This review showed that the cerebellum of sodium fluoride treated animals exhibited degenerative changes especially in Purkinje cell layer, while the molecular and granular layers were less affected Ultra-structurally, increased the nuclear membrane irregularity, dilated rough endoplasmic reticulum and vacuolated mitochondria of Purkinje cells were observed

Fluoride is a chemical element which is widely distributed in the environment. It is a natural component of the earth's crest and occurs in varying concentration in rocks, soil, water and air. It is present in several chemical forms either organic or inorganic, one of the commonest inorganic fluorides is sodium fluoride (NaF) [1]. The main source of fluoride is tap water [2]. Other sources were food and drugs. Food containing fluoride included sea food and bony meals, fluoride concentrates in bones of most mammals Also dark green vegetables as the tea plant accumulate fluoride from soil and water [3]. Drugs which contains fluoride were mainly dental gels, tooth pastes and mouth rinses[4]. Cooking in Teflon lined cookware also increase the concentration of fluoride in our daily foods prepared inside them [5]. Excess fluoride intake causes fluorosis which is a progressive degenerative disorder known by clinical manifestations in bones and teeth [6].
Aim of our study is collect Data about effect of NaF on cerebellum as apart of central nerves system.

General Information of Sodium Fluoride

It is soluble in water. It is noncombustible. It is corrosive to aluminum. It is used as an insecticide. It is also used to fluorinate water supplies, as a wood preservative, in cleaning compounds, manufacture of glass, and for many other uses [7].

Sodium Fluoride Toxicity

Fluorosis has become an endemic problem worldwide. Toxic effects of high fluoride intake are observed in soft tissue such as liver, kidney, cerebrum and cerebellum[8]. Long term intake of high levels of fluoride in human causes neurological complications such as paralysis of limbs, vertigo, and spasticity in extremities and impaired mental acuity [9].

Sodium Fluoride Toxicity in Reproductive System

There is a study was designed to study the effect of NaF exposure for different durations. Naresh Kumar found significant decrease in Sperm count, motility, progressive motility and weight of epididymis [Figure 1]. but no change in the testicular weight in adult rabbits treated by 20 mg/kg body weight NaF for 30 days was given by using a tube attached to a hypodermic needle , and when extend the period to 60 days he observed a significant decrease in all the parameters [10].

Figure 1: A photomicrograph of rabbits testis fed on NaF (20 mg/ kg) for 30 days showed a lack of differentiation and maturation of spermatocytes and infiltration in the interstitial area of the seminiferous tubules without mature spermatozoa in the lumens of the seminiferous tubules (H&E stain x 200).

Sodium Fluoride Toxicity in Digestive System 

We found from our reading one study speak about there is gastrointestinal toxicity diagnosis by Histopathological examination as erosion and necrosis of the duodenum surface mucosa with hemorrhages, necrosis of Brunner's gland, clumped submucosa, and hypertrophy of muscles in muscular mucosa from using of NaF and there result appear in Young rabbits weighing 400-600 g injected daily with 5 mg NaF/kg for 15 weeks and then sacrificed [11] [Figure 2].

Figure 2: A photomicrograph of mice liver exposed to 5 mg/L/kg NaF for 15 days showed cellular disarray, congestion, cellular degeneration, and cellular vacuoles (Hematoxylin and Eosin (H&E) stain X 200).

Sodium Fluoride Toxicity in Urinary System 

There is kidney toxicity appear by histopathological examination as necrosis in glomerulus, Convoluted tubules and Bowman’s capsule lumen [Figure 3]. when he used adult albino mice in de-ionized water 5 ppm of NaF for 15 days and then sacrificed [12].

Figure 3: A photomicrograph of mouse kidney exposed to 5ppm/ 15 days fluoride showed necrosis in glomerulus, degenerative changes in Bowman’s capsule and alterations in glomerulus’s tubular region (H&E stain X 200).

Sodium Fluoride Toxicity in Nervous System 

Sodium Fluoride Toxicity on Brain
Earlier studies evaluated the brain histology after NaF inhalation at 300 ppm for 6 hr/day, 5 days week for 13 weeks and found mild or no histological changes indicating that this treatment was reversible [13] [Figure 4].

