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Fluoride Effects: The Two Faces of Janus
Abstract
The behavior of fluoride ions in the human organism is a classic example of double-edged sword. On the one hand the daily supplementation with fluoride is undoubtedly an important preventing factor in protecting teeth from caries, and, as an important mitogenic stimulus for osteoblasts, it may enhance mineral deposition in bone, but on the other hand fluoride, above a threshold concentration, has been demonstrated to be toxic. We present here a brief review of fluoride metabolism and exposure, its use in caries prevention and its effects on bone, followed by an updating about the main hypotheses concerning its mechanism of action and toxicity. The effects of fluoride have been related mainly to its ability to evoke the activation of G proteins and the inhibition of phosphotyrosine phosphatases, leading to an intracellular increase of tyrosine phosphorylation and activation of the mitogen-activated protein kinase pathway, and its capacity to cause generation of reactive oxygen species. We present also a unifying hypothesis accounting for these apparently different effects, although the available experimental models and conditions are highly variable in the literature. A lot of experiments still need to be performed to clarify the positive and negative effects of fluoride. Finding the mechanisms accounting for fluoride toxicity is an important point: indeed, the use of fluoride has been proposed in the preparation of new biomaterials to be inserted in the bone, in order to improve their stable and safe integration.
... Our study demonstrates that F exposure has a dose-dependent impact on zebrafish larvae, affecting survival rates and developmental milestones, leading to malformations as observed from previous studies [37][38][39]. The calculated LC 50 for NaF in zebrafish larvae was 204 ppm, which aligns with previously reported values in other fish species [40]. Low and moderate F dosages (25 and 50 ppm) were selected for further investigation, reflecting levels commonly found in natural water sources [41,42]. ...
... The increase in bone mineral density, as visualized through Alizarin Red staining, further confirms the positive role of F at low concentrations in promoting osteogenesis and mineral deposition. These results are in line with earlier studies suggesting that low levels of F stimulate osteoblast activity and mineralization [49][50][51]. However, at 50 ppm, F exposure led to a decline in mineral deposition and bone quality. ...
The presence of high levels of fluoride (F) in groundwater is a major issue worldwide. Although F is essential for healthy teeth and bones, excessive exposure can cause fluorosis or F toxicity. This condition primarily affects the hard tissues due to their high F retention capacity. F accumulation alters bone formation and resorption mechanisms interfering with mineral homeostasis and eventually manifests as skeletal fluorosis. Albeit the numerous studies on skeletal fluorosis, the effect of F on developmental osteogenesis is inconclusive. In light of this, we studied the effect of F on osteogenic differentiation, bone development, and mineralization in zebrafish. Zebrafish embryos were subjected to a low (25 ppm NaF), and a moderately high (50 ppm NaF) dose, along with a control (E3 medium alone) until 7 days postfertilization (dpf). The F content in the larvae was quantified to reveal a dose‐dependent increase in the exposed groups. Alizarin Red and alkaline phosphatase (ALP) staining suggested enhanced mineralization in the F‐treated groups. Quantitative analyses of the ALP activity and hydroxyproline (Hyp) content revealed similar results. Alcian blue staining of pharyngeal cartilages showed that F exposure alters the morphology of the major cartilages, indicating a possible craniofacial defect. Moreover, gene expression analyses of the bone markers associated with osteogenic differentiation, early mineralization, and remodeling ( runx2a/b , bmp4 , ocn , osx , col1a1 , alp , rank , rankl , and opg ) showed enhanced expression in the low F group. While the 50 ppm F group showed a decline in osteogenic activity, a considerable increase in the expression of mineralization markers was observed. The expression levels of cartilage markers sox9a and sox9b , remained insignificant, indicating the effect of F toxicity on osteogenesis and mineralization. Also, F exposure interferes with bone metabolism through altered osteogenic differentiation, development, and mineralization in zebrafish larvae.
... The group II phosphatases contain metallic centers and are inhibited uncompetitively by fluoride. However, several studies have shown the inhibitory effect of fluoride on the phosphatases without metal cofactors but the mechanism of inhibition is still unknown 46,47 . ...
