

    CAS  Article  PubMed  Google Scholar

  20. Bhatnagar M, Sukhwal P, Suhalka P et al (2011) Effects of fluoride in drinking water on NADPH-diaphorase neurons in the forebrain of mice: a possible mechanism of fluoride neurotoxicity. Fluoride 44(4):195

    CAS  Google Scholar

  21. Niu R, Xue X, Zhao Y et al (2015) Effects of fluoride on microtubule ultrastructure and expression of Tub?1a and Tub?2a in mouse hippocampus. Chemosphere 139:422–427. https://doi.org/10.1016/j.chemosphere.2015.07.011

    CAS  Article  PubMed  Google Scholar

  22. Shalini B, Sharma JD (2015) Beneficial effects of Emblica officinalis on fluoride-induced toxicity on brain biochemical indexes and learning-memory in rats. Toxicol Int 22(1):35. https://doi.org/10.4103/0971-6580.172254

    CAS  Article  PubMed  PubMed Central  Google Scholar

  23. Madhusudhan N, Basha PM, Rai P et al (2010) Effect of maternal fluoride exposure on developing CNS of rats: protective role of Aloe vera, Curcuma longa and Ocimum sanctum. http://nopr.niscair.res.in/handle/123456789/9989

  24. Needham LL, Grandjean P, Heinzow B et al (2011) Partition of environmental chemicals between maternal and fetal blood and tissues. Environ Sci Technol 45(3):1121–6. https://doi.org/10.1021/es1019614

    CAS  Article  PubMed  Google Scholar

  25. Vani ML, Reddy KP (2000) Effects of fluoride accumulation on some enzymes of brain and gastrocnemius muscle of mice. Fluoride 33(1):17–26

    CAS  Google Scholar

  26. Shivarajashankara YM, Shivashankara AR, Bhat PG et al (2002) Histological changes in the brain of young fluoride-intoxicated rats. Fluoride 35(1):12–21

    CAS  Google Scholar

  27. Saunders NR, Liddelow SA, Dziegielewska KM (2012) Barrier mechanisms in the developing brain. Front Pharmacol 3:46. https://doi.org/10.3389/fphar.2012.00046

    Article  PubMed  PubMed Central  Google Scholar

  28. Dec K, ?ukomska A, Maciejewska D et al (2017) The influence of fluorine on the disturbances of homeostasis in the central nervous system. Biol Trace Elem Res 177(2):224–234. https://doi.org/10.1007/s12011-016-0871-4

    CAS  Article  PubMed  Google Scholar

  29. Ge Y, Chen L, Yin Z et al (2018) Fluoride-induced alterations of synapse-related proteins in the cerebral cortex of ICR offspring mouse brain.  Chemosphere 201:874–883

    CAS  Article  Google Scholar

  30. Zhang Z, Xu X, Shen X et al (2008)  Effect of fluoride exposure on synaptic structure of brain areas related to learning-memory in mice.  Fluoride 41:139–143

    CAS  Google Scholar

  31. Zigu Z, Xiaoyu W, Weiwei N et al (2017) Effects of calcium on drinking fluorosis-induced hippocampal synaptic plasticity impairment in the offspring of rats. Transl Neurosci 8(1):191–200. https://doi.org/10.1515/tnsci-2017-0026

    CAS  Article  PubMed  PubMed Central  Google Scholar

  32. Niu R, Chen H, Manthari RK et al (2018) Effects of fluoride on synapse morphology and myelin damage in mouse hippocampus. Chemosphere 194:628–633. https://doi.org/10.1016/j.chemosphere.2017.12.027

    CAS  Article  PubMed  Google Scholar

  33. Zhou Z, Wang H, Zheng B et al (2017) A rat experimental study of the relationship between fluoride exposure and sensitive biomarkers. Biol Trace Elem Res 180(1):100–109. https://doi.org/10.1007/s12011-017-0984-4

    CAS  Article  PubMed  Google Scholar

  34. 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. https://doi.org/10.1002/jat.1474

    CAS  Article  PubMed  Google Scholar

  35. Choi AL, Sun G, Zhang Y, Grandjean P (2012) Developmental fluoride neurotoxicity: a systematic review and meta-analysis. Environ Health Perspect 120(10):1362–1368. https://doi.org/10.1289/ehp.1104912

    CAS  Article  PubMed  PubMed Central  Google Scholar

  36. Bashash M, Marchand M, Hu H et al (2018) Prenatal fluoride exposure and attention deficit hyperactivity disorder (ADHD) symptoms in children at 6–12 years of age in Mexico City. Environ Int 121:658–666. https://doi.org/10.1016/j.envint.2018.09.017

    CAS  Article  PubMed  Google Scholar

  37. Dec K, ?ukomska A, Skonieczna-?ydecka K et al (2019) Long-term exposure to fluoride as a factor promoting changes in the expression and activity of cyclooxygenases (COX1 and COX2) in various rat brain structures. Neurotoxicol 74:81–90. https://doi.org/10.1016/j.neuro.2019.06.001

    CAS  Article  Google Scholar

  38. Nkpaa KW, Onyeso GI (2018) Rutin attenuates neurobehavioral deficits, oxidative stress, neuro-inflammation and apoptosis in fluoride treated rats. Neurosci Lett 682:92–99. https://doi.org/10.1016/j.neulet.2018.06.023

    CAS  Article  PubMed  Google Scholar

  39. Liu M, Chen F, Sha L et al (2014) (?)-Epigallocatechin-3-gallate ameliorates learning and memory deficits by adjusting the balance of TrkA/p75 NTR signaling in APP/PS1 transgenic mice. Mol Neurobiol 49(3):1350–1363. https://doi.org/10.1007/s12035-013-8608-2