Figure 4: A photomicrograph of rat brain exposed to 300 ppm sulfuryl fluoride for 13 weeks showed vacuoles in brain white tracts and neuropil of the caudate-putamen but without necrosis or neuronal destruction (H&E stain X 330).
Observed generalized congestion and hemorrhages in vital organs (i.e. liver, heart, kidney, spleen, lung and brain) of rats treated with (NaF). Lakshmi, Pratap and Reddya found oxidation effect in brain. The enzymes SOD, Glutathione S-transferases (GST), and catalase decreased significantly (p<0.01) in contrast to Xanthine oxidase (XOD) activity, which moderately increased. Succinate dehydrogenase (SDH), Lactate dehydrogenase (LDH), Alanine transaminase (ALT), aspartate aminotransferase (AAT), and Creatine phospho kinase (CPK) activities and membrane-bound enzymes, Sodium (Na+), Potassium (K+), Magnesium (Mg++ and Calcium (Ca++) Adenosin Tri phosphatase (ATPase) and Acetylcholine (AChE) were decreased significantly (p<0.01) in brain are affected by fluoride with (20 mg/kg/body weight) for 14 days in adult female mice[14,15,16].

Sodium Fluoride Toxicity in Spinal Cord
Doaa, Nour-Edien and others found affect (NaF) at a dose of 12 mg/kg/day, for four weeks orally by gastric intubation received in adult male albino rats affect the grey matter of spinal cord, the histopathological alteration detected by using light and electron microscopy. In H&E-stained sections, showed various degrees of neurodegeneration in both the ventral and dorsal horns. Many cells were shrunken with dark cytoplasm and loss of nuclear details. Some of these cells were surrounded by vacuolated neuropil. Other cells showed central chromatolysis “cytoplasmic hyalinization”. Few cells appeared as ghost-like cells. The neuropil of both the ventral and dorsal horns showed some areas of vacuolation and many abnormal blood vessels. Some of these blood vessels had distorted endothelium while others were dilated and congested. In silver-stained sections, showed many shrunken cells with dark cytoplasm and loss of nuclear details. The neuropil showed many areas of vacuolation. Also, some degenerated axons with segmental disruption of myeline were observed in the neuropil. In Toluidine blue (TB) stained sections, the cytoplasm of motor neurons showed a significant decrease of Nissl’s granules content (p<0.01) that appeared faint blue in color [17,18] [Figure 5].

Figure 5: A photomicrograph of adult male rat brain exposed to 12 mg/kg/day NaF, for four weeks showed apparent decrease of Nissl’s granules content (arrows) in the motor neurons that appeared faint blue in color (Toluidine blue,×400).
Sodium Fluoride Toxicity on Locomotor Behavior and Memory
Vanaja Paul and others found that effect of NaF on locomotor behavior is observed when they used NaF at 20 mg/kg dose level daily for 60 days in adult female rats. The activities of total cholinesterase and acetylcholinesterase were determined in blood and brain regions, but no change was observed in the motor coordination and Acetylcholinesterase activity in cerebral cortex, brain stem and cerebellum of these animals. A cholinergic mechanism through a change in the activity of acetylcholinesterase may not account for this effect, since NaF treatment did not alter the activity this enzyme in brain regions [19]. 
Sodium Fluoride Toxicity on Cerebellum
The present review described the alterations in the histological structure of rat cerebellar cortex resulting from administration of NaF. Reported that any lesion to the cerebellar cortex was manifested in some animals as muscle weakness, tremors, loss of equilibrium, gait disturbance and hind limbs paralysis. Histological structure of the cerebellar cortex was disrupted, particularly the Purkinje cell layer that was the most affected cell population, while the molecular and granular layers were less affected [9].
 These results are similar to Omayma who found histological changes occurring in the cerebellar cortex, her result showed severe degenerative changes especially in Purkinje cells. There was multilayer disposition of these cells associated with structural changes in the form of dilated Rough endoplasmic reticulum (RER) and Golgi complex, swollen mitochondria in addition to marginated nuclear chromatin. The surrounding neuropil appeared vacuolated with accumulation of neuroglial cells. Many myelinated nerve fibers displayed disruption in myelination and irregular neurofilaments. On the other side, these result appear in 10 mg/kg NaF orally once daily for three months in adult male albino rats [20]. The results of [21,22] found that rabbits treated by NaF at 30 and 60 days these changes lead to paralysis of limbs and the histopathological alterations showed necrosis of Purkinje cells and edema with necrosis in the granular cell layer. The Purkinje cells of brains and cerebellar cortex showed degenerative changes in the form of loss of their characteristic pyriform shap, pyknotic or karyolitic nuclei, vacuolated cytoplasm and loss of many Purkinje cells in some areas [Figure 6-9].

