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Molecular mechanisms of fluoride toxicity
... It rarely appears in the natural environment in its elemental form (Zohoori and Duckworth, 2017). Conversely, fluoride is abundant in the environment, taking on various forms as it combines with other elements (Barbier et al., 2010). on a delicate balance of this element in the body: on the one hand, too little fluoride can lead to poor bone mineralisation and a high prevalence of dental caries. ...
... aluminium industry) or as an artificial additive in foodstuffs, water or dental care products (WHO, 1992;Ayoob and Gupta, 2006;Ghosh et al., 2013;Zohoori and Duckworth, 2017). Despite this wide variety of sources, water is considered to be the main source of fluoride, with concentrations varying between geographic regions and influenced by parameters such as pH, temperature and water hardness (WHO, 1984;Ayoob and Gupta, 2006;Barbier et al., 2010;Zohoori and Duckworth, 2017;Chowdhury et al., 2019). Groundwater in volcanic regions is particularly rich in fluoride. ...
... As a consequence, while fluoride concentrations in unpolluted surface waters are usually between 0.01-0.3 mg/l, groundwater in volcanic areas and in areas with geological deposits of marine origin usually contain high fluoride concentrations, up to 30-50 mg/l (Barbier et al., 2010;Shamsollahi et al., 2015;Zohoori and Duckworth, 2017). These figures are higher than World Health Organization (WHO) recommendations for fluoride intake in drinking water, which should not exceed 1.5 mg/l, because higher doses could lead to poisoning (WHO, 1992;. ...
La fluorose osseuse est une pathologie liée à l’ingestion prolongée de grandes quantités de fluorure, qui entraine notamment une augmentation de la densité des os. Cette maladie sévit souvent à l’état endémique dans certaines zones volcaniques où les eaux souterraines contiennent des doses élevées de fluor. Cette étude vise à proposer une approche multidisciplinaire combinant observations paléopathologiques et analyses archéométriques pour le diagnostic de la fluorose osseuse des restes humains provenant de sépultures secondaires à crémation de la période romaine (IIe siècle av. J.-C. – Ier siècle apr. J.-C.). L’échantillon étudié est composé de 45 individus originaires de la ville de Cumes (Campanie, sud de l’Italie), dans la région volcanique des Champs Phlégréens. Les lésions pathologiques ont été enregistrées selon un protocole d’observations macroscopiques. La détection et les mesures de fluor ont été effectuées par Spectroscopie d’émission atomique de plasma induit par laser (LIBS). Les résultats ont permis de confirmer que les os des habitants de Cumes présentaient des concentrations élevées de fluor et des lésions pathologiques très probablement liés à la fluorose osseuse. 49 % des sujets étudiés a été classé dans les catégories de suspicion modérée à forte de fluorose, indiquant une potentielle intoxication environnementale. Cela est probablement liée au caractère volcanique de la région et à la consommation des eaux souterraines.
... However, P. aeruginosa biopriming significantly restored these traits to near-control levels, likely through its growth-promoting effects and reduced F uptake. Similar improvements in the grain yield have been reported in T. aestivum L. and Z. mays L. following PGPR inoculation [73][74][75][76]. ...
... Fluoride stress led to excessive ROS accumulation in O. sativa L., increasing significantly in the roots (43% and 55%) and leaves (67% and 80%) compared to control plants ( Figure 4A,B). This ROS surge, a hallmark of oxidative stress, resulted from F poisoning, which enhanced ROS production and disrupted antioxidant enzyme activities by binding to sulfhydryl groups, thereby preventing protein synthesis [76]. Similar overproduction of ROS under F stress has also been reported in Olea europaea L. [65], Camellia sinensis L. [95], Eriobotrya japonica L. [96], and T. aestivum L. [97]. ...
Plant growth-promoting bacteria (PGPB) are free-living microorganisms that actively reside in the rhizosphere and affect plant growth and development. These bacteria employ their own metabolic system to fix nitrogen, solubilize phosphate, and secrete hormones to directly impact the metabolism of plants. Generating sustainable agricultural production under various environmental stresses requires a detailed understanding of mechanisms that bacteria use to promote plant growth. In the present study, Pseudomonas aeruginosa (MW843625), a PGP soil bacterium with a minimum inhibitory concentration (MIC) of 150 mM against fluoride (F), was isolated from agricultural fields of Chhattisgarh, India, and was assessed for remedial and PGP potential. This study concentrated on biomass accumulation, nutrient absorption, and oxidative stress tolerance in plants involving antioxidative enzymes. By determining MDA accumulation and ROS (O2•⁻ and H2O2) in Oryza sativa L. under F (50 ppm) stress, oxidative stress tolerance was assessed. The results showed that inoculation with P. aeruginosa enhanced the ability of O. sativa L. seedlings to absorb nutrients and increased the amounts of total chlorophyll (Chl), total soluble protein, and biomass. In contrast to plants cultivated under F-stress alone, those inoculated with P. aeruginosa along with F showed considerably reduced concentrations of F in their roots, shoots, and grains. The alleviation of deleterious effects of F-stress on plants owing to P. aeruginosa inoculation has been associated with improved activity/upregulation of antioxidative genes (SOD, CAT, and APX) in comparison to only F-subjected plants, which resulted in lower O2•⁻, H2O2, and MDA content. Additionally, it has also been reflected from our study that P. aeruginosa has the potential to increase the activities of soil enzymes such as urease, phosphatase, dehydrogenase, nitrate reductase, and cellulase. Accordingly, the findings of the conducted study suggest that P. aeruginosa can be exploited not only as an ideal candidate for bioremediation but also for enhancing soil fertility and the promotion of growth and development of O. sativa L. under F contamination.
... a p < 0.01 compared vs the NT group, bbb p < 0.0001 compared vs Trolox 200 µM group, ccc p < 0.0001 compared vs 500 µM F − group is well documented [14]. Epidemiological studies carried out in regions with high F − water content, have reported an increase in neurological alterations related to cognitive capacity in children such as the intelligence quotient (IQ) and disturbances of learning and memory processes [14,[58][59][60]. Accordingly, in vivo studies show that F − can permeate the brain blood barrier (BBB) after a chronic exposure [61,62]. ...
... Taking into consideration that glial cells outnumber neurons and that an exquisite glial-neuronal interplay takes place in glutamatergic synapses highly enriched in F − accumulated structures like the cerebellum and the hippocampus we decided to use two astrocytic models, one with a recognized increase in the exchanger expression (U373-MG cells) and one extremely characterized in terms of its involvement in Glu recycling (BGC) and that is also involved in Glu-dependent gene expression regulation [66]. As the most electronegative element, F − effects on cellular components are very extensive, it can disrupt signaling cascades and other regulatory processes such as post-translational regulators [58]. We focused on glutamatergic transmission; Glu has a pivotal role in synaptic plasticity, and its molecular regulation correlates with neurodevelopment [67]. ...
Fluoride exposure in drinking water has been widely related to impairment of cognitive function. Even though this ion has been described as neurotoxic for more than two decades, the molecular mechanisms of fluoride neurotoxicity are not fully understood, however, increasing evidence suggests that glial cells are the site of early injury in fluoride neurotoxicity. Nevertheless, a convergence point of many studies is the effect on glutamatergic neurotransmission and the generation of reactive oxygen species. In this context, we evaluated here the expression and regulation of the cystine/glutamate exchanger upon fluoride exposure since this transporter is in the interface between excitotoxicity and the antioxidant response. We demonstrate here the functional expression of the cystine /glutamate exchanger in both the U373 human glioblastoma cells and chick cerebellar Bergmann glia cells. Using a [³H]-L-Glutamate uptake assay, we demonstrate that fluoride increases the activity of the exchanger in a time and dose-dependent manner. This augmentation is mitigated by the antioxidant Trolox. To gain insight into fluoride neurotoxicity mechanisms, we evaluated its effect on human antigen R, a RNA binding protein, that binds to the 3'-UTR region of exchanger mRNA increasing its half time life. An increase in human antigen R protein was recorded after a 6 h fluoride exposure, suggesting that this ion regulates the exchanger through this RNA-binding protein. Furthermore, we show that fluoride exposure increases both the exchanger and human antigen R mRNAs half-life. These results provide insights into fluoride neurotoxicity mechanisms and support the notion of a central role of glial cells in neuronal glutamatergic transmission disruption that leads to neuronal cell death.
... It is very abundant in the Earth's crust (an average of 0.32 g/kg), being found in soils, water and the air. Fluoride concentrations range from 25 µM to 100 mM in water resources, and it may be the most abundant anion in certain groundwaters [1,2]. Consumption of water with a fluoride content close to 0.2 mM can produce dental fluorosis in children, while skeletal fluorosis, a more severe disease, may result from regularly drinking water with higher levels of fluoride (0.2 to 0.8 mM). ...
... It has a 2-micron (2 m) origin of replication, which yields a high number of plasmid copies (14-34) per cell. [31] pIPP1-699 1,2 Plasmid derived from pRS699b bearing the promoter and coding sequence of gene IPP1 from S. cerevisiae inserted upstream of the PMA1 terminator. [40] pIPP1-416 1 ...
Fluorine accounts for 0.3 g/kg of the Earth’s crust, being widely distributed in the environment as fluoride. The toxic effects of this anion in humans and other organisms have been known for a long time. Fluoride has been reported to alter several cellular processes although the mechanisms involved are largely unknown. Inorganic pyrophosphatases (PPases) are ubiquitous enzymes that hydrolyze inorganic pyrophosphate (PPi), a metabolite generated from ATP. In Saccharomyces cerevisiae, the enzyme responsible for PPi hydrolysis in the cytosol (IPP1) is strongly inhibited by fluoride in vitro. The essentiality of IPP1 for growth has been previously demonstrated using YPC3, a yeast mutant with conditional expression of the corresponding gene. Here, YPC3 was used to generate cells that tolerate high concentrations of fluoride by (a) the overexpression of IPP1 or its human ortholog, or (b) the substitution of IPP1 by the fluoride-insensitive PPase from Streptococcus mutans. The results obtained suggest that maintaining appropriate levels of PPase activity in the cytosol is essential for the adaptation of S. cerevisiae to high fluoride concentrations. The increase in fluoride tolerance allows YPC3 cells transformed with suitable plasmids to be selected on rich non-selective medium supplemented with this anion.
... As a result, crucial metabolic processes are disrupted (Pamela, 2011). Metabolic functions such as glycolysis are vital for maintaining the normal physiology of fish (Barbier, 2010). ...
... A study by Barbier et al., (2010) described a number of cellular processes in which fluoride can have adverse effects. Effects identified by various experimental studies include alteration of gene expression, disruption of enzyme activity (mainly inhibition), inhibition of protein synthesis and secretion, and generation of reactive oxygen species (ROS). ...
The toxicity of fluoride in aquatic organism increases with the rise in level of fluoride concentration, duration of exposure, and water temperature, while it diminishes with an increase in intraspecific size and the water levels of calcium and chloride. Freshwater invertebrates and fishes, particularly net spinning caddisfly larvae and migrating adult salmon, are more susceptible to fluoride toxicity compared to estuarine and marine species. In soft waters characterized by low ionic content, even a fluoride concentration as minimal as 0.5 mg F−/l can significantly harm invertebrates and fishes, prompting recommendations for safe levels below this threshold to safeguard freshwater organisms from fluoride contamination. Fluoride toxicity is becoming increasingly prevalent in various regions globally. Elevated fluoride levels in water jeopardize aquatic life, just as excess fluoride in drinking water poses risks to both animals and humans. Fish inhabiting freshwater contaminated with fluoride suffer adverse effects. Fluoride infiltrates and accumulates within their bodies, subsequently entering the food chain. While low fluoride levels are not life threatening, persistent bioaccumulation leads to toxic consequences in living organisms, which can have fatal outcomes. A comprehensive understanding of fluoride exposure and toxicity is essential for devising effective control and preventative strategies against fluoride pollution. Managing fluoride intoxication in fish is crucial to mitigate health risks for humans consuming fluoride affected fish and to enhance aquaculture yields.
... One such consequence is the development of dental or skeletal fluorosis, posing a significant concern for human health, and hence significant attention should be paid in the detection of fluoride at its low concentration [15]. The European Food Safety Authority (EFSA) has set a daily intake limit of 0.05 mg/kg body weight for both children and adults, aiming to mitigate the risk of dental caries [16,17]. In this regard, the identification and measurement of Zn 2+ and F − levels in biological and environmental systems using colorimetric and fluorogenic chemosensors provide valuable insights into cation/anion behaviour and potential environmental repercussions [18][19][20]. ...