    CAS  Article  PubMed  Google Scholar

  40. Li X, Zhang J, Niu R et al (2019) Effect of fluoride exposure on anxiety-and depression-like behavior in mouse. Chemosphere 215:454–460. https://doi.org/10.1016/j.chemosphere.2018.10.070

    CAS  Article  PubMed  Google Scholar

  41. Blaylock RL (2004) Excitotoxicity: a possible central mechanism in fluoride neurotoxicity. Fluoride 37(4):301–314

    CAS  Google Scholar

  42. Strunecka A, Strunecky O (2020) Mechanisms of fluoride toxicity: from enzymes to underlying integrative networks. Appl Sci 10(20):7100. https://doi.org/10.3390/app10207100

    CAS  Article  Google Scholar

  43. Spittle B (2011) Neurotoxic effects of fluoride. Fluoride 44(3): 117. https://apps.webofknowledge.com/CitedFullRecord.do?product=WOS&search_mode=CitedFullRecord&isickref=WOS:000295953600001

  44. Spittlea B, Meiersb RP, Spittle BJ Fluoride Poisoning: is fluoride in your drinking water—and from other sources—making you sick?

  45. Ding LI (1983) The nervous system complications of chronic fluorosis. Chin Endem 2:97–98

    Google Scholar

  46. Bellinger DC (2018) Environmental chemical exposures and neurodevelopmental impairments in children. Ped. Med 1(9). https://doi.org/10.21037/pm.2018.11.03

  47. Chen J, Niu Q, Xia T et al (2018) ERK1/2-mediated disruption of BDNF–TrkB signaling causes synaptic impairment contributing to fluoride–induced developmental neurotoxicity. Toxicol 410:222–230. https://doi.org/10.1016/j.tox.2018.08.009

    CAS  Article  Google Scholar

  48. Sharma C, Suhalka P, Bhatnagar M (2018) Curcumin and resveratrol rescue cortical–hippocampal system from chronic fluoride-induced neurodegeneration and enhance memory retrieval. Int J Neurosci 128(11):1007–1021. https://doi.org/10.1080/00207454.2018.1458727

    CAS  Article  PubMed  Google Scholar

  49. Mullenix PJ, Denbesten PK, Schunior A et al (1995) Neurotoxicity of sodium fluoride in rats. Neurotoxicol Teratol 17(2):169–177. https://doi.org/10.1016/0892-0362(94)00070-T

    CAS  Article  PubMed  Google Scholar

  50. Basha PM, Rai P, Begum S (2011) Fluoride toxicity and status of serum thyroid hormones, brain histopathology, and learning memory in rats: a multigenerational assessment. Biol Trace Elem Res 144(1):1083–1094. https://doi.org/10.1007/s12011-011-9137-3

    CAS  Article  PubMed  Google Scholar

  51. Pereira M, Dombrowski PA, Losso EM et al (2011) Memory impairment induced by sodium fluoride is associated with changes in brain monoamine levels. Neurotox Res 19(1):55–62. https://doi.org/10.1007/s12640-009-9139-5

    CAS  Article  PubMed  Google Scholar

  52. 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(4):781–798. https://doi.org/10.1007/s12640-018-9870-x

    CAS  Article  PubMed  PubMed Central  Google Scholar

  53. Lu F, Zhang Y, Trivedi A et al (2019) Fluoride related changes in behavioral outcomes may relate to increased serotonin. Physiol Behav 206:76–83. https://doi.org/10.1016/j.physbeh.2019.02.017

    CAS  Article  PubMed  PubMed Central  Google Scholar

  54. Zhu W, Zhang J, Zhang Z (2011) Effects of fluoride on synaptic membrane fluidity and PSD-95 expression level in rat hippocampus. Biol Trace Elem Res 139(2):197–203. https://doi.org/10.1007/s12011-010-8654-9

    CAS  Article  PubMed  Google Scholar

  55. Ferreira MK, Aragão WA, Bittencourt LO et al (2021) Fluoride exposure during pregnancy and lactation triggers oxidative stress and molecular changes in hippocampus of offspring rats. Ecotoxicol Environ Saf 208:111437. https://doi.org/10.1016/j.ecoenv.2020.111437

    CAS  Article  PubMed  Google Scholar

  56. Kinawy AA (2019) The potential roles of aluminum chloride and sodium fluoride on the neurotoxicity of the cerebral cortex, hippocampus, and hypothalamus of male rat offspring. J Basic Appl Zool 80(1):1–9. https://doi.org/10.1186/s41936-019-0086-2

    Article  Google Scholar

  57. Joëls M (2008) Functional actions of corticosteroids in the hippocampus. Eur J Pharmacol 583(2–3):312–321. https://doi.org/10.1016/j.ejphar.2007.11.064

    CAS  Article  PubMed  Google Scholar

  58. Lou DD, Guan ZZ, Liu YJ et al (2013) The influence of chronic fluorosis on mitochondrial dynamics morphology and distribution in cortical neurons of the rat brain. Arch Toxicol 87(3):449–457. https://doi.org/10.1007/s00204-012-0942-z

    CAS  Article  PubMed  Google Scholar

  59. Qian W, Miao K, Li T, Zhang Z (2013) Effect of selenium on fluoride induced changes in synaptic plasticity in rat hippocampus. Biol Trace Elem Res 155(2):253–260. https://doi.org/10.1007/s12011-013-9773-x