Figure 6: A photomicrograph of a section in the cerebellar cortex of a 10 mg/kg NaF once daily for three months rat showed severely affected area with disappearance of many Purkinje cells. Notice, few shrunken irregular and scattered Purkinje cells (P) surrounded with vacuolated neuropil.

Figure 7: A photomicrograph of adult male rat cerebellar cortex exposed to 10 mg/kg NaF once daily for three months showed few shrunken irregular and scattered Purkinje cells (P) surrounded with vacuolated neuropil. H&E X 400.

Figure 8: A photomicrograph of adult male rat cerebellar cortex exposed to 10 mg/kg NaF once daily for three months showed Purkinje cells with absence of Nissels granules. The surrounding neuropil is vacuolated and many neuroglial cells (→) accumulate around Purkinje cells. H&E x 1000

Figure 9: A photomicrograph of adult male rat cerebellar cortex exposed to 10 mg/kg NaF once daily for three months showed many layers of distorted Purkinje cells with massive accumulation of cytoskeletal elements (P). The molecular layer showed irregularly arranged nerve fibers (→). Glees & Marsland,s silver stain x 250.

Also another study [23] reported that exposure to high dose of fluoride 25.57 (mg/kg) for 30 and 60 days, there was various degrees of reduction and pyknosis in the Nissel's granules of Purkinje cells [Figure 10].

Figure 10: A photomicrograph of rat cerebellar cortex exposed to 25.57 (mg/kg) 20-day-old of fluoride showed various degrees of pathology in the Nissl substance and the dendrites were elongated or absent. In some neurons spheroid bodies were present in the neuroplasm.

Saad El-Dien and others observed features of neurodegeneration in cerebellum of rats after 12 mg/Kg fluoride for two months treatment. The Purkinje cells appeared shrunken, deeply stained, with hardly identified nuclei [37]  [Figure 11 and 12].

Figure 11: A photomicrograph of the rat cerebellar cortex exposed to 12mg/Kg fluoride for two months showed; multilayer disposition of Purkinje cells (P) with darkly stained cytoplasm and hardly identified nuclei, irregular outline of Bergmann astrocytes nuclei (A) and dilated blood capillaries (Bc). Toluidine Blue(x 1,000).

Figure 12: An electron micrograph of rat cerebellar cortex exposed to fluoride 12mg/Kg body weight for two months, showed marked indentation of the nuclear membrane (arrow), dilated perinuclear and rough endoplasmic reticulum cisternae (R) and multiple lysosomes in Purkinje cell.

Sodium Fluoride Toxicity in Reproductive System: On applying the Tukey post-hoc test between them, he observed that there was a significant decrease in the sperm count while the other parameters showed a non-significant decrease [10].

Sodium Fluoride Toxicity in Digestive and Urinary Systems: Khadar and Jayantha shown cellular disarray, congestion, cellular degeneration, and cellular vacuoles in digestive and urinary organs of mice exposed to 5 mg/L/kg NaF for 15 days [20].

Sodium Fluoride Toxicity in Spinal Cord: The neurons showed positive immune reaction to caspase-3 which was indicated by dark brown staining of the cytoplasm and nuclei of these neurons, In Glial fibrillary acidic protein (GFAP) stained sections the neuropil showed a significant increase in the size of astrocytes (p<0.01). In Electron microscopy showed nerve cells with irregular nuclei and condensation of chromatin inside the nucleus. The cytoplasm contained swollen vacuolated mitochondria with destructed cristae. The rough endoplasmic reticulum was dilated taking a globular shape. Also, some areas of vacuolation could be detected inside the cytoplasm [17,18].

Sodium Fluoride Toxicity on Locomotor Behavior and Memory: Multiple studies observed that chronic NaF intoxication can lead to memory impairment in some memory tasks, increases noradrenaline (NA) and serotonin 5-hydroxytryptamine receptors (5-HT) in the striatum, hippocampus and neocortex. Dopamine (DA) increase was restricted to the striatum. Short-term NaF withdrawal did not reverse these NaF-induced changes, and both NaF treatments led to a mild fluorosis in rat incisors. No treatment effect was seen in body weight or fluid/water consumption. These results indicate that NaF induces memory impairment that outlasts short term NaF withdrawal (2 weeks) and may be associated with NA and 5-HT increases in discrete brain regions, when they use NaF intake 100 ppm in drinking water for 30 days in adult male rats [25,26,27].