Three thiosemicarbazone‐based bifunctional chemosensors 2‐(3‐ethoxy‐2‐hydroxybenzylidene)hydrazinecarbothioamide (S1), 2‐(3‐ethoxy‐2‐hydroxybenzylidene)‐ N ‐methylhydrazinecarbothioamide (S2) and 2‐(3‐ethoxy‐2‐hydroxybenzylidene)‐ N ‐phenylhydrazinecarbothioamide (S3) have been designed and synthesized. The sensor molecules displayed highly selective and sensitive colorimetric detection towards Co ²⁺ , Ni ²⁺ , Cu ²⁺ , Zn ²⁺ and Fe ³⁺ cations and F ⁻ anion, in addition to the remarkable selective ‘turn on’ fluorometric responses for Zn ²⁺ cation and F ⁻ anion. The high binding constant values are observed when S2 binds with Zn ²⁺ cation (2.83 × 10 ⁶ M ⁻¹ ) and S1 binds with F ⁻ anion (1.16 × 10 ⁶ M ⁻¹ ) with lower detection limit of 1.26 and 1.69 μM, respectively The theoretical studies endorsed the emission responses observed in the fluorescence spectral studies and the binding mode of chemosensors with sensed ions. Interestingly, the bioimaging studies with the chemosensors using Dr G cells and zebrafish larvae demonstrated the detection of Zn ²⁺ /F ⁻ ions at relatively lower concentration. Additionally, the chemosensors were successfully integrated into the molecular logic gate systems and the smartphone‐assisted RGB colour values, which enabled the real‐time detection of Zn ²⁺ /F ⁻ ions in various environmental and biological samples.
... In HEK-293, the mechanisms of Cd-induced apoptosis was well established by Mao et al., (2007). Elsewhere, high levels of fluoride cause numerous detrimental effects on cell metabolism and physiology, such as inflammatory responses, oxidative stress leading to the generation of reactive oxygen species and lipid peroxidation, inhibition of protein synthesis, and cell cycle progression as well as significant alterations in gene expression and DNA repair (Barbier et al. 2010). Most of these alterations repeatedly lead to apoptosis (Bai et al. 2010). ...
The phosphate fertilizer industry (PFI) in M’dhilla-Gafsa, Tunisia, discharges untreated effluents, creating environmental concerns due to unknown composition and toxic effects, leading to potential ecological and human health risks. This study characterized wastewater from three sampling points (SP1, SP2, SP3), and revealed their high acidity pH (2–3) and salinity (32.5–96.23 g/L). BOD5/COD ratios indicated the high recalcitrance (0.01–0.1) of the effluents, reflecting their low biodegradability and persistence in the environment. Excessive levels of phosphorus (206–2094 mg/L), fluoride (154–1071 mg/L), and sulfates (835.5–9266 mg/L) were detected by ionic chromatography. ICP-MS analysis highlighted for the first time the potentially toxic elements (PTEs) content in Tunisian PFI effluent, such us Cd (0.31–0.44 mg/L), Al (7.1–27.8 mg/L), Mn (1.9–3.5 mg/L), B (15.9–25.2 mg/L), Fe (15.7–28.7 mg/L), Ni (0.37–0.48 mg/L), and Cr (1.1–2.12 mg/L). These levels exceeded the permissible national and international limits for industrial discharges, as well as those of the World Health Organization (WHO) for drinking water, indicating serious potential environmental risks. Moreover, phytotoxicity tests on Medicago sativa, Pisum sativum, and Zea mays showed decreased amylolytic and proteolytic activities during germination. Blood toxicity assays indicated significant hemolytic effects. Indeed, 50% of SP1, SP2, and SP3 wastewaters caused hemolysis percentages equal to 52.04%, 57%, and 66.77%, respectively, implying therefore an acute toxicity of the effluents. Additionally, HEK-293 cells mortality was higher after exposure to effluents, with IC50 of 12.06%, 24.23%, and 17.68% for SP1, SP2, and SP3, respectively. These findings emphasized the potential risks posed by PFI effluents to the surrounding ecosystem and the agricultural sector, leading to the contamination of the food chain. This alarming threat imposes stricter wastewater treatment measures and regulatory enforcement in the PFI sector.
... Fluorosis, which is the clinical consequence of excessive fluoride intake, is a serious problem for public health (Barbier et al. 2010). It has been reported that high-dose fluoride intake may create injury of tissues such as the liver, kidney, brain, and testis, as well as skeletal and dental fluorosis (Shamsollahi et al. 2015;Altindağ and Özdek 2021). ...
The present study aimed to investigate the possible protective effects of chitosan (CS) on fluoride-induced nephrotoxicity. 28 rats were divided into four groups (n = 7). The Control group received drinking water. Sodium fluoride (NaF) group received 100 mg/L NaF in drinking water. NaF + CS group received 100 mg/L NaF and 250 mg/kg/day CS by gastric gavage. CS group was given 250 mg/kg/day CS by gavage. The study period lasted 12 weeks. Total kidney volume, Bowman’s capsule volume, Bowman’s space volume, Tubular volume and Glomerulus volume were measured by stereological methods. Immunohistochemically, caspase-3 and TNF-alpha expressions were evaluated. Biochemically, levels of urea and creatinine were measured. In addition, a histopathological evaluation of the kidney was performed. According to the control group, an increase was observed in all stereological parameters except glomerulus volume in the NaF group. CS treatment inhibited the increase in stereological parameters. Fluoride increased expressions of caspase-3 and TNF-α in the kidney, and serum urea and creatine levels, but CS decreased these parameters. In addition, pathological changes in the kidney caused by fluoride such as tubular dilatation, enlargement of the Bowman’s space, and deterioration in tubular epithelial cells were restored with CS treatment. The conclusions of the current study reveal that fluoride can cause nephrotoxicity and CS treatment can prevent fluoride-induced nephrotoxicity.
Graphical abstract
... This may be attributed to high phosphorous concentration in high fluoride water and its association with PTH and vitamin D, which may decrease serum phosphate levels compared to non-RO group children. Seasonal fluctuations were observed in some studies, though not recorded in the present study 26,27 . ...
Water is vital for the human body. Due to concerns over tap water, preference for taste, and convenience, there has been increased consumption of reverse osmosis (RO) water. Various metal ions (e.g., magnesium, calcium, sodium) are essential for human growth and function. Evaluate and compare serum calcium, magnesium, phosphate, alkaline phosphatase, and vitamin D levels in children consuming RO, non-RO, and high-fluoride drinking water. This comparative study included children aged 9–13. Participants were divided into three groups: RO water drinkers, non-RO water drinkers, and those consuming high-fluoride water. A questionnaire gathered socio-demographic, medical, sunlight exposure, and including a validated food frequency questionnaire (FFQ) for nutrient intake. Water samples were analyzed per APHA guidelines for calcium, magnesium, phosphorous, fluoride, and TDS. Urine samples assessed calcium and creatinine, while automated chemistry analyzers measured calcium, phosphorous, and alkaline phosphatase. Vitamin D levels were analyzed using immunoassay. Participants across all age groups were evenly distributed among the three water type groups. Drinking water type significantly correlated with serum and ionic calcium, magnesium, alkaline phosphatase, and serum phosphate levels. Higher 24-h urine calcium and creatinine were found in the high-fluoride group. Regression analysis showed significant associations between drinking water calcium, magnesium, phosphate, TDS, and serum levels after adjusting for age, gender, socioeconomic status, and dietary intake. (serum calcium = β = 0.006, p < 0.001, serum magnesium = β = 0.002, p < 0.001,serum phosphate = β = − 1.260, p = 0.016). Drinking water type impacts serum calcium, magnesium, phosphate, and alkaline phosphatase levels in children.
... Na/K ATPase is a membrane protein that plays an important role in maintaining the electrochemical membrane potential in cells. It is also involved in the provision of intracellular and extracellular electrolyte balances (32). F binds to the proteins of ion channels in cell membranes and inhibits them, causing the deterioration of membrane potential (33). ...
Objective: Fluoride toxicity primarily contributes to the production of reactive oxygen and nitrogen derivatives, trigger the cell death pathways by causing lipid peroxidation and DNA damage. Boric acid (BA) contributes to preservation of membrane integrity and function and maintenance of redox balance due to its high affinity to some metabolites in the organism. The aim of this study was to investigate the protective effect of BA on neurodegenerative processes against the toxic effects of sodium fluoride (NaF) administered at different doses on rat brain synaptosomes. Material and Methods: Synaptosomes obtained from the rat frontal cortex were administered at different doses of sodium fluoride (NaF) to determine the most toxic dose of NaF. Determined toxic dose of NaF for synaptosomes and BA concentrations were administered in vitro at 37°C for 30min and then the parameters of malondialdehyde (MDA) level, superoxide dismutase (SOD) activity, Na/K ATPase activity and DNA fragmentation value were measured spectrophotometrically. Results: There was a statistically significant difference between measured parameters, when the 80mg/L NaF group was compared with the control group. We found that 10 and 25 mM BA treatment provided a significant improvement in MDA, SOD, Na/K ATPase and DNA fragmentation compared to the 80mg/L NaF group. The 5 mM BA concentration was not found effective dose according to other doses. Conclusion: In conclusion, BA has potential for neuroprotective effects against cellular damage caused by NaF. The results suggest that the BA can be a neuroprotective therapeutic agent for fluoride toxicity.
... These proteins play critical characteristics in tumor cell survival under stress conditions making them key targets for anticancer drug development. Recent investigation have concentrated on inhibiting heat shock proteins to influence apoptosis in cancer cells, demonstrating the effectiveness of combined strategies involving fluorinated phospholipids and heat shock protein inhibition in enhancing therapeutic consequences [13]. ...
Fluorinated phospholipid analogs Edelfosine and Ilmofosine drug reveal expressive potential as antineoplastic factors though targeted interaction with heat shock protein (HSP70KDa1A), an essential mediator in cancer pathophysiology. Using evolved computational approaches, this research evaluated their ADMET (absorption, distribution, metabolism, excretion and toxicity) profiles receptor binding affinities and molecular dynamics. Molecular docking discernible vigorous interactions with Edelfosine drug displaying greater binding stability and consistent hydrogen bonding as confirmed by 100 ns molecular dynamics simulations. Comparative interpretation emphasized Edelfosine drug enhanced pharmacokinetic properties depicted by lower RMSD values, stable solvent-accessible surface area and reduced structural fluctuations relative to Ilmofosine drug. Functional annotation and phylogenetic investigation affirmed the evolutionary conservation and pivotal biological function of heat shock protein (HSP70KDa1A). These findings position Edelfosine drug as a promising candidate for targeted cancer therapy appropriated further experimental validation to elucidate its mechanisms of action and therapeutic efficacy.
... Induction of ROS that occurs as a result of F poisoning increases the production of O 2 •-, as well as its subsequent by-products, such as H 2 O 2 and OH . . Additionally, it has also been demonstrated that F can bind to sulfhydryl groups, which prevents proteins from being synthesized and incapacitates the activities of antioxidant enzymes [122]. As a result, an excessive accumulation of ROS is caused (2). ...
Plant‐growth promoting bacteria (PGPB) are free‐living microorganisms that actively
reside in the rhizosphere and affects plants growth and development. These bacteria employ their own metabolic system to fix nitrogen, solubilize phosphate, and secrete hormones to directly impact metabolism of plants. Gaining a sustainable agricultural production under various environmental stresses requires a detailed understanding of mechanisms that bacteria use to promote plants growth. In the present study, Pseudomonas aeruginosa (MW843625), a PGP soil bacterium with a minimum
inhibitory concentration (MIC) of 150 mM against fluoride (F) was isolated from agricultural fields of Chhattisgarh, India, and was assessed for remedial and PGP potential. This study concentrated on biomass accumulation, nutrient absorption, and oxidative stress tolerance in plants involving antioxidative enzymes. By determining MDA accumulation and ROS (O2.‐ and H2O2) in Oryza sativa L. under F (50 ppm) stress, oxidative stress tolerance was assessed. The results showed that inoculation with P. aeruginosa enhanced the ability of Oryza sativa L. seedlings to absorb nutrients, and increased the amounts of total chlorophyll (Chl), total soluble protein, and biomass. In contrast to plants cultivated under F‐stress alone, those inoculated with P. aeruginosa along with F showed considerably reduced concentration of F in their roots, shoots, and grains. The alleviation of deleterious effects of F‐stress on plants owing to P. aeruginosa inoculation has been associated with improved activity/ up‐regulation of antioxidative genes (SOD, CAT, and APX) in comparison to only F subjected plants, which resulted in lower O2.‐, H2O2, and MDA content. Additionally, it has also been reflected from our study that P. aeruginosa has the potential to increase the activities of soil enzymes such as urease, phosphatase, dehydrogenase, nitrate reductase and cellulase. Accordingly, the findings of the conducted study suggests that P. aeruginosa can be exploited not only as an ideal candidate for bioremediation but also enhancing soil fertility and promotion of growth and development of Oryza sativa L. under F contamination.