The fluoride contamination in the soil imposes a serious impact on the soil characteristics as it affects the microbial activity and diversity in soil owing to its antimicrobial action. The antimicrobial activity of fluoride is mainly mediated by, (1) enzyme inhibition, (2) alteration of proton transfer via cell membranes, and (3) inhibition of biochemical processes in the microorganisms. The main sources of fluoride contamination in the soil are industrial discharge, weathering of rocks, and atmospheric deposition. Soil microorganisms play a very important role in the mineralization process and thus help in nutrient recycling during biogeochemical cycles. The mineralization of organic matter to nutrients by microorganisms is metabolism-dependent so the alteration of the activity of key enzymes by the fluoride changes the microbial diversity of soil. The microbial enzyme activity is highly susceptible to change in environmental factors and is therefore considered the most used parameter for soil pollution studies.
... Fluoride becomes harmful to health at amounts below/above this recommendation and it is considered as a double-edged sword due to its high metabolic changes in human body (Goldberg 2018). The WHO (2011) estimated that groundwater source having high fluoride desorption, that is, > 1.5 mg/L affects globally around 266 million people worldwide (Gazzano et al. 2010). Drinking water with excessive levels of fluoride can lead to dental, skeletal, and non-skeletal fluorosis and other serious public health problems in India (Lavanya, Shree, and Ramani 2024). ...
Fluoride is highly threatening to human health, and it is a serious issue worldwide, especially in India, because several states in India are at high risk of fluoride contamination in drinking water. In this study, the groundwater from Dharmapuri and Krishnagiri districts was chosen for estimation of quality and fluoride level. The 20 samples were collecetd from two districts, water quality and fluoride were estimated using standard protocols. The results showed that in Dharmapur districts, including Dharmapuri and Morappur, the water quality was very poor and the water was in bad condition, and also the water quality and fluoride levels were above the acceptable limits of WHO and TWAD board norms. In Krishnagiri district, such as Hosur, and Larger domestic water samples were highly polluted. The Pochampalli and Hangar, Anjetti, and area ground waters were in poor condition, the rest of the area's water quality and fluoride level are moderate, and may increase in the upcoming years. The quality of water and fluoride levels have crossed the permissible limits of WHO and TWAD board standards in several sites of Krishnagiri and Dharmapuri districts. Frequent monitoring, more awareness programs, fluoride removal advanced eco‐friendly, and highly efficient technologies are needed to manage these pollutants issues.
... manifests as specific changes in human teeth, bones, and surrounding tissues, resulting from excessive fluoride levels in food and drinking water [5]. Reports indicate that 32 % of people worldwide suffer from health issues related to fluorosis, which is endemic in around 22 countries [6,7]. Individual variations in nutritional status, fluoride dosage, and overall health significantly influence the severity of dental or skeletal fluorosis [4,8]. ...
Introduction
With advancements in detection equipment and an increase in the frequency of examinations, thyroid nodules and goiter in children have garnered attention.
Objective
This study aims to determine the effects of high iodine and fluoride exposure on thyroid nodules and goiter in school-aged children.
Methods
We recruited children aged 8 to 12 from rural Jiangsu, China, based on the concentrations of iodine and fluoride in local drinking water and urine. Participants were divided into four groups: a group with high fluoride and iodine (HFHI), a group with high fluoride (HF), a group with high iodine (HI), and a control group (CONTROL). Fluoride levels in both drinking water and urine samples were measured using the ion-selective electrode method. Urinary iodine (UI) was assessed using inductively coupled plasma mass spectrometry, and children's thyroids were examined with portable ultrasound equipment equipped with a linear 7.5-MHz probe.
