Fluoride Action Network

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Excerpts

1 Introduction

Given the widespread presence of fluorine in the natural environment, individuals are exposed to fluoride via food intake, inhalation, and dermal contact. Drinking water represents the largest exposure source. In particular, in highly fluoridated regions and in some developed areas that fluoridate the public water supply to reduce dental caries, fluoride may result in a health hazard [1,2].

Fluoride is required for normal growth and development of teeth and bones but can lead to fluorosis if taken excessively. Specifically, fluorosis can adversely affect the skeleton and teeth, and may induce structural and functional changes in soft tissues including brain tissue [3]. Epidemiological data show that chronic exposure to high fluoride in water is closely associated with a lower intelligence quotient in children [4,5,6]. In fluorosis-endemic areas, a certain high dose of fluoride intake is a potential risk factor for cognitive impairment in elderly people [7]. Moreover, structural changes in nerve cells and brain functions in experimental animals subjected to chronic fluorosis have been described such as nuclear shrinkage, mitochondrial swelling, neurodegeneration, and deterioration of learning and memory [8,9,10]. These findings suggest a direct link between excessive exposure to fluoride and brain function impairment, but little is known about mechanisms underlying these phenomena.

Oxidative stress-induced neurotoxicity is considered a mechanism of brain impairment caused by fluorosis. Once fluoride has formed lipid-soluble complexes in the blood, it can cross the blood–brain barrier, penetrate brain cells, and accumulate in brain tissue, causing detrimental neurological effects [11]. Reactive oxygen species (ROS) and free radicals can be generated when the fluoride content is high in the brain and cause oxidative damage and cell apoptosis in neurons [12], which may be controlled by apoptosis-related genes [13,14,15]. The literature suggests that increased ROS and lipid peroxidation (LPO) and decreased antioxidant enzyme activity occur in the brains of fluoride-intoxicated rats and that histopathological changes can be observed, especially swelling of mitochondria and endoplasmic reticulum dilation in neurons [9,16]. Also, some studies confirm that specific antioxidants may protect against this damage [17].

Anthocyanins, the largest group of water-soluble pigments responsible for fruit and vegetable color, are flavonoids reputed to have biological antioxidant activity due to their capacity as hydrogen donors [18]. They can also stabilize and delocalize unpaired electrons, and their ability to chelate transition metal ions may be useful [19]. Anthocyanin-rich maize purple plant pigment (MPPP) extracted from maize purple plant has been said to have antioxidant traits [3,20], but few reports of MPPP in fluoride-treated rat brains exist. Thus, we studied MPPP and any potential neuroprotective effects against fluoride toxicity.

3.1 Ultrastructural observation of brain

Ultrastructural analysis of the experimental rat brains is shown in Figure 2. For controls (Figure 2a), one oval nucleus with visible, clear nucleoli and double nuclear membranes, abundant mitochondria, and endoplasmic reticulum were found in neurons. In fluoride-treated rats (Figure 2b), nerves were deformed, lacked a nuclear membrane, and had chromatin condensation, swollen mitochondria, and broken cristae, and evidence of apoptosis was present. In rats treated with fluoride and MPPP, brain cells had swollen mitochondria but fewer abnormal mitochondria compared to group II, and pathological nuclear changes were reduced (Figure 2c and d).

5 Conclusions

Oxidative stress plays a role in fluoride-induced toxicity and provokes pathological changes and neuronal apoptosis in rat brains. Anthocyanin-rich MPPP may restore brain health via its antioxidant properties. However, further research is required to understand how MPPP may be neuroprotective.

*Full text article online at https://www.degruyter.com/view/journals/tnsci/11/1/article-p89.xml

References

  • [1]

    Khan SA, Singh RK, Navit S, Chadha D, Johri N, Navit P, et al. Relationship between dental fluorosis and intelligence quotient of school going children in and around Lucknow district: a cross-sectional study. J Clin Diagn Res. 2015;11:ZC10-15.

  • [2]

    Waugh D, Potter W, Limeback H, Godfrey M. Risk assessment of fluoride intake from tea in the republic of Ireland and its implications for public health and water fluoridation. Int J Environ Res Public Health. 2016;13(3):259.