... Al has also been suggested to reduce the toxicity of F − [37]. An in vitro study in the rat pheochromocytoma cell line (PC12 cells) provided evidence of hormetic effects of NaF against Al maltotate; at low Our current knowledge of the toxicity of F − at the cellular level is based on in vivo and in vitro studies, including studies on oral, brain and blood cells, showing that F − is capable of inducing apoptosis via both intrinsic and extrinsic pathways [20][21][22][23]. Fluoride can affect cell metabolism and cell physiology, depending on factors such as cell type, concentration and duration of exposure. ...
The importance of fluorine and aluminum in all aspects of daily life has led to an enormous increase in human exposure to these elements in their various forms. It is therefore important to understand the routes of exposure and to investigate and understand the potential toxicity. Of particular concern are aluminum–fluoride complexes (AlFx), which are able to mimic the natural isostructural phosphate group and influence the activity of numerous essential phosphoryl transferases. Our review of salts of ionic AlFx species, which plausibly form the framework of complexes with biomolecules, revealed that the octahedral configuration of aluminum in the active site of the enzyme is preferred over the trigonal-bipyramidal structure. The effects of varying concentrations of fluoride, aluminum and AlFx—from micromolar to millimolar levels—on the viability and apoptosis rate of THP-1 monocytes were investigated using phosphate buffer solution as a culture media to simulate physiological conditions. Our results suggest that aluminum can reduce the direct toxicity of fluoride through the formation of AlFx. In view of the results found, further in vitro studies are required to clarify the toxicity mechanisms of these species.
... In the present study, significant depletion of GSH, GPx, SOD and CAT activity was observed in the cardiac tissue of rats after fluoride exposure. According to Barbier et al. (2010), there was a marked rise in LPO and a dramatic drop in antioxidant levels, both of which could be detrimental to heart tissues. Both QC and NQC treatments raised cardiac tissue GSH, GPx, SOD, and CAT activity, although the NQC group showed a much higher percentage of improvement. ...
... These proteins play critical characteristics in tumor cell survival under stress conditions making them key targets for anticancer drug development. Recent investigation have concentrated on inhibiting heat shock proteins to influence apoptosis in cancer cells, demonstrating the effectiveness of combined strategies involving fluorinated phospholipids and heat shock protein inhibition in enhancing therapeutic consequences [13]. ...
Fluorinated phospholipid analogs Edelfosine and Ilmofosine drug reveal expressive potential as antineoplastic factors though targeted interaction with heat shock protein (HSP70KDa1A), an essential mediator in cancer pathophysiology. Using evolved computational approaches, this research evaluated their ADMET (absorption, distribution, metabolism, excretion and toxicity) profiles receptor binding affinities and molecular dynamics. Molecular docking discernible vigorous interactions with Edelfosine drug displaying greater binding stability and consistent hydrogen bonding as confirmed by 100 ns molecular dynamics simulations. Comparative interpretation emphasized Edelfosine drug enhanced pharmacokinetic properties depicted by lower RMSD values, stable solvent-accessible surface area and reduced structural fluctuations relative to Ilmofosine drug. Functional annotation and phylogenetic investigation affirmed the evolutionary conservation and pivotal biological function of heat shock protein (HSP70KDa1A). These findings position Edelfosine drug as a promising candidate for targeted cancer therapy appropriated further experimental validation to elucidate its mechanisms of action and therapeutic efficacy.
... Industrial waste water is also a common source of fluoride contamination like paper & pulp industry (Emamjomeh et al., 2011). Human are generally exposure to fluoride by consuming the fluoride contaminant drinking water, tooth paste, fluoride gel, natural mineral and sediment (Barbier et al., 2010). ...
This work investigated the fluoride removal efficiency by calcium oxide-based polyaniline nanocomposite (CaO-PAn NC) and optimization study using Response Surface Methodology (RSM) and Artificial Neural Network (ANN). The kinetic and isotherm studies were well explained by pseudo-second-order and Langmuir isotherm model. The maximum fluoride adsorption capacity was 186.58 mg/g. The thermodynamics studies indicate the adsorption process was spontaneous and endothermic in nature. The optimal value for fluoride removal by CaO-PAn NC and the interactive effect of input variables pH, dosage, temperature and reaction time was investigated using RSM and ANN. The performances were determined using statistical tool regression coefficient (R²), Root mean square error (RMSE), Standard error of prediction (SEP) and Absolute average deviation (AAD). RSM with R² (0.9984), AAD (0.0401), RMSE (0.0902), SEP (0.2089) was at higher side of accuracy than ANN with R² (0.9877), AAD (0.1223), RMSE (0.5897), SEP (0.6409). The maximum fluoride removal was predicted to be 91.05% and 92.01% by RSM and ANN at (pH ̴ 7, time 65 min, temperature 35 °C, dose 0.55 g/L) respectively. The PAn nanocomposite can be reused up to 6th cycles for defluoridation mechanism.
... Additionally, the pathogenesis of fluorosis involves oxidative stress mediated by reactive oxygen species. [19][20][21][22] Among the various ROS, hypochlorite is particularly significant. [23][24][25] ClO − , a potent oxidant, not only oxidizes a broad spectrum of biomolecules within cells but also catalyzes the generation of free radicals. ...
Fluoride (F-) are common in the environment and are beneficial in moderate amounts but can be harmful at high concentrations, leading to conditions such as fluorosis influenced by reactive oxygen species (ROS), including hypochlorite (ClO-). This study introduces PZ-DT, a novel fluorescent probe with a phenothiazine core, designed for the sequential detection of F- and ClO-. PZ-DT emits orange-red fluorescence with a Stokes shift greater than 200 nm upon F- detection, demonstrating excellent selectivity and sensitivity, boasting a quantum yield of 19.33 % and a detection limit of 0.71 μM. Upon interaction with F-, PZ-DT forms PZ-F, which exhibits a blue shift in fluorescence upon ClO- detection, maintaining a Stokes shift of over 100 nm, a quantum yield of 36.2 %, and a detection limit of 19.97 nM. In serum analysis, PZ-DT shows a linear relationship between fluorescence intensity and F- concentration, enhancing its potential for quantitative analysis. In cellular imaging, PZ-DT highlights F- in the red channel and ClO- in the green and blue channels, allowing clear visualization of F- and ClO- interactions at the cellular level. In live mouse models, PZ-DT facilitates the visualization of F- dynamics and exposure decay, providing insights into its metabolic processes and potential health effects. These characteristics underscore its utility in the early diagnosis of fluoride-related diseases.
... Oxidative stress is a common mechanism underlying F − toxicity [39]. The accumulation of F − disrupts cellular homeostasis by directly attacking superoxide anions and interfering with oxygen metabolism, consequently increasing the generation of ROS [40]. In our study, a considerable increase in ROS levels was noticed in the NaF-treated group, confirming previous findings in rats [41], humans [42], and zebrafish [43]. ...
Fluoride (F⁻) is a major groundwater contaminant spread across the world. In excess concentrations, F⁻ can be detrimental to living beings. F⁻ exposure is linked to cellular redox dyshomeostasis, leading to oxidative stress‐mediated pathologies including heart dysfunction. Due to its potent antioxidant properties, various phytochemicals are found to alleviate the symptoms of F⁻ toxicity. Hence, we explore the protective effect of esculin (Esc), a coumarin glucoside on F⁻‐induced oxidative stress and cardiotoxicity in zebrafish larvae. The experimental groups consisted of NaF (50 ppm) and Esc (100 μM) groups treated alone and in combination with a control group for 6 h. The groups were maintained till 78 hpf after which the level of oxidants (ROS, LPO, and PCC) and antioxidants (GST, GSH, GPx, SOD, and CAT) were assessed. The results revealed that Esc pretreatment restored the depleted antioxidant markers and reduced the levels of oxidant in the Esc+NaF group, exhibiting its antioxidant potential. In addition, analyses of the heartbeat rate and hemoglobin integrity using o‐Dianisidine staining were conducted in the control and experimental groups. Esc treatment prevents F⁻ induced cardiac changes including tachycardia and altered blood flow. Further, the mRNA expression level of antioxidant genes (nrf2, gstp1, hmox1a, prdx1, and nqo1) and cardiac developmental genes (bmp2b, nkx2.5, myh6, and myl7) confirmed that Esc acts as a potent free radical scavenger and antioxidant defense enhancer, protecting zebrafish larvae from NaF‐induced oxidative stress and heart dysfunction.
... Fluoride exhibits cytotoxicity that is directly related to permeating cells as a weak acid [58,59]. Fluoride is also a known inhibitor of many enzymes that catalyse phosphoryl transfer reactions, predominantly by interacting with metal co-factors [59][60][61]. Likewise, in vitro studies on E. coli and gram-positive Arthrobacter atrocyaneus demonstrated that the primary enzyme for assembling long-chain polyPs, polyP kinase I, is inhibited by fluoride [62,63]. ...
Inorganic polyphosphates (polyPs) are energy-storing biopolymers synthesized by all three domains of life. PolyP accumulation has been well studied with respect to its role in stress response, but its role in dental disease has received less attention. Dental decay can be promoted by changes in pH as well as the chemical activity of ions such as phosphate in oral fluids at the enamel interface. Previous work has shown that the drawdown of phosphate from biofilm fluids can alter the saturation state of oral fluids to thermodynamically favour mineral dissolution. The members of the Lactobacillaceae are known to accumulate polyP and play a role in early-stage and late-stage dental caries. In this study, we examined the effects of potential metabolic inhibitors on polyP accumulation in Lacticaseibacillus rhamnosus . We observed that two inhibitors of the enzyme responsible for polyP synthesis, gallein and fluoride, inhibited polyP accumulation in a balanced medium. However, fluoride and gallein treatments amended with either glucose or lactate were found to enhance polyP accumulation. These results illustrate the potential complexity of polyP metabolism in the oral environment.
Nature-based solutions (NbS) mimic and integrate natural processes to endow with resilient and sustainable wastewater treatment methods. This study investigates complicated NbS frameworks that deal with wastewater issues by fusing modern technology with ecological engineering concepts. In order to maximise pollution exclusion while lowering energy and resource expenditure, the optional integrated systems make use of vegetated buffer strips, bioreactors supplemented with microbial consortia and built wetlands. Through an analysis of case studies and experimental projects, we exhibit how NbS may develop system resilience to climatic inconsistency, reduce pollution and rebuild ecosystems. This study emphasises NbS as a practicable way to endorse environmental sustainability in wastewater treatment and accomplish circular economy objectives. This chapter emphasises various methods employed by researchers in the area of fluoride removal from water and the mechanisms involved in fluoride removal.
Introduction. The multiplicity of the factors of the industrial environment, long-term affecting the body in workers in the aluminum industry due to the peculiarities of the technological production of aluminum is related to a high compilation in the air of electrolysis buildings of multi-component suspensions, the predominant of which are fluorides, which have a systemic effect on homeostasis. The development of arterial hypertension is determined by a complex of hemodynamic, neurohormonal, metabolic, and environmental factors associated with individual risk. Mini-satellite NOS3-VNTR, intron 4 of the gene of endothelial nitric oxide synthase is the most important biological mediator, the contribution of which to the development of cardiovascular pathology is undoubtedly high. Evaluation of the early manifestation of hypertension is of priority importance and associated with the definition of genotypes of predisposition / resistance to its development in metallurgists under the conditions of fluoride intoxication. Materials and methods. One hundred seventy three metallurgists were examined: 92 cases with a proven diagnosis of chronic fluorine intoxication, 81 person with individual signs of fluorine exposure to the skeleton (comparison group). VNTR4 polymorphism of the eNOS3 gene was analyzed using the PCR method, and their relationship with the development of arterial hypertension against the background of chronic fluoride intoxication was assessed. Results. The associative relationship of the VNT4 polymorphic locus genotypes with fluoride intoxication and concomitant arterial hypertension in non-ferrous metallurgy workers was studied. The distribution of genotypes corresponded to the law of equilibrium populations. Genotype 4a/4a is associated (χ2=9.4810; OR=3.233; p=0.002076) with the development of fluoride intoxication. Homozygote for allele b (4b/4b) is associated with resistance to the studied pathology (χ2=13.5461; OR=0.291; p=0.000233). The level of individual heterozygosity increases: genotype 4a/4b is significantly associated with the development of arterial hypertension against the background of chronic fluoride intoxication (p<0.05). Limitations. The study is limited by the number of people examined, it is advisable to increase the sample and population control. Conclusion. The identified genotypes act as markers of the risk of developing hypertension against the background of fluoride intoxication, which makes it possible to recommend genetic testing when forming risk groups to avoid early labour losses in production.