    CAS  Article  PubMed  Google Scholar

  60. Ekambaram P, Paul V (2001) Calcium preventing locomotor behavioral and dental toxicities of fluoride by decreasing serum fluoride level in rats. Environ Toxicol Pharmacol 9(4):141–146. https://doi.org/10.1016/S1382-6689(00)00063-6

    CAS  Article  PubMed  Google Scholar

  61. Turkekul R, Arihan SK, Yildirim S et al (2020) Effect of acute and chronic fluoride administration on bone histopathology, bone fluoride accumulation, and Locomotor activity in an animal model of Paleopathological fluorosis. Fluoride 53(1):77–89

    CAS  Google Scholar

  62. Bartos M, Gumilar F, Bras C et al (2015) Neurobehavioural effects of exposure to fluoride in the earliest stages of rat development. Physiol Behav 147:205–212. https://doi.org/10.1016/j.physbeh.2015.04.044

    CAS  Article  PubMed  Google Scholar

  63. Banji D, Banji OJ, Pratusha NG et al (2013) Investigation on the role of Spirulina platensis in ameliorating behavioural changes, thyroid dysfunction and oxidative stress in offspring of pregnant rats exposed to fluoride. Food Chem 140(1–2):321–331. https://doi.org/10.1016/j.physbeh.2015.04.044

    CAS  Article  PubMed  Google Scholar

  64. Niu R, Sun Z, Cheng Z et al (2008) Effects of fluoride and lead on N-methyl-D-aspartate receptor 1 expression in the hippocampus of offspring rat pups. Fluoride 41(2):101

    CAS  Google Scholar

  65. Nagy PM, Aubert I (2015) Overexpression of the vesicular acetylcholine transporter enhances dendritic complexity of adult-born hippocampal neurons and improves acquisition of spatial memory during aging. Neurobiol Aging 36(5):1881–1889. https://doi.org/10.1016/j.neurobiolaging.2015.02.021

    CAS  Article  PubMed  Google Scholar

  66. Shan KR, Qi XL, Long YG et al (2004) Decreased nicotinic receptors in PC12 cells and rat brains influenced by fluoride toxicity—a mechanism relating to a damage at the level in post-transcription of the receptor genes. Toxicol 200(2–3):169–177. https://doi.org/10.1016/j.tox.2004.03.013

    CAS  Article  Google Scholar

  67. Anand P, Singh B (2013) A review on cholinesterase inhibitors for Alzheimer’s disease. Arch Pharmacal Res 36(4):375–399. https://doi.org/10.1007/s12272-013-0036-3

    CAS  Article  Google Scholar

  68. Alshogran OY, Khalil AA, Oweis AO et al (2018) Association of brain-derived neurotrophic factor and interleukin-6 serum levels with depressive and anxiety symptoms in hemodialysis patients. Gen Hosp Psychiatry 53:25–31. https://doi.org/10.1016/j.genhosppsych.2018.04.003

    Article  PubMed  Google Scholar

  69. Zhou G, Hu Y, Wang A et al (2021) Fluoride stimulates anxiety-and depression-like behaviors associated with SIK2-CRTC1 signaling dysfunction. J Agric Food Chem 69(45):13618–13627

    CAS  Article  Google Scholar

  70. Bartos M, Gumilar F, Gallegos CE et al (2018) Alterations in the memory of rat offspring exposed to low levels of fluoride during gestation and lactation: involvement of the ?7 nicotinic receptor and oxidative stress. Reprod Toxicol 81:108–114. https://doi.org/10.1016/j.reprotox.2018.07.078

    CAS  Article  PubMed  Google Scholar

  71. Kim YS, Woo J, Lee CJ et al (2017) Decreased glial GABA and tonic inhibition in cerebellum of mouse model for attention-deficit/hyperactivity disorder (ADHD). Exp Neurobiol 26(4):206. https://doi.org/10.5607/2Fen.2017.26.4.206

    Article  PubMed  PubMed Central  Google Scholar

  72. Weston J (2008) Biochemistry of magnesium. Chem Organomagnesium Compd 29:315–367

    Article  Google Scholar

  73. Jiang S, Su J, Yao S et al (2014) Fluoride and arsenic exposure impairs learning and memory and decreases mGluR5 expression in the hippocampus and cortex in rats. PLoS ONE 9(4):e96041. https://doi.org/10.1371/journal.pone.0096041

    CAS  Article  PubMed  PubMed Central  Google Scholar

  74. Strunecka A, Patocka J, Blaylock RL et al (2007) Fluoride interactions: from molecules to disease. Curr Signal Transduct Ther 2(3):190–213. https://doi.org/10.2174/157436207781745300

    CAS  Article  Google Scholar

  75. Strunecka A, Blaylock RL, Patocka J et al (2018) Immunoexcitotoxicity as the central mechanism of etiopathology and treatment of autism spectrum disorders: a possible role of fluoride and aluminum. Surg Neurol Int. https://doi.org/10.4103/2Fsni.sni_407_17

    Article  PubMed  PubMed Central  Google Scholar

  76. Ribeiro DA, Cardoso CM, Yujra VQ et al (2017) Fluoride induces apoptosis in mammalian cells: in vitro and in vivo studies. Anticancer Res 37(9):4767–4777. https://doi.org/10.21873/anticanres.11883

    CAS  Article  PubMed  Google Scholar

  77. von Bartheld CS, Bahney J, Herculano-Houzel S (2016) The search for true numbers of neurons and glial cells in the human brain: a review of 150 years of cell counting. J Comp Neurol 524:3865–3895. https://doi.org/10.1002/cne.24040