  • [3]

    Zhang Z, Zhou B, Wang XH, Wang F, Song YL, Liu SN, et al. Maize purple plant pigment protects against fluoride-induced oxidative damage of liver and kidney in rats. Int J Environ Res Public Health. 2014;11:1020–33.

  • [4]

    Nagarajappa R, Pujara P, Sharda AJ, Asawa K, Tak M, Aapaliya P, et al. Comparative assessment of intelligence quotient among children living in high and low fluoride areas of kutch, india-a pilot study. Iran J Public Health. 2013;42(8):813–8.

  • [5]

    Wang SX, Wang ZH, Cheng XT, Li J, Sang ZP, Zhang XD, et al. Arsenic and fluoride exposure in drinking water: children’s IQ and growth in Shanyin county, Shanxi province, China. Environ Health Perspect. 2007;115(4):643–7.

  • [6]

    Trivedi MH, Verma RJ, Chinoy NJ, Patel RS, Sathawara NG. Effect of high fluoride water on intelligence of school children in India. Fluoride. 2007;40:178–83.

  • [7]

    Li M, Gao YH, Cui J, Li YY, Li BY, Liu Y, et al. Cognitive impairment and risk factors in elderly people living in fluorosis areas in China. Biol Trace Elem Res. 2016;172(1):53–60.

  • [8]

    Liu F, Ma J, Zhang H, Liu P, Liu YP, Xing B, et al. Fluoride exposure during development affects both cognition and emotion in mice. Physiol Behav. 2014;124:1–7.

  • [9]

    Jiang C, Zhang S, Liu H, Guan Z, Zeng Q, Zhang C, et al. Low glucose utilization and neurodegenerative changes caused by sodium fluoride exposure in rat’s developmental brain. Neuromol Med. 2014;16(1):94–105.

  • [10]

    Shashi A. Histopathological investigation of fluoride induced neurotoxicity in rabbits. Fluoride. 2003;36(2):95–105.

  • [11]

    Mullenix PJ, Denbesten PK, Schunior A, Kernan WJ. Neurotoxicity of sodium fluoride in rat. Neurotoxicol Teratol. 1995;17(2):169–77.

  • [12]

    Perumal E, Paul V, Govindarajan V, Panneerselvam L. A brief review on experimental fluorosis. Toxicol Lett. 2013;223(2):236–51.

  • [13]

    Zhang M, Wang A, He W, He P, Xu B, Xia T, et al. Effects of fluoride on the expression of NCAM, oxidative stress, and apoptosis in primary cultured hippocampal neurons. Toxicology. 2007;236(3):208–16.

  • [14]

    Adebayo OL, Shallie PD, Salau BA, Ajiani EO, Adenuga GA. Comparative study on the influence of fluoride on lipid peroxidation and antioxidants levels in the different brain regions of well-fed and protein undernourished rats. J Trace Elem Med Biol. 2013;27(4):370–4.

  • [15]

    Lee JH, Jung JY, Jeong YJ, Park JH, Yang KH, Choi NK, et al. Involvement of both mitochondrial and death receptor-dependent apoptotic pathways regulated by Bcl-2 family in sodium fluoride-induced apoptosis of the human gingival fibroblasts. Toxicology. 2008;243(3):340–7.

  • [16]

    Kaur T, Bijaria RK, Nehru B. Effect of concurrent chronic exposure of fluoride and aluminium on rat brain. Drug Chem Toxicol. 2009;32(3):215–21.

  • [17]

    Madhusudhan N, Basha PM, Begum S, Ahmed F. Fluoride induced neuronal oxidative stress and its amelioration by antioxidants in developing rats. Fluoride. 2009;42:179–87.

  • [18]

    Dini C, Zaro MJ, Vina SZ. Bioactivity and functionality of anthocyanins: a review. Curr Bioact Compd. 2019;15(5):507–23.

  • [19]

    Devi PS, Kumar MS, Das SM. DNA damage protecting activity and free radical scavenging activity of anthocyanins from red sorghum (sorghum bicolor) bran. Biotechnol Res Int. 2012;2012:258787.