Health authorities have promoted community water fluoridation (CWF) to prevent dental caries for more than 75 years. However, growing evidence has raised questions about the safety of this public health intervention, particularly for young children who are at risk of excess fluoride intake. Divergent opinions about the risk–benefit ratio of CWF have ignited a global debate. The efficacy of topical fluoride in preventing dental caries is strong, whereas contemporary evidence for systemic administration of fluoride is weaker. Inequalities in access to dental care and topical fluorides introduce an additional layer of complexity. This review discusses evidence showing that fluoride ingestion is not essential for caries prevention, offers little benefit to the fetus and young infant, and can cause dental fluorosis and cognitive deficits. In an environment where fluoride is available from multiple sources, community-based administration of systemic fluoride may pose an unfavorable risk–benefit ratio for pregnant women and young children.
This paper addresses the upconversion of blue light to ultraviolet-C (UVC) with Pr³⁺-activated materials for antibacterial applications of UVC. It discusses the processes through which UV radiation provides biocidal effects on microorganisms, along with the most popular UVC sources employed in these processes. We describe the electronic and optical properties of the Pr³⁺ ion, emphasizing the conditions the host material must meet to obtain broad and intense emission in the UVC from parity-allowed transitions from the 4f5d levels and provide a list of materials that fulfill these conditions. This paper also delineates lanthanide-based upconversion, focusing on Pr³⁺ blue to UVC upconversion via the ³P0 and ¹D2 intermediate states, and suggests routes for improving the quantum efficiency of the process. We review literature related to the use of upconversion materials in antimicrobial photodynamic treatments and for the blue to UVC upconversion germicidal effects. Further, we propose the spectral overlap between the UVC emission of Pr³⁺ materials and the germicidal effectiveness curve as a criterion for assessing the potential of these materials in antimicrobial applications. Finally, this paper briefly assesses the toxicity of materials commonly used in the preparation of upconversion materials.
Fluoride ions (F⁻) play an important role in preventing cavities and treating osteoporosis, but excessive exposure can lead to serious health problems such as fluorosis and kidney damage. These dual characteristics highlight the need for selective and sensitive methods to detect fluoride ions for health monitoring. Accordingly, in this study, we investigated the anion-binding ability of Py-CT4, a fluorescent chemosensor in which pyrene is linked to calix[4]triazole via an ester linker. Notably, Py-CT4 exhibited significant fluorescence quenching for F⁻ compared to other anions, and its fluorescence intensity gradually decreased with increasing F⁻ concentration. This phenomenon is driven by electron transfer from calix[4]triazole to pyrene, initiated by hydrogen bonding with F⁻ and followed by F⁻-induced deprotonation of calix[4]triazole. The selectivity of Py-CT4 for F⁻ appears to stem from its relatively flexible structure and low acidity compared to the previously reported Py-CT4+. Py-CT4 thus represents the first macrocyclic receptor based on charge-neutral 1,2,3-triazole that selectively recognizes F⁻ through fluorescence quenching. Compared to traditional detection methods, Py-CT4 utilizes the advantages of fluorescent detection, such as higher sensitivity, faster response times, and ease of use, for fluoride ion detection. Py-CT4 also demonstrates excellent selectivity for F⁻ even in the presence of competing anions. These features make Py-CT4 a promising tool for monitoring fluoride ions in biological and environmental systems, providing valuable insights into public health and safety.
Two novel nitrogen hybrid fluorescent sensors based on the ESIPT mechanism were successfully synthesized for the detection of fluoride ions (F ⁻ ), and they exhibit high sensitivity and selectivity with a fast response. The detection limits even reach the parts per billion level. With the addition of F ⁻ , both sensors showed a ratiometric fluorescence change with a large Stokes shift. According to the hydrogen‐1 ( ¹ H) NMR titration, it was confirmed that the desilication reaction occurred between the sensors and F ⁻ . This work provides guidance for the subsequent development of F ⁻ fluorescence sensors.
Background
Excessive fluoride exposure leads to increased oxidative stress and lipid peroxidation, causing harmful effects on the metabolic organs in the human body. Betanin, a pigment obtained from beetroot, is seen to have powerful anti-inflammatory and antioxidant. The study was conducted to determine the role of betanin in fluoride induced hepato-renal toxicity in Wistar rats.
Methods
Twenty four rats were divided into four groups. Group Ⅰ (control) rats received 1 mL distilled water; group Ⅱ rats were administered 10 mg/kg of sodium fluoride (NaF); group Ⅲ received 10 mg/kg NaF and 50 mg/kg (low dose) betanin; group Ⅳ received 10 mg/kg NaF and 200 mg/kg (high dose) betanin. Animals were dosed orally for 90 days. Various markers of liver and kidney function as well as oxidative stress were measured. Liver and kidney samples were examined for histopathology.
Results
Animals in group Ⅱ had significantly increased levels of serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, creatinine, and blood urea nitrogen compared to the NaF + betanin treated animals (group Ⅲ & Ⅳ). Malondialdehyde, nitric oxide levels were significantly lower in rats treated with NaF + betanin (low & high dose). Histologically, in group II rats, signs of interstitial nephritis were seen in the kidneys while liver sections showed clear indication of features of fatty liver and inflammatory cell infiltration. Treatment with betanin alleviated the severity of histopathological changes induced by NaF.
Conclusions
Betanin significantly ameliorated NaF-induced oxidative stress and inflammation, therefore, has potential to be used as protective agent against fluoride induced hepato-renal toxicity.
Fluoride (F), present naturally in soil and water, is a lethal inorganic pollutant that needs to be treated immediately even at lower amounts. It interacts with flora, fauna, and other living things, including bacteria, to disrupt many metabolic pathways and adversely influence a range of physiochemical properties. Because conventional F remediation methods are costly, labor-intensive, and time-consuming, they are not practical for sustainable agriculture. Higher plants, fungus, bacteria, and algae are used as viable substitutes in biotechnological techniques such as bioremediation to control F contamination, rehabilitate polluted soil, as well as improve crop. The efficiency of natural native factors may be improved and preferred above dangerous substances in sustainable agriculture. With an emphasis on their application in cleaning up F-contaminated areas, this chapter examines the potential applications of a number of biological approaches in environmental cleanup. Furthermore, it highlights the importance of a thorough systematic review of modern biotechnological approaches to enhance plant-microbe relations and encourage fluoride degradation. This demonstrates most current developments in the field of treating F-polluted environments with microbial assistance.
Fluoride toxicity, resulting from prolonged exposure to elevated fluoride levels leading to oxidative stress, poses significant health risks, affecting various bodily systems and cellular processes. It also upregulates hormonal mechanisms, causing hormonal disruption in exposed individuals. Extracellular matrix degradation and bone deformity are expected impacts of fluoride toxicity, which are executed by elevated levels of Cyt c, Beclin 1, calcium, and Nf-kB. Due to the excessive release of calcium ions in the cytosol, it was depleted from its natural reservoir in the body, like teeth and bone, which finally leads to dental fluorosis, enamel hypo mineralization, weakening tooth structure, and susceptibility to decay. Skeletal fluorosis was also found commonly in fluoride-exposed individuals, which finally leads to bone and joint abnormalities. Fluoride also hampers ATP formation by interfering with glycolysis pathways, and it alters metabolic and reproductive hormones, causing impaired spermatogenesis, reduced sperm quality, and infertility. Hepatic effects manifest as hepatocyte degeneration and necrosis, contributing to liver damage. Developmental effects include genetic damage to DNA, IQ deficits, and increased risk of developmental abnormalities. Neurological impacts involve structural changes in the brain, memory issues, and neuronal loss. In this way, it was evident that Fluoride toxicity affects cellular organelles, inducing oxidative stress, apoptosis, and disrupting hormonal balance, mediated through alterations in cellular signaling pathways, transcription factors, and protein synthesis. It alters different genes implicated in bone metabolism, hormone signaling, and immune function, which leads to harmful impacts of fluoride on human health.
Fluoride is the ionic form the element fluorine and most widely distributed on earth surface. It is the most electronegative element and never exists in its elemental form and always associated with other element as fluoride. It is normally present in many foods and available as dietary supplements. Approximately 0.06–0.09% fluoride found in earth crust. It is universally present in water, soil, plants and animals. Ground water and surface water is frequently contaminated with fluoride from weathering of fluoride containing rocks, sediments and leaching and considered one of the potent environment pollutants. Many anthropogenic and industrial activities such as mining, semiconductor preparation, brick industry, glass manufacturing, electroplating, iron and aluminium smelters generate fluoride rich effluent. It is an indispensable element presents both in animals and humans body and play crucial role in mineralization of skeleton and development of tooth enamel. Fluoride is a double-edged sword. As per WHO, when it is consumed in inadequate quantity i.e. >0.5 ppm, trigger health issue including dental carries, reduce bone mineralization and reduce dental enamel formation specially in children and young generation. In disparity when it is consumed in excess i.e. <1 ppm cause significant health risk both adult and old and may induce various patho-physiological symptoms and disease in human.
This book chapter delves into the critical issue of fluoride contamination in groundwater, investigating the toxicological implications of exposure and proposing remedies for this urgent environmental challenge. Fluoride, a naturally occurring element, can infiltrate groundwater sources, resulting in elevated levels that surpass safety guidelines for human consumption. By conducting a thorough examination of current literature, this chapter elucidates the toxicological impact of chronic fluoride exposure on human health, emphasizing its effects on various physiological systems. It scrutinizes research revealing the detrimental effects of prolonged fluoride intake, including dental and skeletal fluorosis, neurotoxicity, and other health issues. Furthermore, the chapter explores a variety of remedial actions to address fluoride contamination in groundwater effectively. Strategies such as de-fluoridation techniques, community-driven water treatment initiatives, and policy implementations are considered to combat this environmental predicament and protect public health. Ultimately, the chapter endeavors to heighten awareness of the dangers posed by fluoride in groundwater, stressing the significance of water quality monitoring and advocating for efficient remediation methods. By offering insights into the toxicological ramifications of fluoride exposure and potential solutions, it aims to educate decision-makers, researchers, and communities on addressing this critical environmental and public health issue.
Growing human activities around the world in the form of industries, agriculture, mining, vehicular, etc. are introducing toxic substances into our environment. Toxic pollutants in our environment are harming the human population, plants, and animals. Environmental monitoring is essential to protect humans and the environment from toxic substances. Many new types of sensors are being developed for monitoring different types of toxic substances. Among them, portable miniaturized sensors represent cost-effective sensing systems, which can be transported to remote areas with considerable ease. An ideal on-site chemical analysis system must be inexpensive, fully automated, and compatible with a broad range of samples. For instance, they can also be utilized for monitoring the presence of foreign substances in the human body.
The present review covers emerging miniaturized sensor technologies for various environmental contaminants that fall into the following categories: (a) volatile organic contaminants (b) toxic metal ions (c) anions (d) biological contaminants, and (e) pesticides. The aim of the review is to present various miniature sensors from the user and constructor’s point of view. A comparative review of emerging sensor technologies with respect to their sensitivity, selectivity, and applicability can help the reader in developing new technology for future environment pollution concerns and also direct them to utilize existing technologies for a particular environmental problem.
Retrosynthetically designed and syntheses of three unprecedented core modified N‐confused porphyrinoids exhibiting vis‐NIR absorption with tunable aromaticity is reported. Controlled modification of types of oxidants (chloranil vs. DDQ) has led to the isolation of 18π‐aromatic porphyrinoid 7 (upon chloranil oxidation) while DDQ oxidation has led to 18 e σ‐aromatic porphyrinoids 8 and 9. All the three SN3 hybrid N‐confused porphyrinoids 7–9 have been thoroughly characterized via solution state spectroscopic measurements and in‐depth DFT studies for concluding π‐aromaticity of 7 and σ‐aromaticity of 8 and 9. While 7 could recognize the fluoride anion with high selectivity via deprotonation rather than an anion recognition based mechanism, acetate anion binding studies clearly revealed NH⋅⋅⋅AcO⁻ H‐bonding interaction in the host‐guest complex [7‐AcO⁻] supporting an anion recognition based mechanism. Porphyrinoids 8 and 9 remain unsusceptible to anion recognition. The conformational preorganization and anion induced deprotonation leading to conformational reorganization have been extensively studied by solution state spectroscopic techniques and in depth DFT level theoretical calculations.