Sodium Fluoride Toxicity on Cerebellum: Reported that administration of NaF 200 mg/kg body weight at 30 and 60 days of age of rats, result in damage to the system associated with structural and functional biosynthesis of cell protein, and proved histopathological by appearance of distorted shrunken Purkinje and surrounded by perineural spaces which indicated the reduction of their sizes and withdrawal of their nerve processes [28]. Advanced study showed that NaF treated rats for 30 and 60 days that might reflect the association between NaF and oxidative stress. This association enhanced lipid peroxidation and decreased glutathione levels with disturbance of protein, the nuclear and cytoplasmic changes approved by electron microscopic examination of cerebellar cortex of revealed features of neurodegeneration [29]. The most remarkable changes were observed in some Purkinje neurons, these changes were in the form of: nuclear irregularity, dilatations of rough endoplasmic reticulum and mitochondrial vacuolations with loss of their cristae [28]. In the another study reported the fluoride treated rats for 30 days showed that the myelinated and unmyelinated axons revealed degenerative structural changes in the form of vacuolation, destruction of some mitochondria and irregularity of myelin sheath, these changes were increased in rats aged 60 days, the disruption in myelination was attributed to the changes in myelin basic protein secondary to membrane damage and axonal degeneration after exposure to NaF, the defect in myelination was also attributed to increased water content in degenerating nerve causing intra myelinic edema with irregularity and separation of myelin lamellae [30]. Also in another study reported that fluoride treated rats for 60 days showed that the Purkinje cells in some sections arranged in multiple layers rather than a single layer, that the prolonged exposure to neuronal insult could lead to adaptive response in the form of crowding of Purkinje cells, that in a trial to re-establish the synaptic contact with other neurons in order to perform their function, the fluoride treated rats for 60 days showed engorgement of blood capillaries with blood cells and extravasations of RBCs in the interstitial spaces in between the granular cells. Also fluoride treated rats revealed severe pathological alterations as evidenced by congestion of the meningeal, cerebral and cerebellum blood capillaries, in addition to congestion of choroid plexus in the ventricle. Large hemorrhagic areas were also detected in the cerebral cortex, cerebellum white matter as well as in the ventricles around choroid plexuses. Explained the cause of extravasations that NaF affected the vascular endothelial cells leading to releases of nitric oxide which produced vasodilatation [22,31,32]. [33,34] attributed the neurodegenerative effects of fluoride to the binding of fluoride ions with antioxidant Nacetyl- cysteine, glutathione and other free radical destroying enzymes, triggering oxidative stress that leads to cell damage and even cell apoptosis. It was also observed that NaF increased nitric oxide synthase activity. This enzyme plays a major role in all neurodegenerative diseases, primarily by damaging mitochondrial energy production, inhibiting glutamate reuptake and stimulating lipid peroxidation [35,36] attributed the diverse actions of fluoride to the inhibition of a variety of enzymes as metalloenzymes that were proved to be involved in many essential metabolic processes as glycolysis, oxidative phosphorylation and neurotransmission. Dilated and congested blood vessels observed after fluoride treatment. In this study were explained by [37] who stated that NaF affected the vascular endothelial cells leading to release of nitric oxide, which is an endothelial relaxing factor. [20]Attributed the vacuolation observed in the neuropil to the shrinkage of cells and withdrawal of their processes secondary to cytoskeletal affection, thus leaving pericellular spaces. They also attributed the disruption in myelination after NaF treatment to the increased water content in degenerating nerve causing intramyelinic edema with separation of myelin lamellae. Hemorrhage observed in the neuropil [38] who stated that fluorides react with the soluble calcium compounds in the body to form insoluble calcium fluoride and thus act as anticoagulants. Their arrangement was disrupted; some disappeared completely while in other areas they exhibited multilayer accumulation. This might be caused by displacement from some areas to be accumulated in others. Most of them lost the pyriform shape and showed irregular outline.

Administration of NaF in male albino rats manifested as muscle weakness, tremors, loss of equilibrium, gait disturbance and limbs paralysis and the histological structure of the cerebellar cortex was disrupted with severe degenerative changes especially in the Purkinje cell layer with variant degrees of reduction and pyknosis in the Nissel's granules also degenerative structural changes in the form of vacuolation, destruction of some mitochondria and irregularity of myelin sheath.

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Corresponding Author: Naser A EISawy, Department of Anatomy and Embryology, Faculty of Medicine, Zagazig University, Egypt, E-mail: naser_elsawy@ymail.com

Copyright: © 2021 All copyrights are reserved by Naser A EISawy, published by Coalesce Research Group. This This work is licensed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.