  • [20]

    Jing L, Zhang Z, Xi SH, Yang XX. Effects of maize purple plant pigment on the expression of hepatic lipogenic genes in fluorosis rats, Chin. J Mod Med. 2015;25:6–9.

  • [21]

    Zhou B, Li XH, Wang XH, Guo LY, Zhang Z, Xu C. Identification of main compositions in maize purple plant pigment. Nat Prod Res Dev. 2008;20:842–5.

  • [22]

    Zhang ZY, Han B, Qian C. Rapid detection method for trace fluoride with microplate reader. Chin J Publ Heal. 2011;27:255–6.

  • [23]

    Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein dye binding. Anal Biochem. 1976;72:248–54.

  • [24]

    Akinrinade ID, Memudu AE, Ogundele OM. Fluoride and aluminium disturb neuronal morphology, transport functions, cholinesterase, lysosomal and cell cycle activities. Pathophysiol. 2015;22(2):105–15.

  • [25]

    Fawell J, Bailey K, Chilton J, Dahi E, Fewtrell L, Magara Y. Fluoride in drinking-water, 19 June 2016, World Health Organisation, http://www.who.int/water_sanitation_health/publications/fluoride_drinking_water_full.pdf.

  • [26]

    Inkielewicz-Stepniak I, Czarnowski W. Oxidative stress parameters in rats exposed to fluoride and caffeine. Food Chem Toxicol. 2010;48(6):1607–11.

  • [27]

    Patel PD, Chinoy NJ. Influence of fluoride on biological free radical reactions in ovary of mice and its reversal. Fluoride. 1998;31:27–30.

  • [28]

    Birkner E, Grucka-Mamczar E, Kasperczyk S, Zalejska-Fiolka J, Kasperczyk A, Chlubek D, et al. The influence of sodium fluoride on the concentration of malondialdehyde and 7-ketocholesterol and the activity of superoxide dismutase in blood plasma of rabbits with experimental hypercholesterolemia. Fluoride. 2008;41:199–205.

  • [29]

    Hassan HA, Abdel-Aziz AF. Evaluation of free radical-scavenging and anti-oxidant properties of black berry against fluoride toxicity in rats. Food Chem Toxicol. 2010;48(8–9):1999–2004.

  • [30]

    Dubey N, Khan AM, Raina R. Sub-acute deltamethrin and fluoride toxicity induced hepatic oxidative stress and biochemical alterations in rats. Bull Environ Contam Toxicol. 2013;91(3):334–8.

  • [31]

    Atmaca N, Atmaca HT, Kanici A, Anteplioglu T. Protective effect of resveratrol on sodium fluoride-induced oxidative stress, hepatotoxicity and neurotoxicity in rats. Food Chem Toxicol. 2014;70:191–7.

  • [32]

    Rice-Evans CA, Miller NJ, Bolwell PG, Bramley PM, Pridham JB. The relative antioxidant activities of plant-derived polyphenolic flavonoids. Free Radic Res. 1995;22(4):375–83.

  • [33]

    Kanupriya, Prasad D, Ram MS, Kumar R, Sawhney RC, Sharma SK, et al. Cytoprotective and antioxidant activity of rhodiola imbricata against tert-butyl hydroperoxide induced oxidative injury in U-937 human macrophages. Mol Cell Biochem. 2005;275(1–2):1–6.

  • [34]

    Zulaikhah ST. The role of antioxidant to prevent free radicals in the body. Sains Medika. 2017;8(1):39–45.

  • [35]

    Li Z, Xie M, Yang F, Liu J. Antioxidant activity of high purity blueberry anthocyanins and the effffects on human intestinal microbiota. LWT-Food Sci Technol. 2020;117:108621.

  • [36]

    Noda Y. Antioxidant activity of nasunin, an anthocyanin in egg plant peels. Toxicology. 2000;148:119–23.

  • [37]

    Yan N, Liu Y, Liu SN, Cao S, Wang F, Wang Z, et al. Fluoride-induced neuron apoptosis and expressions of inflammatory factors by activating microglia in rat brain. Mol Neurobiol. 2016;53(7):4449–60.

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