Results
The detection rates of thyroid nodules in the HFHI, HF, HI, and CONTROL groups were 10.4 %, 6.5 %, 7.7 %, and 2.8 %, respectively. The goiter detection rates were 3.8 %, 2.9 %, 3.8 %, and 1.1 %, respectively. In the HFHI group, statistically significant correlations were found between urinary fluoride (UF) and thyroid nodules (P = 0.011, adjusted OR and 95 % CIs were 2.29 [1.21, 4.32]), as well as between UI and thyroid nodules (P = 0.038, adjusted OR and 95 % CIs were 1.58 [1.04, 2.40]), and between UI and goiter (P = 0.014, adjusted OR and 95 % CI were 2.31 [1.19, 4.48]). In the HI group, there was a statistically significant link between UI and goiter (P = 0.005, adjusted OR and 95 % CI were 2.45 [1.31, 4.58]).
Conclusions
Combined high iodine and fluoride exposure may have an adverse effect on thyroid nodules in school-age children.
... Fluoride helps the enamel remineralize [2] and also interferes with bacterial enzyme enolase activity inhibiting bacterial metabolism, thereby playing a major role in preventing dental caries. Long-term ingestion of fluoride, especially in infants and children, causes fluorosis [3]. Fluoride levels above 2 parts per million (ppm) can cause different types of fluorosis during development, such as opaque white patches, dentin hypersensitivity, mottled and pitted enamel, and severe chronic fluoride toxicity, which can damage heart cells, make ligaments hard, and cause kyphosis and changes in muscle size and shape [4]. ...
Introduction
Salt is an essential component of the Indian diet. Edible salt contains fluoride, and its concentration varies depending on the source and manufacturing process. This study aimed to assess the fluoride concentration of commonly available varieties of edible salts in India.
Methodology
This in vitro study was conducted with four different types of edible salts viz. iodized salt, rock salt, pink salt, and black salt. Two brands of each salt available in the market were procured. Fluoride estimation was conducted using the sodium 2-(parasulphophenylazo-)- 1,8-dihydroxy-3,6-naphthalene disulphonate (SPADNS) method using Fluoride High-Range Checker® HC (Hanna Equipments India Pvt. Ltd., Mumbai, India) with HI739-26 reagent. The reaction between fluoride and the reagent forms a colorless complex in the sample. The concentration is then determined from the color produced, measured in parts per million (ppm).
Results
Iodized salt showed the least fluoride content (12.5 ± 7.5 ppm), while it was highest for black salt (77.5 ± 19.9 ppm). There was a statistically significant difference between the study groups (p=0.009). Rock salt also showed high amounts of fluoride (40.8 ± 52.4 ppm).
Conclusion
Fluoride content in different types of edible salt varied, though well within the prescribed limits. This calls for nutritional labelling of fluoride to help the consumer make informed choices.
... Fluoride (F-) is a substance that has been used in the prevention and treatment of dental caries for many years. However, when large amounts are ingested, fluoride gives rise to a condition known as fluorosis (1) . Fluoride enters the body spontaneously or as a therapeutic resource. ...
When large amounts of Fluoride are consumed produces insulin resistance, but exercise can reverse insulin resistance in rats, because of a high fluoride uptake by bone tissue. However, bone quality has not been studied in those experiments. Therefore, the aim of this work was to evaluate bone quality in rats treated with fluoride when performing exercise. Sprague-Dawley rats were divided into 3 groups (n=6 per group): Control (drinking water without fluoride), Fluoride (drinking water with fluoride 15 mg/L for 30 days) and Exercise (daily running on a treadmill and drinking water with fluoride 15 mg/L for 30 days). Then, bone mineral density, mechanical and histological properties and bone fluoride level were measured. No effect of treatment on any bone parameters were observed. These results indicate that exercise normalizes glucose metabolism in insulin-resistant rats by bone fluoride uptake; however, this increase in bone fluoride does not manifest in bone deterioration.
By using a trapezoidal cage (1), highly selective recognition of F- (S>1000) was achieved in highly competitive environments composed of a large excess of various common anions. Through NMR, fluorescence,...