    Article  Google Scholar

  78. López-Bayghen E, Rosas S, Castelán F, Ortega A (2007) Cerebellar Bergmann glia: an important model to study neuron–glia interactions. Neuron Glia Biol 3(2):155–167. https://doi.org/10.1017/S1740925X0700066X

    Article  PubMed  Google Scholar

  79. Martínez-Lozada Z, Guillem AM, Flores-Méndez M et al (2013) GLAST/EAAT1-induced glutamine release via SNAT3 in Bergmann glial cells: evidence of a functional and physical coupling. J Neurochem 125:545–554. https://doi.org/10.1111/jnc.12211

    CAS  Article  PubMed  Google Scholar

  80. Dienel GA (2019) Brain glucose metabolism: integration of energetics with function. Physiol Rev 99:949–1045. https://doi.org/10.1152/physrev.00062.2017

    CAS  Article  PubMed  Google Scholar

  81. Sanabria-Castro A, Alvarado-Echeverría I, Monge-Bonilla C (2017) Molecular pathogenesis of Alzheimer’s disease: an update. Ann Neurosci 24(1):46–54. https://doi.org/10.1159/000464422

    Article  PubMed  PubMed Central  Google Scholar

  82. 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. https://doi.org/10.1016/j.etap.2015.07.003

    CAS  Article  PubMed  Google Scholar

  83. Wang R, Reddy PH (2017) Role of glutamate and NMDA receptors in Alzheimer’s disease. J Alzheimers Dis 57(4):1041–1048. https://doi.org/10.3233/JAD-160763

    CAS  Article  PubMed  PubMed Central  Google Scholar

  84. Benarroch EE (2011) Na+, K+-ATPase: functions in the nervous system and involvement in neurologic disease. Neurol 76(3):287–293. https://doi.org/10.1212/WNL.0b013e3182074c2f

    Article  Google Scholar

  85. Benarroch EE (2018) Glutamatergic synaptic plasticity and dysfunction in Alzheimer disease: emerging mechanisms. Neurol 91(3):125–132. https://doi.org/10.1212/WNL.0000000000005807

    Article  Google Scholar

  86. Pivovarova NB, Andrews SB (2010) Calcium-dependent mitochondrial function and dysfunction in neurons. FEBS J 277(18):3622–3636. https://doi.org/10.1111/j.1742-4658.2010.07754.x

    CAS  Article  PubMed  PubMed Central  Google Scholar

  87. Eng LF, Ghirnikar RS, Lee YL (2000) Glial fibrillary acidic protein: GFAP-thirty-one years (1969–2000). Neurochem Res 25(9):1439–1451. https://doi.org/10.1023/A:1007677003387

    CAS  Article  PubMed  Google Scholar

  88. Yang Z, Wang KK (2015) Glial fibrillary acidic protein: from intermediate filament assembly and gliosis to neurobiomarker. Trends Neurosci 38:364–374. https://doi.org/10.1016/j.tins.2015.04.003

    CAS  Article  PubMed  PubMed Central  Google Scholar

  89. Zhang KL, Lou DD, Guan ZZ (2015) Activation of the AGE/RAGE system in the brains of rats and in SH-SY5Y cells exposed to high level of fluoride might connect to oxidative stress. Neurotoxicol Teratol 48:49–55. https://doi.org/10.1016/j.ntt.2015.01.007

    CAS  Article  PubMed  Google Scholar

  90. Kennedy KA, Sandiford SD, Skerjanc IS et al (2012) Reactive oxygen species and the neuronal fate. Cell Mol Life Sci 69:215–221. https://doi.org/10.1007/s00018-011-0807-2

    CAS  Article  PubMed  Google Scholar

  91. Wilson C, Muñoz-Palma E, González-Billault C (2018) From birth to death: a role for reactive oxygen species in neuronal development. Semin Cell Dev Biol 80:43–49. https://doi.org/10.1016/j.semcdb.2017.09.012

    CAS  Article  PubMed  Google Scholar

  92. Zhang M, Wang A, He W et al (2007) Effects of fluoride on the expression of NCAM, oxidative stress, and apoptosis in primary cultured hippocampal neurons. Toxicol 236:208–216. https://doi.org/10.1016/j.tox.2007.04.007

    CAS  Article  Google Scholar

  93. Samanta A, Chanda S, Bandyopadhyay B et al (2016) Establishment of drug delivery system nanocapsulated with an antioxidant (+)-catechin hydrate and sodium meta borate chelator against sodium fluoride induced oxidative stress in rats. J Trace Elem Med Biol 33:54–67. https://doi.org/10.1016/j.jtemb.2015.09.003

    CAS  Article  PubMed  Google Scholar

  94. Dasuri K, Zhang L, Keller JN (2013) Oxidative stress, neurodegeneration, and the balance of protein degradation and protein synthesis. Free Radic Biol Med 62:170–185. https://doi.org/10.1016/j.freeradbiomed.2012.09.016

    CAS  Article  PubMed  Google Scholar

  95. Shuhua X, Ziyou L, Ling Y et al (2012) A role of fluoride on free radical generation and oxidative stress in BV-2 microglia cells. Mediators Inflamm 1–8. https://doi.org/10.1155/2012/102954

  96. Banala RR, Karnati PR (2015) Vitamin A deficiency: an oxidative stress marker in sodium fluoride (NaF) induced oxidative damage in developing rat brain. Int J Dev Neurosci 47:298–303. https://doi.org/10.1016/j.ijdevneu.2015.08.010