Objective. To investigate the dynamics of changes in lipid peroxidation and antioxidant defense in blood and liver tissue under conditions of fluoride exposure before and during biological correction. Materials and methods. In the experimental conditions, 4 series of experiments were conducted on mature white Wistar rats weighing 170-200 g, which were administered an aqueous solution of sodium fluoride at a dose of 10 mg/kg of body weight daily for 30 days, separately and with consistent addition of bioprotectors to the animals’ food. In the first series of experiments, fluoride was administered without bioprotectors, in the second series – with pectin, in the third – pectin and calcium, in the fourth – a complex of pectin, calcium and antioxidants – vitamins C, E, β-carotene, selenium. Animals in the control groups were given drinking water and supplemented with appropriate bioprotectors. The content of diene conjugates, malondialdehyde, superoxide dismutase activity, catalase activity, and antioxidant activity index were determined in blood and liver tissue. The integral coefficient characterizing the antioxidant state of the organism was calculated based on the ratios of the activity of antioxidant defense and the intensity of lipid peroxidation processes. Results. It was found that during the experiment, the level of lipid peroxidation products was increased: diene conjugates in the blood by 168% on day 15 of the experiment, in the liver by 29.8%, on day 30 – in the blood by 36.2%, in the liver by 86.5%, malondialdehyde in the blood by 25.0%-53.0%, in the liver by 27.9%-41.7%, respectively, compared to the control group. Meanwhile, in both periods of observation, the activity of superoxide dismutase increased in the blood by 31.4%-46.0%, in liver tissue by 35.2%-75.2%, catalase activity decreased to a greater extent in the blood by 29.2%-51.4%, in liver tissue by 24.1% to 28.2% compared to the control group. The obtained results indicate an increase in oxidative stress in the dynamics of fluoride intoxication, which is confirmed by the low values of the integral coefficients. Pectin practically did not contribute to the improvement of antioxidant defense under conditions of prolonged fluoride intake. The addition of calcium with pectin to the diet of animals significantly improved the course of metabolic processes in the lipid peroxidation-antioxidant defense system. In the liver tissue, lipid peroxidation indicators were recorded at the control level, while in the blood the level of diene conjugates remained high, malondialdehyde exceeded the control values by 27.8%, and antioxidant defense was low. The enzymatic link of antioxidant defense was more active than the non-enzymatic link, with an antioxidant activity index lower by 31.7% compared to the control group. Calcium ions bind fluoride ions to form a hardly soluble calcium fluoride compound in the digestive tract, which inhibits fluoride absorption in the intestines and fluoride intake in the blood. Thanks to pectin, calcium fluoride can be excreted from the body. The addition of antioxidants to the diet of animals normalized the studied indicators of lipid peroxidation and the activity of superoxide dismutase and catalase in liver tissue, the integral coefficients were also almost at or close to the control level. Antioxidant defense is more active in liver tissue than in blood. Conclusions. Sodium fluoride caused oxidative stress in the test animals. The addition of pectin, calcium, vitamins C, E, β-carotene and selenium to the diet of the laboratory animals simultaneously activates metabolic processes, establishes a balance in the lipid peroxidation system - antioxidant defense of blood and liver tissue and can be used to correct antioxidant defense under conditions of negative fluoride exposure. Keywords. Sodium fluoride, blood, liver tissue, conjugated dienes, malondialdehyde, superoxide dismutase, catalase, bioprotectors.
Eight healthy female Inner Mongolia cashmere goats were divided randomly into two groups. To explore the effect of industrial fluoride pollution on the expression of type II collagen gene (COL2A1) in their rib cartilage, the control group of 3 goats was pastured in a safe low-fluoride area for 24 months and the fluorosed group of 5 goats was sent to pasture in Baotou, an industrial fluoride pollution area, for 24 months. At the end of 24 months, the COL2A1 gene expression levels in the rib cartilage of the control and fluorosed group were quantified with the help of conventional reverse transcription polymerase chain reaction (RT-PCR) and real-time RT-PCR. The results indicate that industrial fluoride pollution can affect the expression of the COL2A1 gene in rib cartilage of Inner Mongolia cashmere goats, inducing a high expression level of that gene.
The natural geological and geochemical environment, in addition to providing beneficial mineral content and bioessential elements to groundwaters, may also give rise to undesirable or toxic properties through a deficiency or an excess of various elements. In this paper the controls on the release of toxic elements are considered together with the geochemical conditions that give rise to excess and deficiency. In the context of groundwater pollution it is important first to define the natural baseline concentrations of key elements of health importance.
Fluoride (F) becomes toxic at higher doses and induces some adverse effects on various organs, including brain. The mechanisms
underlying the neurotoxicity caused by excess fluoride still remain unknown. The aims of this study were to examine F-induced
oxidative stress (OS) and role of melatonin (MEL) and buffalo pineal proteins (PP) against possible F-induced OS in brain
of rats. The 24 rats were taken in present study and were divided into four groups: control, F, F + PP, and F + MEL. The F
group was given 150mg/L orally for 28days. Combined 150ppm F and 100μg/kg BW (i.p.) PP and F (150ppm) + MEL (10mg/kg
BW, i.p.) were also administered. The activities of enzymatic, viz., superoxide dismutase (SOD), glutathione peroxidase (GPx),
catalase (CAT), glutathione reductase (GR), and non-enzymatic, viz., reduced glutathione (GSH) concentration, and the levels
of malondialdehyde (MDA) in the brain tissue were measured to assess the OS. Fluoride administration significantly increased
brain MDA compared with control group, while GSH levels were decreased in fluoride-treated groups, accompanied by the markedly
reduced SOD, GPx, GR, and SOD activity. Buffalo PP and MEL administration caused brain MDA to decrease but caused SOD, GPx,
GR, GSH, and CAT activities to increase to significant levels in F-treated animals. Together, our data provide direct evidence
that buffalo PP and MEL may protect fluoride-induced OS in brain of rats through mechanisms involving enhancement of enzymatic
and non-enzymatic antioxidant defense system. Therefore, this study suggested that PP and MEL can be useful in control of
neurotoxicity induced by fluoride.
The effect of fluoride intoxication on lipid peroxidation and antioxidant systems in the blood, brain, and liver of rats was studied. Twelve one-month-old albino rats were administered 100-ppm fluoride (as NaF) in their drinking water for four months. In the red blood cells the levels of malondialdehyde (MDA) and glutathione (GSH) increased, along with the activity of glutathione peroxidase (GSH-Px), but the activity of superoxide dismutase (SOD) decreased. In the plasma the level of ascorbic acid increased while that of uric acid decreased. In the brain and liver, MDA and GSH levels increased, as did the activities of GSH-Px and glutathione S-transferase (GST). The level of ascorbic acid increased in the brain, but it decreased in the liver. These results suggest that fluoride enhances lipid peroxidation in the red blood cells, brain and liver of rats and causes increased or decreased enzyme activity associated with free radical metabolism.
In the village of Kheru Nayak Thanda in the Gulbarga district of Karnataka, India, 18 children aged 3 to 10 years with endemic skeletal fluorosis were shown to have oxidative stress as evidenced by elevated levels of malondialdehyde in their red blood cells, indicating increased lipid peroxidation. Significant alterations of antioxidant systems in the blood were confirmed by decreased levels of glutathione and uric acid together with an increase in the activity of glutathione peroxidase as well as the level of ascorbic acid along with a slight decrease in the activity of superoxide dismutase.
The effect of fluoride exposure during gestation and post gestation periods were studied to check the status of oxidant, antioxidant and macromolecular changes in CNS and ameliorative role of antioxidants. The pregnant Wistar albino rats were exposed to 50 and 150 ppm fluoride in drinking water and the pups born to them were used for experimentation. After postpartum, the pups were administered daily selected antioxidants through oral gavage. On 21st postnatal day pups were sacrificed and biochemical parameters were assessed. Fluoride exposure substantially increased the activity/levels of fluoride, LPO, protein oxidation, MAO-B, GOT, GPT and decreased protein thiols, RNA and total proteins in discrete regions of CNS. The findings evidenced fluoride induced dyshomeostasis caused on antioxidants, enzymes, macromolecules and governed the pathophysiological events leading to functional loss in a dose dependent manner. The administration of antioxidants remedied the disquiet caused by high fluoride exposure at extreme vulnerable periods of life.
Fluoride is an essential trace element for human body; however, exposure to high amounts of fluoride has been documented to be correlated with an increasing risk of hair loss. To date, little is known about the mechanism(s) of how fluoride affects hair follicles. Here, we demonstrated that middle (1.0 mmol/L) and high (10.0 mmol/L) concentrations of sodium fluoride (NaF) significantly inhibited hair follicle elongation in vitro, but low NaF (0.1 mmol/L) showed little influence. Moreover, treatment with high levels of NaF resulted in a marked increase in terminal dUTP nick end labeling-positive cells in the outer layer of the outer root sheath, the dermal sheath, and the lower bulb matrix surrounding dermal papilla. Furthermore, the enhanced apoptosis was coupled with an increased oxidative stress manifested as higher malondialdehyde content. Additionally, the presence of selenium considerably antagonized the effects of middle NaF on hair follicles, with regard to either the suppression of hair growth or the induction of oxidative stress and apoptosis. In conclusion, exposure to high levels of fluoride compromises hair follicle growth and accelerate cell apoptosis in vitro. The toxicity of fluoride can be reduced by selenium, at least partially via the suppression of intracellular oxidative stress.
Sixty-three patients with endemic fluorosis (36 males/27 females; mean age 33.9 +/- 8.6 years) and 45 age-, sex-, and body mass index-matched healthy controls (30 males/15 females; mean age 32.7 +/- 8.8 years) were included in this study. Aortic stiffness indices, aortic strain (AS), aortic distensibility (AD), and aortic strain index (ASI) were calculated from the aortic diameters measured by echocardiography and blood pressure obtained by sphygmomanometry. The urine fluoride levels of fluorosis patients were significantly higher than control subjects as expected (1.9 +/- 0.1 mg/l vs. 0.4 +/- 0.1 mg/l, respectively; P < 0.001). AS and AD were significantly lower in fluorosis patients than in the controls (for AS 5.3 +/- 3.6 vs. 8.0 +/- 3.4%; P < 0.001 and for AD 0.2 +/- 0.1 vs. 0.3 +/- 0.1 cm(2) dyn(-1) 10(-3); P < 0.001, respectively). In contrast, significantly higher ASI was observed in fluorosis patients than in the controls (3.4 +/- 0.6 vs. 3.0 +/- 0.4; P < 0.001, respectively). The results of our study demonstrate that elastic properties of ascending aorta are impaired in patients with endemic fluorosis.
CatSper1-4 are a unique family of sperm cation channels, which are exclusively expressed in the testis and play an important role in sperm motility and male fertility. Despite their vital role in male fertility, almost nothing is known about the factors regulating their expression. Here, we investigated the effects of selenium (Se) on the expression of CatSper genes and sperm parameters in aging versus young male mice.
Forty 11-13 months aging male mice and forty 2-3 months young adult male mice were used. The animals were divided in two experimental groups: first group including aging males and second group comprising of young adult males, both treated with Se. The experimental groups were injected intra-peritoneally with Se (0.2 mg/kg) daily, for up to 5 weeks. Two other groups, aging and young adult mice without Se treatment were used as controls. All the animals were rapidly sacrificed by cervical dislocation on the days 21, 28, 35 and 42 after Se treatment. Subsequently, the morphology of the collected sperms was analyzed, and one of the testes from each mouse used for semi-quantitative RT-PCR. The significancy of the data was analyzed using ANOVA.
Our data revealed that there was a significant up-regulation of CatSper genes in the experimental groups compared to the control ones. Furthermore, the results of sperm analysis showed that the sperm parameters were improved in the aging as well as young adult male mice following Se treatment.
Se treatment in the aging subjects could up-regulate the expression of CatSper genes, and therefore results in elevation of sperm motility. Furthermore, Se treatment improved sperm parameters, especially morphology and viability rates.
The kidney plays an important role in maintaining the systemic Ca2+ and Mg2+ balance. Thus the renal reabsorptive capacity of these cations can be amended to adapt to disturbances in plasma Ca2+ and Mg2+ concentrations. The reabsorption of Ca2+ and Mg2+ is driven by transport of other electrolytes, sometimes through selective channels and often supported by hormonal stimuli. It is, therefore, not surprising that monogenic disorders affecting such renal processes may impose a shift in, or even completely blunt, the reabsorptive capacity of these divalent cations within the kidney. Accordingly, in Dent's disease, a disorder with defective proximal tubular transport, hypercalciuria is frequently observed. Dysfunctional thick ascending limb transport in Bartter's syndrome, familial hypomagnesaemia with hypercalciuria and nephrocalcinosis, and diseases associated with Ca2+-sensing receptor defects, markedly change tubular transport of Ca2+ and Mg2+. In the distal convolutions, several proteins involved in Mg2+ transport have been identified [TRPM6 (transient receptor potential melastatin 6), proEGF (pro-epidermal growth factor) and FXYD2 (Na+/K+-ATPase gamma-subunit)]. In addition, conditions such as Gitelman's syndrome, distal renal tubular acidosis and pseudohypoaldosteronism type II, as well as a mitochondrial defect associated with hypomagnesaemia, all change the renal handling of divalent cations. These hereditary disorders have, in many cases, substantially increased our understanding of the complex transport processes in the kidney and their contribution to the regulation of overall Ca2+ and Mg2+ balance.