The first example of N-confused strapped calix[4]pyrrole 5 is presented. Structural integrity of 5 and its regular isomer 4 was unambiguously confirmed by the single crystal X-ray diffraction analysis. Anion binding studies using 1H NMR titration carried out in CDCl3 revealed little but detectable tendency of 5 to interact with anion. On the other hand, the isomeric regular strapped calix[4]pyrrole 4 displayed high selectivity for fluoride anion under similar experimental conditions. The high fluoride selectivity of 4 as well as unexpectedly low anion affinity of 5 was ascribed to the presence of intramolecular hydrogen bonds within the strapping
subunits.
Fluoride-modification of dental titanium (Ti) implants is used to improve peri-implant bone growth and bone-to-implant contact and adhesion strength. In this study, the surface topography, chemistry and biocompatibility of polished Ti surfaces treated with hydrofluoric acid solution (HF) were studied. Murine osteoblasts (MC3T3-E1) were cultured on the different groups of Ti surfaces. Surfaces treated with HF had higher roughness, lower cytotoxicity level and better biocompatibility than controls. For short treatment times (40 and 90 s), fluorine was detected only within the first 5 nm of the surface layer (X-ray Photoemission Spectroscopy, XPS), whereas longer treatment time (120 and 150 s) caused fluoride ions to penetrate deeper (Secondary Ion Mass Spectrometry, SIMS). These results suggest that submerging Ti implants in a weak HF solution instigate time-dependant specific surface changes that are linked to the improved biocompatibility of these surfaces.
Bioactive glasses such as Hench's 45S5 (Bioglass) have applications to tissue engineering as well as bone repair, and the insertion of fluoride in their composition has been proposed to enhance their bioactivity. In view of a potential clinical application, we investigated whether fluoride-containing glasses exert toxic effects on human MG-63 osteoblasts, and whether and how fluoride, which is released in the cell culture medium, might play a role in such cytotoxicity. A 24h incubation with 50 microg/ml (12.5 microg/cm(2)) of fluoride-containing bioactive glasses termed HCaCaF(2) (F content: 5, 10 and 15 mol.%) caused the release of lactate dehydrogenase in the extracellular medium (index of cytotoxicity), the accumulation of intracellular malonyldialdehyde (index of lipoperoxidation), and the increase of glutathione consumption. Furthermore, fluoride-containing glasses inhibited the pentose phosphate oxidative pathway and the glucose 6-phosphate dehydrogenase activity. These effects are ascribable to the fluoride content/release of glass powders, since they were mimicked by NaF solutions and were prevented by dimethyl sulfoxide and tempol (two radical scavengers), by superoxide dismutase (a superoxide scavenger), and by glutathione (the most important intracellular antioxidant molecule), but not by apocynin (an inhibitor of NADPH oxidase). The presence of fluoride-containing glasses and NaF caused also the generation of reactive oxygen species, which was prevented by superoxide dismutase and catalase. The data suggest that fluoride released from glasses is the cause of MG-63 cell oxidative damage and is independent of NADPH oxidase activation. Our data provide a new mechanism to explain F(-) ions toxicity: fluoride could trigger, at least in part, an oxidative stress via inhibition of the pentose phosphate oxidative pathway and, in particular, through the oxidative inhibition of glucose 6-phosphate dehydrogenase.
Abnormal level of fluoride in phreatic groundwater causes serious health hazards in humans and physiological damages in plants. This study showed that occurrence of fluoride is highly sporadic and localized in eastern and southeastern Karnataka and the concentration of fluoride varies from 1 to 7.4 mg/l. The geological strata near the wells influence the fluoride content in phreatic groundwater. Effective and cheap methods of defluoridation are few and hence biological defluoridation may be the best alternative to the conventional methods.
Fluoride is an important element for mineralization of body tissues. The use of topical and systemic fluoride for oral health has resulted in major reductions in dental caries and its associated disability. Fluoridation of public water supplies has been endorsed by over 90 professional health organizations as the most effective dental public health measure in existence. Still, about half of the US population fails to receive the maximum benefits possible from community water fluoridation and the use of fluoride products. Fluoride also plays a role in bone health. The role of high doses of fluoride for prevention of osteoporosis is undergoing active study and is considered experimental at this point. Dietetics professionals should routinely monitor and promote the use of systemic and topical fluorides, especially in children and adolescents. The American Dietetic Association strongly reaffirms its endorsement of the use of systemic and topical fluorides, including water fluoridation, at appropriate levels of intake, as an important public health measure. However, clients should be cautioned that, experimental use of high intakes of fluoride should be avoided unless they are participating in clinical trials.