    CAS  Article  PubMed  Google Scholar

  97. Akinrinade ID, Memudu AE, Ogundele OM et al (2015) Interplay of glia activation and oxidative stress formation in fluoride and aluminium exposure. Pathophysiol 22:39–48. https://doi.org/10.1016/j.pathophys.2014.12.001

    CAS  Article  Google Scholar

  98. Ailani V, Gupta RC, Gupta SK et al (2009) Oxidative stress in cases of chronic fluoride intoxication. Indian J Clin Biochem 24:426–429. https://doi.org/10.1007/s12291-009-0076-0

    CAS  Article  PubMed  PubMed Central  Google Scholar

  99. Spinu N, Bal-Price A, Cronin MT et al (2019) Development and analysis of an adverse outcome pathway network for human neurotoxicity. Arch Toxicol 93:2759–2772. https://doi.org/10.1007/s00204-019-02551-1

    CAS  Article  PubMed  Google Scholar

  100. Strunecka A, Strunecky O (2019) Chronic fluoride exposure and the risk of autism spectrum disorder. Int J Environ Res Public Health 16:3431. https://doi.org/10.3390/ijerph16183431

    CAS  Article  PubMed Central  Google Scholar

  101. Emerit J, Edeas M, Bricaire F (2004) Neurodegenerative diseases and oxidative stress. Biomed Pharmacother 58:39–46. https://doi.org/10.1016/j.biopha.2003.11.004

    CAS  Article  PubMed  Google Scholar

  102. Ridley W, Matsuoka M (2009) Fluoride-induced cyclooxygenase-2 expression and prostaglandin E2 production in A549 human pulmonary epithelial cells. Toxicol Lett 188:180–185. https://doi.org/10.1016/j.toxlet.2009.04.007

    CAS  Article  PubMed  Google Scholar

  103. Hofer MJ, Campbell IL (2016) Immunoinflammatory diseases of the central nervous system–the tale of two cytokines. Br J Pharmacol 173:716–728. https://doi.org/10.1111/bph.13175

    CAS  Article  PubMed  Google Scholar

  104. Zheng C, Zhou XW, Wang JZ (2016) The dual roles of cytokines in Alzheimer’s disease: update on interleukins, TNF-?, TGF-? and IFN-?. Transl Neurodegener 5:1–5. https://doi.org/10.1186/s40035-016-0054-4

    CAS  Article  Google Scholar

  105. Petrelli F, Pucci L, Bezzi P (2016) Astrocytes and microglia and their potential link with autism spectrum disorders. Front Cell Neurosci 10:21. https://doi.org/10.3389/fncel.2016.00021

    CAS  Article  PubMed  PubMed Central  Google Scholar

  106. Yan N, Liu Y, Liu S et al (2016) Fluoride-induced neuron apoptosis and expressions of inflammatory factors by activating microglia in rat brain. Mol Neurobiol 53(7):4449–4460. https://doi.org/10.1007/s12035-015-9380-2

    CAS  Article  PubMed  Google Scholar

  107. Konur S, Ghosh A (2005) Calcium signaling and the control of dendritic development. Neuron 46:401–405. https://doi.org/10.1016/j.neuron.2005.04.022

    CAS  Article  PubMed  Google Scholar

  108. Brini M, Calì T, Ottolini D et al (2014) Neuronal calcium signaling: function and dysfunction. Cell Mol Life Sci 71:2787–2814. https://doi.org/10.1007/s00018-013-1550-7

    CAS  Article  PubMed  Google Scholar

  109. Baudry M, Zhu G, Liu Y et al (2015) Multiple cellular cascades participate in long-term potentiation and in hippocampus-dependent learning. Brain Res 1621:73–81. https://doi.org/10.1016/j.brainres.2014.11.033

    CAS  Article  PubMed  Google Scholar

  110. Kawai Y, Nakao T, Kunimura N et al (2006) Relationship of intracellular calcium and oxygen radicals to cisplatin-related renal cell injury. J Pharmacol Sci 100:65–72. https://doi.org/10.1254/jphs.fp0050661

    CAS  Article  PubMed  Google Scholar

  111. Kubota K, Lee DH, Tsuchiya M et al (2005) Fluoride induces endoplasmic reticulum stress in ameloblasts responsible for dental enamel formation. J Biol Chem 280:23194–23202. https://doi.org/10.1074/jbc.M503288200

    CAS  Article  PubMed  Google Scholar

  112. Wei H, Xie Z (2009) Anesthesia, calcium homeostasis and Alzheimer’s disease. Curr Alzheimer Res 6:30–35. https://doi.org/10.2174/156720509787313934

    CAS  Article  PubMed  PubMed Central  Google Scholar

  113. Teng Y, Zhang J, Zhang Z et al (2018) The effect of chronic fluorosis on calcium ions and CaMKII?, and c-fos expression in the rat hippocampus. Biol Trace Elem Res 182:295–302. https://doi.org/10.1007/s12011-017-1098-8

    CAS  Article  PubMed  Google Scholar

  114. Liao Q, Zhang R, Wang X et al (2017) Effect of fluoride exposure on mRNA expression of cav1. 2 and calcium signal pathway apoptosis regulators in PC12 cells. Environ Toxicol Pharmacol 54:74–79. https://doi.org/10.1016/j.etap.2017.06.018

    CAS  Article  PubMed  Google Scholar

  115. Zhang J, Zhu WJ, Xu XH et al (2011) Effect of fluoride on calcium ion concentration and expression of nuclear transcription factor kappa-B ?65 in rat hippocampus. Exp Toxicol Pathol 63:407–411. https://doi.org/10.1016/j.etp.2010.02.017