Apoptosis is a conserved homeostatic process critical for organ and tissue morphogenesis, development, and senescence. This form of programmed cell death also participates in the etiology of several human diseases including cancer, neurodegenerative, and autoimmune disorders. Although the signaling pathways leading to the progression of apoptosis have been extensively characterized, recent studies highlight the regulatory role of changes in the intracellular milieu (permissive apoptotic environment) in the efficient activation of the cell death machinery. In particular, glutathione (GSH) depletion is a common feature of apoptotic cell death triggered by a wide variety of stimuli including activation of death receptors, stress, environmental agents, and cytotoxic drugs. Although initial studies suggested that GSH depletion was only a byproduct of oxidative stress generated during cell death, recent discoveries suggest that GSH depletion and post-translational modifications of proteins through glutathionylation are critical regulators of apoptosis. Here, we reformulate these emerging paradigms into our current understanding of cell death mechanisms.
Fluorosis is a serious public health problem in many parts of the world. As in the case of many chronic degenerative diseases, increased production of reactive oxygen species has been considered to play an important role, even in the pathogenesis of chronic fluoride toxicity. Black berry is closely linked to its protective properties against free radical attack. Therefore, the aim of this study was to demonstrate the role of black berry juice (BBJ) in decreasing the hepatotoxicity and oxidative stress of sodium fluoride (NaF). Results showed that NaF caused elevation in liver TBARS and nitric oxide (NO), and reduction in superoxide dismutase (SOD), catalase (CAT), total antioxidant capacity (TAC) and glutathione (GSH). Plasma transaminases (AST and ALT), creatine kinase (CK), lactate dehydrogenase (LDH), total lipids (TL), cholesterol, triglycerides (TG), and low density lipoprotein-cholesterol (LDL-c) were increased, while high density lipoprotein-cholesterol (HDL-c) was decreased. On the other hand, BBJ reduced NaF-induced TBARS, NO, TL, cholesterol, TG, LDL-c, AST, ALT, CK and LD. Moreover, it ameliorated NaF-induced decrease in SOD, CAT, GSH, TAC and HDL-c. Therefore, the present results revealed that BBJ has a protective effect against NaF-induced hepatotoxicity by antagonizing the free radicals generation and enhancement of the antioxidant defence mechanisms.
Ca2+ is a universal second messenger used to regulate a wide range of cellular processes such as fertilization, proliferation, contraction, secretion, learning and memory. Cells derive signal Ca2+ from both internal and external sources. The Ca2+ flowing through these channels constitute the elementary events of Ca2+ signalling. Ca2+ can act within milliseconds in highly localized regions or it can act much more slowly as a global wave that spreads the signal throughout the cell, Various pumps and exchangers are responsible for returning the elevated levels of Ca2+ back to the resting state. The mitochondrion also plays a critical role in that it helps the recovery process by taking Ca2+ up from the cytoplasm. Alterations in the ebb and flow of Ca2+ through the mitochondria can lead to cell death. A good example of the complexity of Ca2+ signalling is its role in regulating cell proliferation, such as the activation of lymphocytes. The Ca2+ signal needs to be present for over two hours and this prolonged period of signalling depends upon the entry of external Ca2+ through a process of capacitative Ca2+ entry. The Ca2+ signal stimulates gene transcription and thus initiates the cell cycle processes that culminate in cell division.
Rho, Rac and Cdc42, three members of the Rho family of small GTPases, each control a signal transduction pathway linking membrane receptors to the assembly and disassembly of the actin cytoskeleton and of associated integrin adhesion complexes. Rho regulates stress fibre and focal adhesion assembly, Rac regulates the formation of lamellipodia protrusions and membrane ruffles, and Cdc42 triggers filopodial extensions at the cell periphery. These observations have led to the suggestion that wherever filamentous actin is used to drive a cellular process, Rho GTPases are likely to play an important regulatory role. Rho GTPases have also been reported to control other cellular activities, such as the JNK (c-Jun N-terminal kinase) and p38 MAPK (mitogen-activated protein kinase) cascades, an NADPH oxidase enzyme complex, the transcription factors NF-kappaB (nuclear factor kappaB) and SRF (serum-response factor), and progression through G1 of the cell cycle. Thus Rho, Rac and Cdc42 can regulate the actin cytoskeleton and gene transcription to promote co-ordinated changes in cell behaviour. We have been analysing the biochemical contributions of Rho GTPases in cell movement and have found that Rac controls cell protrusion, while Cdc42 controls cell polarity.
Remodeling of the endothelial cell (EC) cytoskeleton is central to many functions of the endothelium. The Rho family of small GTP-binding proteins have been identified as key regulators of F-actin cytoskeletal dynamics in a variety of cell types. They integrate signals from soluble mediators interacting with cytokine, growth factor tyrosine kinase, and G-protein–coupled receptors (GPCRs); as well as signals from cell–cell, and cell–matrix protein adhesion molecules. Recently, it has become appreciated that effector molecules downstream of Rho GTP-binding proteins also modulate several other well described cell signaling pathways. We review the role these molecules play in the cell, with a particular focus on the EC. HISTORY The Rho family of small GTP-binding proteins, which consists of 22 members, is part of the larger Ras GTP-binding protein superfamily. These approximately 21-kDa proteins cycle between inactive GDP-and active GTP-bound forms to act as a molecular switch in signal transduction pathways. The members of this family are grouped by virtue of a shared structural motif, the Rho insert loop, that is present in the GTPase domain and contributes to the binding specificity for downstream effector molecules (1,2). In addition to this shared structural feature, most Rho family members undergo post-translational modification to link farnesyl or geranylgeranyl groups to the cysteine in a CAAX motif at the C-terminus of the molecule. Subcellular localization of the molecule is directed by the lipid moiety and, in some family members, is also influenced by additional domains in the C-terminus.
Rat peritoneal mast cells, both intact and permeabilized, have been used widely as model secretory cells. GTP-binding proteins and calcium play a major role in controlling their secretory response. Here we have examined changes in the organization of actin filaments in intact mast cells after activation by compound 48/80, and in permeabilized cells after direct activation of GTP-binding proteins by GTP-gamma-S. In both cases, a centripetal redistribution of cellular F-actin was observed: the content of F-actin was reduced in the cortical region and increased in the cell interior. The overall F-actin content was increased. Using permeabilized cells, we show that AIF4-, an activator of heterotrimeric G proteins, induces the disassembly of F-actin at the cortex, while the appearance of actin filaments in the interior of the cell is dependent on two small GTPases, rho and rac. Rho was found to be responsible for de novo actin polymerization, presumably from a membrane-bound monomeric pool, while rac was required for an entrapment of the released cortical filaments. Thus, a heterotrimeric G-protein and the small GTPases, rho and rac, participate in affecting the changes in the actin cytoskeleton observed after activation of mast cells.
To study the effector function of the ADP- ribosylation factor (ARF) 6 GTP-binding protein, we transfected HeLa cells with wild-type, epitope-tagged ARF6. Previously shown to indirectly activate the ARF1 GTPase, aluminum fluoride (AIF) treatment of ARF6-transfected cells resulted in a redistribution of both ARF6 and actin to discrete sites on the plasma membrane, which became increasingly protrusive over time. The effects of AIF were reversible, specific to cells transfected with wild-type ARF6, and resembled the cellular protrusions observed in cells expressing the GTPase defective mutant of ARF6. Importantly, the protrusions observed in cells transfected with ARF6 were distinct from the enhanced stress fibers and membrane ruffles observed in cells transfected with RhoA and Rac1, respectively. In cells forming protrusions, there was an apparent stimulation of macropinocytosis and membrane recycling within the protrusive structures. In contrast, no block in transferrin uptake or alteration of the distribution of clathrin AP-2 complexes was detected in these cells. The AIF-induced, ARF6- dependent formation of protrusive structures was blocked by cytochalasin D and inhibitors of the lipoxygenase pathway. These observations support a novel role for the ARF6 GTPase in modeling the plasma membrane and underlying cytoskeleton.
: This study was conducted to investigate effects of fluoride on lipid peroxidation and antioxidant systems in young pigs. Three groups of crossbred barrows about 50 days old were exposed to 100, 250, and 400 mg F – /kg (from NaF) in their diets for 50 days. Serum malondialdehyde (MDA) and nitric oxide (NO) levels were significantly increased, and the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) were significantly decreased. In thyroid, liver, and kidney tissues, the MDA level was significantly increased, and SOD and GSH-Px activities were significantly decreased. These results suggest that fluoride induces excessive production of NO and reactive oxygen species (ROS), enhances lipid peroxidation, and disturbs the antioxidant system of pigs. Oxidative damage from oxidative stress could therefore be an important pathway for fluoride toxicity in soft tissues.
Abstract: To study the effect of acute fluoride poisoning on nitric oxide and methemoglobin formation, 250 mg/kg bw sodium fluoride was applied alone and verapamil was applied together with fluoride. Blood nitric oxide (Griess reaction) and calcium levels; hemoglobin, methemoglobin and hematocrit values; and erythrocyte counts were determined and compared with those of the controls. After the fluoride application it was found that there was a relative relationship between the increase in nitric oxide and methemoglobin levels and the decrease in calcium, hemoglobin and hematocrit levels and erythrocyte count. It was concluded that the increase seen in blood nitric oxide levels as a result of the ionophore effect of fluoride could come from cNOS, as that increase is related to the decrease in calcium amount.
This book contains eight chapters discussing the history of fluorine and sources of fluorides in the environments. The uptake, transport and accumulation of inorganic fluorides by plants and animals, as well as their effects on these organisms are discussed. Some case histories in Scotland, Oregon (USA), British Columbia (Canada) and Cubatão (São Paulo, Brazil) involving fluoride contamination are examined. Monitoring and identifying effects of fluoride in the field, and the environmental standards to protect humans, other animals and plants are highlighted. Finally, the important properties of some natural organofluorine compounds (particularly monofluoroacetate) and manufactured organofluorine compounds (e.g. pharmaceuticals and agricultural chemicals) are described.
The hydration products, microstructures and pore structures of paste with part of Portland cement replaced by superfine phosphoric slag were investigated by XRD, DTA and SEM in this article. The results shown that the appropriate replacement of Portland cement by superfine phosphoric slag can decrease the amount of portlandite, increase the amount of C–S–H gel, reduce the harmful pores (larger than 100nm), make the structure denser, and improve the microstructure and durability of concrete.
This paper presents a four-step training method for increasing the efficiency of support vector machine (SVM). First, a SVM is initially trained by all the training samples, thereby producing a number of support vectors. Second, the support vectors, which make the hypersurface highly convoluted, are excluded from the training set. Third, the SVM is re-trained only by the remaining samples in the training set. Finally, the complexity of the trained SVM is further reduced by approximating the separation hypersurface with a subset of the support vectors. Compared to the initially trained SVM by all samples, the efficiency of the finally-trained SVM is highly improved, without system degradation. 2004 Pattern Recognition Society. Published by Elsevier Ltd. All rights reserved.
We examined the role of caspases and serine protease(s) in cell death induced by tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). After incubation of adenocarcinoma cells with TRAIL, caspase-3, -8 were activated and the cleavage of Bid induced the release of cytochrome c, from the mitochondria to the cytosol. Tetrapeptide inhibitors of caspase-1, -2, -3, and -8 suppressed DNA fragmentation and attenuated the release of cytochrome c, whereas inhibitors of caspase-5 did not. Interestingly, the general serine protease(s) inhibitor 4-(2-aminoethyl)benzylsulfonyl fluoride (AEBSF) resulted in the arrest of apoptosis. However, the AEBSF did not prevent the release of mitochondrial cytochrome c during TRAIL-induced apoptosis. From these results, we postulate that serine protease(s) may be involved in post-mitochondrial apoptotic events, that lead to the activation of the initiator, caspase-9.
: The role of oxidative stress in fluoride hepatotoxicity was inves-tigated. Three groups of eight 4-week-old Wistar rats were given 50, 100, and 150 mg NaF/L in their drinking water for three months. Serum glutamate pyru-vate transaminase (SGPT) and serum glutamate oxalate transaminase (SGOT) activities increased significantly, suggesting hepatic damage. Alterations of the oxidative and the antioxidant system in the liver were confirmed by the significant increase in malondialdehyde (MDA) together with enhanced super-oxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in that organ. Oxidative damage from oxidative stress therefore appears to be an im-portant pathway for fluoride-induced hepatotoxicity.