Serotonin (5-hydroxytryptamine; 5-HT) caused a transient increase in intracellular Ca2+ in C6BU-1 glioma cells in a concentration-dependent manner; half maximally at 73 nM. The 5-HT2 agonist 1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane also increased the levels of intracellular Ca2+ whereas the 5-HTιc agonist l-(3-chlorophenyl)piperazine and 5-HT1a agonist 8-hydroxy-2-(di-n-propylamino)tetralin were completely ineffective. Ketanserin and spiperone blocked the response to 5-HT at a nanomolar concentration, but the 5-HT3 antagonist MDL 72222 had no effect on it. Thus 5-HT2 receptors are responsible for activating Ca2+ mobilization in C6 glioma cells. Treatment of C6 glioma cells with dexamethasone potentiated the ability of 5-HT to cause intracellular Ca2+ mobilization in both a dose- and time-dependent manner. The dose-response curve for 5-HTwas shifted 9-fold to the left compared to controls, and the Vmax value was also significantly enhanced. This enhanced Ca2+ mobilization was completely inhibited by ketanserin dose-dependently. In addition, the treatment with dexamethasone enhanced fluoride-activated Ca2+ mobilization, suggesting that the enhanced GTP binding protein function is one of the mechanisms responsible for the enhancement of the 5-HT response induced by dexamethasone treatment. This enhancement of agonist activity was mediated by the type II glucocorticoid receptor (GR) since RU 38486, an inhibitor of the type II GR, antagonized the dexamethasone-induced enhancement.Copyright © 1992 S. Karger AG, Basel
The aim of the present study was to investigate the biological mechanisms of the functional attachment of fluoride-modified titanium implants to cortical bone by studying the association of the pull-out test results with gene expression of osteoblast (runx2, osteocalcin, collagen-I and IGF-I), osteoclast (TRAP, H+-ATPase and calcitonin receptor) and inflammation (TNF-α, IL-6 and IL-10) markers from peri-implant bone tissue using real-time RT–PCR, following a 4- and 8-week healing period. After implant detachment, wound fluid from the implant site was collected for LDH and ALP activity analysis. A new method to study volumetric bone mineral density (vBMD) of sub-implant cortical bone was developed using micro-computed tomography. Our results show lower LDH activity and TRAP mRNA levels in fluoride implants after 4 weeks of healing, yet no differences were found either on the pull-out force or expression of bone formation marker genes. After 8 weeks of healing, both pull-out, vBMD and osteocalcin, runx2 and collage type I gene expression were higher in fluoride implants. In conclusion, fluoride-modified implants seem to modulate both inflammation and bone resorption/formation events at the bone–implant interface, suggesting that these biological effects are an intrinsic part of the clinical performance of this surface.
Sodium fluoride at a dose level of 5.0 mg/kg enhanced aminopyrine N-demethylase and NADPH cytochrome c reductase activities and cytochrome P450 and cytochrome b5 levels in rat liver, kidney, lung, intestine and testis, whereas acetanilide hydroxylase activity remained unchanged in kidney and lung and was increased in liver, intestine and testis. Sodium fluoride at 20.0 mg/kg caused a decrease in aminopyrine N-demethylase, acetanilide hydroxylase and NADPH cytochrome c reductase activities and cytochrome P450 and cytochrome b5 levels in all tissues, except for an increase in NADPH cytochrome c reductase activity in the intestine and testis. Fluoride at both dose levels produced only marginal changes in glutathione-S-transferase activity except for a 4-fold increase in the testis at 5.0 mg/kg. Sodium fluoride at 5.0 mg/kg increased lipid peroxidation in all tissues studied. At 20.0 mg/kg there was a decrease in lipid peroxidation in liver, lung and testis and an increase in kidney and intestine.