    CAS  Article  PubMed  Google Scholar

  116. Xu Z, Xu B, Xia T et al (2013) Relationship between intracellular Ca2+ and ROS during fluoride-induced injury in SH-SY5Y cells. Environ Toxicol 28:307–312. https://doi.org/10.1002/tox.20721

    CAS  Article  PubMed  Google Scholar

  117. Ameeramja J, Panneerselvam L, Govindarajan V et al (2016) Tamarind seed coat ameliorates fluoride induced cytotoxicity, oxidative stress, mitochondrial dysfunction and apoptosis in A549 cells. J Hazard Mater 301:554–565. https://doi.org/10.1016/j.jhazmat.2015.09.037

    CAS  Article  PubMed  Google Scholar

  118. Nadei OV, Khvorova IA, Agalakova NI (2020) Cognitive decline of rats with chronic fluorosis is associated with alterations in hippocampal calpain signaling. Biol Trace Elem Res 197:495–506. https://doi.org/10.1007/s12011-019-01993-z

    CAS  Article  PubMed  Google Scholar

  119. Lemasters JJ, Theruvath TP, Zhong Z et al (2009) Mitochondrial calcium and the permeability transition in cell death. Biochim Biophys Acta 1787:1395–1401. https://doi.org/10.1016/j.bbabio.2009.06.009

    CAS  Article  PubMed  PubMed Central  Google Scholar

  120. Sun Z, Niu R, Wang B et al (2011) Fluoride-induced apoptosis and gene expression profiling in mice sperm in vivo. Arch Toxicol 85:1441–1452. https://doi.org/10.1007/s00204-011-0672-7

    CAS  Article  PubMed  Google Scholar

  121. Nagendra AH, Bose B, Shenoy S (2021) Recent advances in cellular effects of fluoride: an update on its signalling pathway and targeted therapeutic approaches. Mol Biol Rep 12:1–3. https://doi.org/10.1007/s11033-021-06523-6

    CAS  Article  Google Scholar

  122. Refsnes M, Schwarze PE, Holme JA et al (2003) Fluoride-induced apoptosis in human epithelial lung cells (A549 cells): role of different G protein-linked signal systems. Hum Exp Toxicol 22:111–123. https://doi.org/10.1191/0960327103ht322oa

    CAS  Article  PubMed  Google Scholar

  123. Lee JH, Jung JY, Jeong YJ et al (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. Toxicol 243:340–347. https://doi.org/10.1016/j.tox.2007.10.026

    CAS  Article  Google Scholar

  124. Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795. https://doi.org/10.1038/nature05292

    CAS  Article  PubMed  Google Scholar

  125. Zhao WP, Wang HW, Liu J et al (2019) Mitochondrial respiratory chain complex abnormal expressions and fusion disorder are involved in fluoride-induced mitochondrial dysfunction in ovarian granulosa cells. Chemosphere 215:619–625. https://doi.org/10.1016/j.chemosphere.2018.10.043

    CAS  Article  PubMed  Google Scholar

  126. Zhao Q, Niu Q, Chen J et al (2019) Roles of mitochondrial fission inhibition in developmental fluoride neurotoxicity: mechanisms of action in vitro and associations with cognition in rats and children. Arch Toxicol 93:709–726. https://doi.org/10.1007/s00204-019-02390-0

    CAS  Article  PubMed  Google Scholar

  127. Araujo TT, Pereira HA, Dionizio A et al (2019) Changes in energy metabolism induced by fluoride: insights from inside the mitochondria. Chemosphere 236:124357. https://doi.org/10.1016/j.chemosphere.2019.124357

    CAS  Article  PubMed  Google Scholar

  128. Yang T, Zhang Y, Li Y et al (2013) High amounts of fluoride induce apoptosis/cell death in matured ameloblast-like LS8 cells by downregulating Bcl-2. Arch Oral Biol 58:1165–1173. https://doi.org/10.1016/j.archoralbio.2013.03.016

    CAS  Article  PubMed  Google Scholar

  129. Cobb CA, Cole MP (2015) Oxidative and nitrative stress in neurodegeneration. Neurobiol Dis 84:4–21. https://doi.org/10.1016/j.nbd.2015.04.020

    CAS  Article  PubMed  PubMed Central  Google Scholar

  130. Benderdour M, Charron G, DeBlois D et al (2003) Cardiac mitochondrial NADP+-isocitrate dehydrogenase is inactivated through 4-hydroxynonenal adduct formation: an event that precedes hypertrophy development. J Biol Chem 278:45154–45159. https://doi.org/10.1074/jbc.m306285200

    CAS  Article  PubMed  Google Scholar

  131. Sun Z, Zhang W, Xue X et al (2016) Fluoride decreased the sperm ATP of mice through inhabiting mitochondrial respiration. Chemosphere 144:1012–1017. https://doi.org/10.1016/j.chemosphere.2015.09.061

    CAS  Article  PubMed  Google Scholar

  132. Wang J, Gao Y, Cheng X et al (2019) GSTO1 acts as a mediator in sodium fluoride-induced alterations of learning and memory related factors expressions in the hippocampus cell line. Chemosphere 226:201–209. https://doi.org/10.1016/j.chemosphere.2019.03.144

    CAS  Article  PubMed  Google Scholar

  133. Tiwari SK, Agarwal S, Tripathi A, Chaturvedi RK (2016) Bisphenol–a mediated inhibition of hippocampal neurogenesis attenuated by curcumin via canonical Wnt pathway. Mol Neurobiol 53:3010–3029. https://doi.org/10.1007/s12035-015-9197-z