Although the epidemiology of malignant bone tumours in children and young adults has been explored, no definitive causation of any specific tumour has yet been identified. We performed a literature review (1970–2008) to find all papers covering possible aetiological factors involved in the development of bone tumours in children and young adults. Several associations have been reported with some consistency: the presence of hernias and Ewing sarcoma; high fluoride exposure and osteosarcoma; and parental farming and residence on a farm, younger age at puberty and family history of cancer for all bone tumours, especially osteosarcoma. Clearly further research is needed to confirm or refute these putative risk factors. It is likely that studies of gene–environment interactions may prove to be the most fruitful of future research. Pediatr Blood Cancer 2009;53:941–952. © 2009 Wiley-Liss, Inc.
Endemic fluorosis is a condition resulting from prolonged ingestion of drinking water which contains excess fluoride. Studies on rats have suggested that fluoride toxicity may produce glucose intolerance and abnormalities in insulin secretion. We studied glucose and insulin profiles following an oral glucose load in patients with endemic fluorosis. Twenty-five young adults (age range, 15–30 years) with endemic fluorosis, and an equal number of matched healthy control subjects with normal fluoride intake were studied. Impaired glucose tolerance was demonstrated in 10 of 25 (40%) patients with endemic fluorosis. Patients with impaired glucose tolerance had significantly higher fasting serum immunoreactive insulin (p<0.05), higher fasting serum fluoride (p<0.001), and a significantly lower fasting glucose to insulin ratio than that in patients with normal glucose tolerance (p<0.001) or control subjects (p<0.05). The fasting serum fluoride levels correlated positively with the area under the glucose curve (r=0.80,p<0.01) in patients with impaired glucose tolerance. Interestingly these abnormalities could be reversed when the village was provided drinking water with fluoride levels within acceptable limits. The present study shows that chronic fluoride toxicity in humans could result in significant abnormalities in glucose tolerance which are reversible upon removal of the excess fluoride.
A series of ZSM-5 samples modified with metal oxides MO (M = Mg, Ca, Sr, Ba and Zn) were employed for the alkylation of 4-methylbiphenyl (4-MBP) with methanol to 4,4'-dimethylbiphenyl (4,4'-DMBP) under fixed-bed down-flow conditions. The methylation results showed that the use of basic metal oxides can effectively enhance the selectivity to the target product 4,4'-DMBP. MgO is the most effective modifier among the metal oxides used and it can improve selectivity to 4,4'-DMBP up to 80% as compared to only 13% over the parent zeolite HZSM-5. The modification effectiveness of metal oxides on 4,4'-DMBP selectivity can be arranged in the order MgO > SrO ZnO CaO > BaO. The optimization of MgO modification through the content, salt types and loading methods revealed that proper MgO loading (5.6 wt%) can be more effective, and the impregnation method is much better than ion exchange. The correlation of physicochemical properties (TPD, TGA, chemical analysis and chemical adsorption, etc.) of the modified HZSM-5 with the catalytic data showed that the high selectivity over ZSM-5 modified with MgO largely results from the effective suppression of 4,4'-DMBP secondary reactions such as isomerization, dealkylation and alkylation.
Forty eight male Balb/c mice, each weighing 30–35 g, were used in the present study. The animals were divided into four equal groups. The first group served as the control group, and the second group was administered royal jelly at a dose of 50 mg/kg bw by gavage for a period of 7 days. The third group received 200 ppm fluoride, as sodium fluoride, for a period of 7 days, in drinking water. Lastly, the fourth group was given 200 ppm fluoride in drinking water, in association with royal jelly at a dose of 50 mg/kg bw by gavage, for a period of 7 days. At the end of the seventh day, blood samples were collected from all groups into heparinised and dry tubes, and liver samples were taken concurrently. Erythrocyte and liver tissue malondialdehyde (MDA) levels and superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) activities were evaluated in the blood and tissue samples obtained. Furthermore, serum cholesterol, triglyceride, glucose, total protein and albumin levels, and aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alcaline phosphatase (ALP) activities were evaluated. In conclusion, fluoride was determined to cause adverse effects in mice, and the administration of royal jelly to these animals alleviated the adverse effects of fluoride.
Several aspects of fluorides in the environment have been researched for decades so there is a great deal of published information. However, the authors consider that there are several important areas where information is lacking, data are contradictory, mechanisms of action have not been explored, or the environmental effects of particular compounds are not known. Therefore, this chapter reviews a selection of such topics: inorganic fluorides in soil; the loss of fluorides from plants; classifying species sensitivity to HF; estimating effects of fluorides on growth and yield; the significance of pollutant interactions; effects of HF on fertilization and seed set; fluorides and insects; and old and new problems associated with organofluorides in the environment.
Serum fluoride, nitric oxide (NO), malondialdehyde (MDA) contents and superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) activities were determined in chicks treated with graded doses of sodium fluoride. Compared with chicks in the control group, in the groups treated with fluoride, serum NO and MDA levels largely increased, and the activities of SOD, GSH-Px, and CAT decreased, most of which changed significantly (P<0.05). Serum fluoride levels significantly and positively correlated with serum NO, MDA levels, respectively (P<0.05), and significantly and negatively with serum SOD, GSH-Px, CAT activities, respectively (P<0.05). The results indicated fluoride was associated with the elevated NO levels and the decreased activities of antioxidant enzymes and the deposit of lipid peroxides (LPO). We suggest the mechanism of fluoride injuring soft tissues as follows: fluoride causes excessive production of NO, LPO and oxygen free radicals, which can damage seriously the structure and function of soft tissues.
While studying the regulation of the cystic fibrosis transmembrane conductance regulator (CFTR), we found that addition of F- to the cytosolic surface of excised, inside-out membrane patches reversibly increased Cl- current in a dose-dependent manner. Stimulation required prior phosphorylation and the presence of ATP. F- increased current even in the presence of deferoxamine, which chelates Al3+, suggesting that stimulation was not due to AlF4-. F- also stimulated current in a CFTR variant that lacked a large part of the R domain, suggesting that the effect was not mediated via this domain. Studies of single channels showed that F- increased the open-state probability by slowing channel closure from bursts of activity; the mean closed time between bursts and single-channel conductance was not altered. These results suggested that F- influenced regulation by the cytosolic domains, most likely the nucleotide-binding domains (NBDs). Consistent with this, we found that mutation of a conserved Walker lysine in NBD2 changed the relative stimulatory effect of F- compared with wild-type CFTR, whereas mutation of the Walker lysine in NBD1 had no effect. Based on these and previous data, we speculate that F- interacts with CFTR, possibly via NBD2, and slows the rate of channel closure.
Fluoride is a well-known G-protein activator. Exposure of cultured cells to its derivatives results in actin cytoskeleton remodelling. Podosomes are actin-based structures endowed with adhesion and matrix-degradation functions. This study investigates actin cytoskeleton reorganization induced by fluoride in endothelial cells.
Treatment of cultured endothelial cells with sodium fluoride (NaF) results in a rapid and potent stimulation of podosome formation. Furthermore, we show that Cdc42 (cell-division cycle 42), Rac1 and RhoA activities are stimulated in NaF-treated cells. However, podosome assembly is dependent on Cdc42 and Rac1, but not RhoA. Although the sole activation of Cdc42 is sufficient to induce individual podosomes, a balance between RhoGTPase activities regulates podosome formation in response to NaF, which in this case are often found in groups or rosettes. As in other models, podosome formation in endothelial cells exposed to NaF also involves Src. Finally, we demonstrate that NaF-induced podosomes are fully competent for matrix protein degradation.
Taken together, our findings establish NaF as a novel inducer of podosomes in endothelial cells in vitro.
High fluoride exposure can result in dental fluorosis. Fluoride and iodine are coexistent in the drinking water of areas in China and may affect the prevalence of dental fluorosis and osteogenesis. The aim of this study was to investigate the relationship between serum calciotropic hormone level, and dental fluorisis in children exposed to different concentrations of fluoride and iodine in drinking water.
A pilot study was conducted in three villages located in the Kaifeng and Tongxu counties of Henan Province, China in 2006. Children aged 8 to 12 years, born and raised in the three villages were recruited. The fluoride levels in the samples of urine from these children were detected by fluoride ion selective electrode. Calcitonin and osteocalcin levels in the serum, and serum calcium were measured by radioimmunassay and flame atomic absorption spectrometry, respectively.
Fluoride levels in urine were significantly lower in children from control area (CA) as compared with those from the high fluoride & iodine areas (HFIA) and the high fluoride area (HFA) (P < 0.05 respectively), and no statistically significant difference was found between the children from HFIA and HFA. Additionally, calcitonin levels in the serum were significantly lower in children from CA and HFA as compared with that from HFIA (P < 0.05 respectively), and osteocalcin levels in the serum was lower in children from CA than those from HFIA (P < 0.05). No statistically significant difference in serum osteocalcin concentrations was found between children from HFA and HFIA.
This study provides an evidence that iodine exposure may modify the serum calciotropic hormone levels related to fluorine exposure.
Biological apatites are characterized by the presence of minor constituents such as magnesium (Mg), chloride (Cl), or fluoride (F) ions. These ions affect cell proliferation and osteoblastic differentiation during bone tissue formation. F-substituted apatites are being explored as potential bonegraft materials. The aim of the present study is to investigate the mechanism of bone formation induced by fluoride-substituted apatite (FAp) by analyzing the effect of FAp on the process of in vivo bone formation. FAps containing different F concentrations (l-FAp: 0.48 wt%, m-FAp: 0.91 wt%, h-FAp: 2.23 wt%) and calcium-deficient apatite (CDA), as positive control, were implanted in rat tibia and bone formation was evaluated by histological examination, immuhistochemistry, in situ hybridization and tartrate-resistant acid phosphatase examinations. The results showed that l-FAp, m-FAp, h-FAp, and CDA biomaterials allowed migration of macrophages, attachment, proliferation, and phenotypic expression of bone cells leading to new bone formation in direct apposition to the particles. However, the l-FAp preparation allowed faster bone conduction compared to the other experimental materials. These results suggest that FAp with low F concentration may be an efficient bonegraft material for dental and medical application.
Higher blood lead (BPb) levels have been reported in children living in communities that receive fluoride-treated water. Here, we examined whether fluoride co-administered with lead increases BPb and lead concentrations in calcified tissues in Wistar rats exposed to this metal from the beginning of gestation. We exposed female rats and their offspring to control water (Control Group), 100mg/L of fluoride (F Group), 30mg/L of lead (Pb Group), or 100mg/L of fluoride and 30mg/L of lead (F+Pb Group) from 1 week prior to mating until offspring was 81 days old. Blood and calcified tissues (enamel, dentine, and bone) were harvested at day 81 for lead and fluoride analyses. Higher BPb concentrations were found in the F+Pb Group compared with the Pb Group (76.7+/-11.0microg/dL vs. 22.6+/-8.5microg/dL, respectively; p<0.001). Two- to threefold higher lead concentrations were found in the calcified tissues in the F+Pb Group compared with the Pb Group (all p<0.001). Fluoride concentrations were similar in the F and in the F+Pb Groups. These findings show that fluoride consistently increases BPb and calcified tissues Pb concentrations in animals exposed to low levels of lead and suggest that a biological effect not yet recognized may underlie the epidemiological association between increased BPb lead levels in children living in water-fluoridated communities.
The present study was aimed to evaluate curcumin as a potential natural antioxidant to mitigate the genotoxic effects of arsenic (As) and fluoride (F) in human peripheral blood lymphocytes. The study was divided into nine groups consisting of negative control, positive control treated with ethyl methane sulphonate (EMS; 1.93 mM) and curcumin control with only curcumin (1.7 microM) in blood culture. As (1.4 microM) and F (34 microM) were added alone as well as in combination, to the cultures, with and without curcumin. Cultures were analysed for chromosomal aberrations (both structural and numerical) and primary DNA damage via comet assay as the genotoxic parameters after an exposure duration of 24h. Results revealed that curcumin efficiently ameliorates the toxic effect of As and F by reducing the frequency of structural aberrations (>60%), hypoploidy (>50%) and primary DNA damage. In conclusion, curcumin mitigates the genotoxic effects of the two well known water contaminants (As and F) effectively and efficiently at the given concentration in vitro.