    CAS  Article  PubMed  Google Scholar

  134. Nageshwar M, Sudhakar K, Reddy NC et al (2017) Neuroprotective effects of curcumin on sodium fluoride induced behavioural and enzymatic changes in brain and muscles of rat. J Environ Biol 38:675. https://doi.org/10.22438/JEB%2F38%2F4%2FMS-169

    CAS  Article  Google Scholar

  135. Kumar NK, Nageshwar M, Reddy KP (2020) Protective effect of curcumin on hippocampal and behavior changes in rats exposed to fluoride during pre-and post-natal period. Basic Clin Neurosci. 11:289. https://doi.org/10.32598/2Fbcn.11.2.1189.1

    CAS  Article  PubMed  PubMed Central  Google Scholar

  136. 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 60:126475. https://doi.org/10.1016/j.jtemb.2020.126475

    CAS  Article  PubMed  Google Scholar

  137. Jardim FR, de Rossi FT, Nascimento MX et al (2018) Resveratrol and brain mitochondria: a review. Mol Neurobiol 55:2085–2101. https://doi.org/10.1007/s12035-017-0448-z

    CAS  Article  PubMed  Google Scholar

  138. Zeng XX, Deng J, Xiang J et al (2019) – Resveratrol attenuated the increased level of oxidative stress in the brains and the deficit of learning and memory of rats with chronic fluorosis. Fluoride 52:149–60

    CAS  Google Scholar

  139. Mesram N, Nagapuri K, Banala RR et al (2017) Quercetin treatment against NaF induced oxidative stress related neuronal and learning changes in developing rats. J King Saud Univ Sci 29:221–229. https://doi.org/10.1016/j.jksus.2016.04.002

    Article  Google Scholar

  140. Hamza RZ, El-Shenawy NS, Ismail HA (2015) 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

    CAS  Article  PubMed  Google Scholar

  141. Daglia M, Di Lorenzo A, Nabavi SF et al (2014) Polyphenols: well beyond the antioxidant capacity: gallic acid and related compounds as neuroprotective agents: you are what you eat! Curr Pharm Biotechnol 15:362–372. https://doi.org/10.2174/138920101504140825120737

    CAS  Article  PubMed  Google Scholar

  142. Nabavi SF, Nabavi SM, Latifi AM et al (2012) Mitigating role of quercetin against sodium fluoride-induced oxidative stress in the rat brain. Pharm Biol 50:1380–1383. https://doi.org/10.3109/13880209.2012.675341

    CAS  Article  PubMed  Google Scholar

  143. Ran LY, Xiang J, Zeng XX et al (2021) Integrated transcriptomic and proteomic analysis indicated that neurotoxicity of rats with chronic fluorosis may be in mechanism involved in the changed cholinergic pathway and oxidative stress. J Trace Elem Med Biol 64:126688. https://doi.org/10.1016/j.jtemb.2020.126688

    CAS  Article  PubMed  Google Scholar

  144. ?ukomska A, Baranowska-Bosiacka I, Dec K et al (2021) Changes in gene and protein expression of metalloproteinase-2 and-9 and their inhibitors TIMP2 and TIMP3 in different parts of fluoride-exposed rat brain. Int J Mol Sci 22:391. https://doi.org/10.3390/ijms22010391

    CAS  Article  Google Scholar

  145. Mondal P, Shaw P, Bhowmik AD et al (2021) Combined effect of arsenic and fluoride at environmentally relevant concentrations in zebrafish (Danio rerio) brain: alterations in stress marker and apoptotic gene expression. Chemosphere 269:128678. https://doi.org/10.1016/j.chemosphere.2020.128678

    CAS  Article  PubMed  Google Scholar

  146. Shalan A, El-Sayed S, El-Sayed G, El-Said ES (2021) Effect of Moringa olefiera on neurotoxicity induced by sodium fluoride in rats. Mansoura Vet Med J 22:91–96. https://doi.org/10.35943/MVMJ.2021.188544

    Article  Google Scholar

  147. Reddy YP, Tiwari S, Tomar LK et al (2021) Fluoride-induced expression of neuroinflammatory markers and neurophysiological regulation in the brain of Wistar rat model. Biol Trace Elem Res 199:2621–2626. https://doi.org/10.1007/s12011-020-02362-x

    CAS  Article  PubMed  Google Scholar

  148. Dec K, ?ukomska A, Skonieczna-?ydecka K et al (2020) Chronic exposure to fluoride affects GSH level and NOX4 expression in rat model of this element of neurotoxicity. Biomolecules 3:422. https://doi.org/10.3390/biom10030422

    CAS  Article  Google Scholar

  149. Jaiswal P, Mandal M, Mishra A (2020) Effect of hesperidin on fluoride-induced neurobehavioral and biochemical changes in rats. J Biochem Mol Toxicol 34:e22575. https://doi.org/10.1002/jbt.22575

    CAS  Article  PubMed  Google Scholar

  150. Zhao Q, Tian Z, Zhou G et al (2020) SIRT1-dependent mitochondrial biogenesis supports therapeutic effects of resveratrol against neurodevelopment damage by fluoride. Theranostics 10:4822. https://doi.org/10.7150/thno.42387

    CAS  Article  PubMed  PubMed Central  Google Scholar

  151. Jiang P, Li G, Zhou X et al (2019) Chronic fluoride exposure induces neuronal apoptosis and impairs neurogenesis and synaptic plasticity: role of GSK-3?/?-catenin pathway. Chemosphere 214:430–435. https://doi.org/10.1016/j.chemosphere.2018.09.095