Comparative proteomics was performed to identify proteins in the liver of Takifugu rubripes in response to excessive fluoride exposure. Sixteen fish were randomly divided into a control group and an experimental group. The control group was raised in soft water alone (F(-) = 0.4 mg/L), and the experimental group was raised in the same water with sodium fluoride at a high concentration of 35 mg/L. After 3 days, proteins were extracted from the fish livers and then subjected to two-dimensional polyacrylamide gel electrophoresis analysis. The matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS) was applied to identify the proteins that were differentially expressed from the two groups of fish. Among an average of 816 and 918 proteins detected in the control and treated groups, respectively, 16 proteins were upregulated and 35 were downregulated (P < 0.01) in the fluoride-treated group as compared with those in the control group. Twenty-four highly differentially expressed proteins were further analyzed by MALDI-TOF/TOF-MS, and eight were identified by Mascot. These eight proteins include disulfide isomerase ER-60, 4SNc-Tudor domain protein, SMC3 protein, Cyclin D1, and mitogen-activated protein kinase 10, as well as three unknown proteins. Consistent with their previously known functions, these identified proteins seem to be involved in apoptosis and other functions associated with fluorosis. These results will greatly contribute to our understanding of the effects of fluoride exposure on the physiological and biochemical functions of Takifugu and the toxicological mechanism of fluoride causing fluorosis in both fish and human.
Sperm hyperactivation is crucial for a successful fertilization; however, the influence of fluoride (F) to hyperactivation is still in its infancy. The purpose of this study was to investigate the effect of sodium fluoride (NaF) on sperm hyperactivation, Ca2+/CALM-CAMK2 signaling, and CatSper1 and CatSper2 mRNA expression in mice sperm. Adult male Kunming mice were administrated with 30, 70, and 150 mg NaF/l (corresponding to 2.84 +/- 0.29, 6.28 +/- 0.61, and 14.18 +/- 1.00 mg F/kg body weight per day) through drinking water for 49 days. The results showed that NaF reduced the sperm hyperactivated motility in a dose-dependent manner. Compared with the controls, intracellular Ca2+ concentration and CAMK2 protein were significantly decreased in mice treated with 70 and 150 mg NaF/l, while no effect on CALM was determined in all treatment groups. Furthermore, decreased sperm CatSper1 mRNA expression was also observed in response to middle and higher doses of NaF (70, 150 mg/l) with comparison to the control group, whereas no change in the mRNA expression of CatSper2 was detected in NaF administrated groups. Treatment with 30 mg NaF/l exhibited slight effects on the above indexes with no statistical difference. These findings indicated that exposure to 70 and 150 mg/l NaF for 49 days could result in low hyperactivation via alteration of Ca2+ signaling pathway involving CatSper1 in sperm from mice.
We have assessed whether the combined exposure to arsenic (As) and fluoride (F) exerts a different effect than the exposure to As alone on the pattern of expression of apoptosis and inflammatory genes by immune cells. RNA was extracted from peripheral blood mononuclear cells from twenty individuals exposed or not to As or F or both. Then, cDNA was isolated, and the expression of 180 genes related to apoptosis and inflammation was tested by a cDNA array test. We found significant differences in the expression of 9 apoptosis and 15 inflammation genes in the three exposed groups compared to non-exposed individuals. In addition, subjects exposed to As or F or both showed different patterns of expression of at least 19 genes. Our data indicate that the combined exposure to As and F has a different effect on gene expression than the exposure to As or F alone.
Oral mucosal tissue can serve as a long-term fluoride reservoir following topical application and retain a small amount of fluoride in oral environment for prevention of dental caries. The aim of this study was to determine the effect of low level sodium fluoride (NaF) on the proliferation and migration of epithelial cells in vitro. Human primary gingival epithelial cells and human epidermal HaCaT keratinocytes were used. Cultured epithelial cells, treated with various concentrations of NaF ranging from 5 microM to 500 microM, were investigated by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assay, wound healing assay, invasion assay and quantitative real-time PCR. MTS assay revealed that fluoride added to human gingival epithelial cells elevated cell proliferation at a concentration of 5 microM or more. The wound healing assay and invasion assay confirmed this observation. Quantitative real-time PCR revealed that low concentration of NaF up-regulated fibronectin mRNA expression in fluoride-treated cells compared with controls. These results suggest that a low concentration of NaF is able to induce cell proliferation, migration, and matrix production in epithelial cells. Our results provide new information on epithelial cell adhesion and may thus aid in the understanding of periodontal physiology.
Boron may be beneficial for bone growth and maintenance, central nervous system function, and the inflammatory response, and silicon may be beneficial for bone maintenance and wound healing. Fluoride is not an essential element but amounts provided by contamination may be beneficial for bone strength. Fluoride toxicity may be a concern in parenteral nutrition. Further studies are warranted to determine whether there are optimal amounts of boron and silicon that should be delivered to typical and special population patients receiving parenteral nutrition. In addition, further studies are needed to determine whether providing the dietary guideline of adequate intake amounts of fluoride parenterally would prevent or treat parenteral nutrition osteopenia.
The mechanisms underlying fluoride-induced apoptosis in neurons still remain unknown. To investigate apoptosis, caspase-3 activity, and mRNA expression of Fas, Fas-L, and caspases (-3 and -8) induced by fluoride, human neuroblastoma (SH-SY5Y) cells were incubated with 0, 20, 40, and 80 mg/L sodium fluoride (NaF) for 24 h in vitro. The data show that cell viability in the 40 and 80 mg/L fluoride groups were significantly lower than that of the control group. The percentages of apoptosis in the 40 and 80 mg/L fluoride groups were markedly higher than those in the control group, and they increased with the increase in fluoride concentration. The activity of caspase-3 and mRNA expression levels for Fas, Fas-L, and caspases (-3 and -8) in the 40 and 80 mg/L fluoride groups were significantly higher than those in the control group. An agonistic anti-Fas monoclonal antibody (CH-11) significantly augmented apoptosis induction by fluoride, showing a synergistic effect, while a Fas-blocking antibody (ZB4) partly inhibited fluoride-induced apoptosis of SH-SY5Y cells. The results indicate that fluoride exposure could induce apoptosis in SH-SY5Y cells, and the Fas/Fas-L signaling pathway may play an important role in the process.
This study intended to determine the effects of various concentrations of fluoride (1, 10, 50 and 100 ppm) in drinking water for a period of 12 weeks on changes in haem biosynthesis pathway, oxidative stress and neurological variables supported by histopathological observations and fluoride in rats. The data indicates significant alterations in the parameters related to haeme synthesis pathway like inhibition of blood delta-aminolevulinic acid dehydratase, delta-aminolevulinic acid synthetase, oxidative stress like depletion of glutathione (GSH) and increase in oxidized glutathione (GSSG) and thiobarbituric acid reactive substances. These changes were accompanied by depletion in GSH:GSSG ratio, whole brain biogenic amine levels and a dose-dependent increase in fluoride concentration. Interestingly and most significantly, these changes were more pronounced at lower concentrations of fluoride compared with higher fluoride dose. Biochemical changes were supported by the histological observations, which also revealed that at high concentrations of fluoride, toxic effects and damages to organs were more pronounced. These changes support our earlier findings regarding the role of decreased ionic mobility of fluoride ion at higher concentrations, leading to less pronounced toxicity.
Fincoal type fluorosis has only been reported from China, but its pathogenesis is unclear. Many people believe that fluorosis is associated with oxidative stress. Oxidative stress can be reduced at higher selenium (Se) level. Heat shock protein (HSP70) is the most conserved and induced against different stressors. The aim of this study is to detect the expression of HSP70 in fluorosis patients and explore the role of Se in fluorosis protection. The subjects were divided into four groups: "High Se + F group" (n = 50), "High F group" (n = 50), "High Se group" (n = 20) and "Control group" (n = 46). Expression of HSP70 was evaluated by Western blotting and real-time PCR techniques. The concentration of fluoride, content of Se in hair, activity of antioxidant enzymes (GSH-Px, SOD, CAT) and content of malondialdehyde (MDA) were determined. The relative amount of HSP70 gene transcription was significantly higher in "High Se + F group" than the other groups. The same results were found for expression of HSP70 protein to beta-actin ratio. There was a significant difference between "High Se + F group" and "High F group" regarding MDA content and glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and catalase (CAT) activity. These results suggest that oxidative stress plays an important role in the pathogenesis of the Fincoal type fluorosis and it can be reduced at higher Se level.
We studied the effects of combined exposure to arsenic and fluoride on (i) brain biogenic amines, oxidative stress and its correlation with glutathione and linked enzymes; (ii) alterations in the structural integrity of DNA; and (iii) brain and blood arsenic and fluoride levels. Efficacy of alpha-tocopherol in reducing these changes was also determined. Male mice were exposed to sodium meta arsenite (50 ppm) and sodium fluoride (50 ppm) individually and in combination for ten weeks. Animals were given vitamin E supplementation (5 mg/kg, i.m., alternate days) throughout the experiment. Exposure to arsenic and fluoride significantly decreased the levels of brain biogenic amines. However; acetyl cholinesterase (AChE) and monoamine oxidase (MAO) activities showed an increase on fluoride exposure. There was also an increase in reactive oxygen species, thiobarbituric acid reactive species level, glutathione S-transferase and glutathione peroxidase activities and decreased superoxide dismutase activity, GSH:GSSG ratio, glucose 6-phosphate dehydrogenase activity. Combined exposure to these toxicants produced more pronounced effects on AChE, MAO, SOD and catalase activities. Infrared spectra showed less toxicity during combined exposure as the characteristic peaks of cytosine and alpha-helical structure of DNA were observed in normal and arsenic plus fluoride-exposed animals. Vitamin E reduced brain fluoride level and tissue oxidative stress but had no effect on arsenic. Combined exposure to arsenic and fluoride does not necessarily lead to more pronounced toxicity and interestingly exhibit some antagonistic effects. Vitamin E supplementation may be of added value in reverting some of the toxic effects.
The consumption of drinking water rich in fluoride has toxic effects on the central nervous system. In cell biology research, fluoride is currently used as a phosphatase inhibitor. The aim of the present study was to evaluate the effect of fluoride on different physiological processes in GH4C1 pituitary tumour cells. We used a range of different fluoride concentrations, from levels below normal human serum concentrations (0.23 and 1.2 micromol/L) to those observed in chronically exposed persons (10.7 micromol/L) and above (107 and 1072 micromol/L). Treatment of 10.7 micromol/L fluoride resulted in a discrete induction of DNA synthesis, without a change in cell number. Cell migration, a behaviour stimulated by growth factors, was increased in cells treated with 2.4 micromol/L. At this fluoride concentration, changes in phosphorylation status of both cytoskeletal and cytosolic protein fractions, as well as in actin cytoskeletal arrangements were observed. The GH4C1 fluoride treated cells had significantly less cellular protein than control cells, suggesting an effect of fluoride on hormone secretion and protein synthesis in this endocrine cell. The bioreduction of MTT was significantly increased with a wide range of fluoride concentrations. With the highest fluoride concentration, 1072 micromol/L, all of the analysed parameters were significantly reduced, suggesting that this dose is highly toxic in GH4C1 cells. Our results show that biologically relevant concentrations of fluoride are capable of increasing cell migration in tumour cells, suggesting that exposure to fluoride could stimulate tumour invasion.
Chronic exposure to high fluoride (F(-)) may lead to local tissue disturbances, known as fluorosis. F(-) is an oxidising agent and a well-known reversible enzymatic inhibitor that interferes with the enzyme activity of at least 80 proteins. The goals of the current study were to evaluate whether F(-) exposure affected the oral glucose tolerance test (OGTT) in C57BL6 mice; and to determine the mechanisms at work in glucose homeostasis at the cellular level, in mouse pancreatic beta-cells (betaTC-6) exposed to F(-). Mice received 45 mgl(-1) F(-), as NaF, via drinking water, and cells were exposed for 12h to NaF (equivalent to 0, 0.007, 0.045, 0.180, 1.35 or 2.26 mM F(-)) at a basal or stimulatory glucose concentration (2.8 or 16.6mM, respectively). Mice showed marginal hyperglycemia an impaired glucose tolerance after 4 weeks of F(-) exposure, while beta-cells exposed to 1.35 and 2.26 mM F(-) had significantly lower insulin mRNA expression and subsequent secretion in the presence of the stimulatory glucose concentration. Western blot analyses did not show any alteration in the levels of glucose transporter-2 protein beta-cells on exposure to F(-)in vitro. However, oxidative stress evaluated by the functional activity of superoxide dismutase (SOD) and generation of the superoxide anion (O(2)(-)), showed significantly decreased SOD activity, in a dose-dependent manner. This was accompanied by an increase in the generation of O(2)(-), and decreased mitochondrial membrane potential in F(-) exposed cells. Insulin secretion was lower in beta-cells exposed to F(-), even in the presence of glibenclamide, the ATP-sensitive K(+) (K(ATP)) channel blocker, suggesting down-regulation of the K(ATP) channel in the cell. Exposure to high levels of F(-) in drinking water may decrease insulin mRNA and its secretion from beta-cells, and might therefore affect the OGTT.