    CAS  Article  PubMed  Google Scholar

  152. Manusha S, Sudhakar K, Reddy KP (2019) Protective effects of Allium sativum extract against sodium fluoride induced neurotoxicity. Int J Pharm Sci Res 10:625–33. https://doi.org/10.13040/IJPSR.0975-8232.10(2).625-33

    CAS  Article  Google Scholar

  153. Bartos M, Gumilar F, Gallegos CE et al (2019) Effects of perinatal fluoride exposure on short-and long-term memory, brain antioxidant status, and glutamate metabolism of young rat pups. Int J Toxicol 38:405–414. https://doi.org/10.1177/1091581819857558

    CAS  Article  PubMed  Google Scholar

  154. Shanmugam T, Abdulla S, Yakulasamy V et al (2018) Mechanism underlying the neurotoxicity induced by sodium fluoride and its reversal by epigallocatechin gallate in the rat hippocampus: involvement of NrF2/Keap-1 signaling pathway. JoBAZ 79:1–9. https://doi.org/10.1186/s41936-018-0020-z

    Article  Google Scholar

  155. Niu Q, Chen J, Xia T et al (2017) Excessive ER stress and the resulting autophagic flux dysfunction contribute to fluoride-induced neurotoxicity. Environ Pollut 233:889–899. https://doi.org/10.1016/j.envpol.2017.09.015

    CAS  Article  PubMed  Google Scholar

  156. Adedara IA, Abolaji AO, Idris U et al (2017) Neuroprotective influence of taurine on fluoride-induced biochemical and behavioral deficits in rats. Chem Biol Interact 261:1. https://doi.org/10.1016/j.cbi.2016.11.011

    CAS  Article  PubMed  Google Scholar

  157. Sun Z, Zhang Y, Xue X et al (2018) Maternal fluoride exposure during gestation and lactation decreased learning and memory ability, and glutamate receptor mRNA expressions of mouse pups. Hum Exp Toxicol 37:87–93. https://doi.org/10.1177/0960327117693067

    CAS  Article  PubMed  Google Scholar

  158. Shashi A, Kumar J (2016) Neuropathological changes in hippocampus in albino rat in fluoride toxicity. Inter J Basic and Appl Med Sci. 17–25.

  159. Sarkar C, Pal S, Das N et al (2014) Ameliorative effects of oleanolic acid on fluoride induced metabolic and oxidative dysfunctions in rat brain: experimental and biochemical studies. Food Chem Toxicol 66:224–236. https://doi.org/10.1016/j.fct.2014.01.020

    CAS  Article  PubMed  Google Scholar

  160. Atmaca N, Atmaca HT, Kanici A et al (2014) Protective effect of resveratrol on sodium fluoride-induced oxidative stress, hepatotoxicity and neurotoxicity in rats. Food Chem Toxicol 70:191–197. https://doi.org/10.1016/j.fct.2014.05.011

    CAS  Article  PubMed  Google Scholar

  161. Liu YJ, Gao Q, Wu CX, Guan ZZ (2010) Alterations of nAChRs and ERK1/2 in the brains of rats with chronic fluorosis and their connections with the decreased capacity of learning and memory. Toxicol Lett 192:324–329. https://doi.org/10.1016/j.toxlet.2009.11.002

    CAS  Article  PubMed  Google Scholar

  162. Kaur T, Bijarnia RK, Nehru B (2009) Effect of concurrent chronic exposure of fluoride and aluminum on rat brain. Drug Chem Toxicol 32:215–221. https://doi.org/10.1080/01480540902862251

    CAS  Article  PubMed  Google Scholar

  163. Chirumari K, Reddy PK (2007) Dose-dependent effects of fluoride on neurochemical milieu in the hippocampus and neocortex of rat brain. Fluoride 40(2):101–110

    CAS  Google Scholar

  164. Bera I, Sabatini R, Auteri P et al (2007) Neurofunctional effects of developmental sodium fluoride exposure in rats. Eur Rev Med Pharmacol 11:211

    CAS  Google Scholar

  165. Bhatnagar M, Rao P, Sushma J et al (2002) Neurotoxicity of fluoride: neurodegeneration in hippocampus of female mice. Ind J Exper Biol (IJEB) 40(5):546–54. http://nopr.niscair.res.in/handle/123456789/17383

  166. Lai C, Chen Q, Ding Y et al (2020) Emodin protected against synaptic impairment and oxidative stress induced by fluoride in SH-SY5Y cells by modulating ERK1/2/Nrf2/HO-1 pathway. Environ Toxicol 35:922–929. https://doi.org/10.1002/tox.22928

    CAS  Article  PubMed  Google Scholar

  167. Chen L, Ning H, Yin Z et al (2017) The effects of fluoride on neuronal function occurs via cytoskeleton damage and decreased signal transmission. Chemosphere 185:589–594. https://doi.org/10.1016/j.chemosphere.2017.06.128

    CAS  Article  PubMed  Google Scholar

  168. Yan L, Liu S, Wang C et al (2013) JNK and NADPH oxidase involved in fluoride-induced oxidative stress in BV-2 microglia cells. Mediators Inflamm 2013:895975. https://doi.org/10.1155/2013/895975

    CAS  Article  PubMed  PubMed Central  Google Scholar

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Funding

The authors thank the Tamil Nadu State Council for Higher Education (TANSCHE), India (RGP/2019-20/BU/HECP-0027) for financial support.

Affiliations

  1. Bharathiar University, Coimbatore, Tamilnadu, India

    Harsheema Ottappilakkil, Srija Babu, Satheeswaran Balasubramanian, Suryaa Manoharan & Ekambaram Perumal

Corresponding author

Correspondence to Ekambaram Perumal.

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