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Genetic factors influence the effects of fluoride (F) on amelogenesis and bone homeostasis but the underlying molecular mechanisms remain undefined. A label-free proteomics approach was employed to identify and evaluate changes in bone protein expression in two mouse strains having different susceptibilities to develop dental fluorosis and to alter bone quality. In vivo bone formation and histomorphometry after F intake were also evaluated and related to the proteome. Resistant 129P3/J and susceptible A/J mice were assigned to three groups given low-F food and water containing 0, 10 or 50 ppmF for 8 weeks. Plasma was evaluated for alkaline phosphatase activity. Femurs, tibiae and lumbar vertebrae were evaluated using micro-CT analysis and mineral apposition rate (MAR) was measured in cortical bone. For quantitative proteomic analysis, bone proteins were extracted and analyzed using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS), followed by label-free semi-quantitative differential expression analysis. Alterations in several bone proteins were found among the F treatment groups within each mouse strain and between the strains for each F treatment group (ratio ≥1.5 or ≤0.5; p<0.05). Although F treatment had no significant effects on BMD or bone histomorphometry in either strain, MAR was higher in the 50 ppmF 129P3/J mice than in the 50 ppmF A/J mice treated with 50 ppmF showing that F increased bone formation in a strain-specific manner. Also, F exposure was associated with dose-specific and strain-specific alterations in expression of proteins involved in osteogenesis and osteoclastogenesis. In conclusion, our findings confirm a genetic influence in bone response to F exposure and point to several proteins that may act as targets for the differential F responses in this tissue.

Background. We describe a heart transplant patient with painful periostitis and exostoses who was receiving long-term therapy with voriconazole, which is a fluoride-containing medication. Elevated plasma and bone fluoride levels were identified. Discontinuation of voriconazole therapy led to improvement in pain and reduced fluoride and alkaline phosphatase levels. Methods. To determine whether voriconazole is a cause of fluoride excess, we measured plasma fluoride levels in 10 adult post-transplant patients who had received voriconazole for at least 6 months and 10 post-transplant patients who did not receive voriconazole. To assess the effect of renal insufficiency on fluoride levels in subjects receiving voriconazole, half were recruited on the basis of a serum creatinine level of ≥1.4 mg/dL on their most recent measurement, whereas the other 5 subjects receiving voriconazole had serum creatinine levels <1.4 mg/dL. All control subjects had serum creatinine levels of ≥1.4 mg/dL. Patients were excluded from the study if they received a fluorinated pharmaceutical other than voriconazole. Results. All subjects who received voriconazole had elevated plasma fluoride levels, and no subjects in the control group had elevated levels (14.32 μmol/L ± 6.41 vs 2.54 ± 0.67 μmol/L; P<.001). Renal function was not predictive of fluoride levels. Plasma fluoride levels remained significantly higher in the voriconazole group after adjusting for calcineurin inhibitor levels and doses. Half of the voriconazole group subjects had evidence of periostitis, including exostoses in 2 patients. Discontinuation of voriconazole therapy in patients with periostitis resulted in improvement of pain and a reduction in alkaline phosphatase and fluoride levels. Conclusions. Voriconazole is associated with painful periostitis, exostoses, and fluoride excess in posttransplant patients with long-term voriconazole use.

An understanding of all aspects of fluoride metabolism is critical to identify its biological effects and avoid fluoride toxicity in humans. Fluoride metabolism and subsequently its body retention may be affected by physiological responses to acute exercise. This pilot study investigated the effect of exercise on plasma fluoride concentration, urinary fluoride excretion and fluoride renal clearance following no exercise and three exercise intensity conditions in nine healthy adults after taking a 1-mg Fluoride tablet. After no, light, moderate and vigorous exercise, respectively, the mean (SD) baseline-adjusted i) plasma fluoride concentration was 9.6(6.3), 11.4(6.3), 15.6(7.7) and 14.9(10.0) ng/ml; ii) rate of urinary fluoride excretion over 0–8 h was 46(15), 44(22), 34(17) and 36(17) μg/h; and iii) rate of fluoride renal clearance was 26.5(9.0), 27.2(30.4), 13.1(20.4) and 18.3(34.9) ml/min. The observed trend of a rise in plasma fluoride concentration and decline in rate of fluoride renal clearance with increasing exercise intensity needs to be investigated in a larger trial. This study, which provides the first data on the effect of exercise with different intensities on fluoride metabolism in humans, informs sample size planning for any subsequent definitive trial, by providing a robust estimate of the variability of the effect.

From 2009 to 2015, this patient had lived in the Kakuma refugee camp (Rift Valley Province, Kenya), which houses 184 966 inhabitants.2,3 He had chronic, debilitating, diffuse axial bone pain, insidiously worsening over the previous 5 years, beginning with lumbar and hip pain. Here we have presented a single case of severe skeletal fluorosis; however, entire populations, such as Kakuma's approximately 185 000 residents, who depend on naturally occurring fluoride-contaminated well water, might be affected en masse.2–4 Many countries with naturally high water-fluoride concentrations host large refugee populations, including Ethiopia, Iraq, Kenya, South Sudan, Syria, and Turkey.4,7,10 Displaced populations who depend on well water in these areas can be at particular risk, especially children with developing skeletons and lower volumes of distribution. Academic support for GEF and GAK is provided by the Cumming School of Medicine, O'Brien Institute for Public Health, and the W21C Research and Innovation Centre at the University of Calgary and Alberta Health Services.

Despite the 1,000-fold difference between the fluoride concentrations ([F]) in dentifrices and fluoridated drinking water, clinical and epidemiological studies have shown that they have similar cariostatic effects. This double-blind, crossover study was done to determine whether the [F] in dental plaque is related more to the [F] of the dentifrice used or to the plaque concentrations of calcium and magnesium. The subjects (n = 13) were adults and residents of a city served with fluoridated drinking water. After 1 week of using a fluoridated dentifrice (940 ppm) or a placebo dentifrice, whole saliva and plaque were collected 1.0 h and approximately 12 h after the last use of the dentifrices. The average salivary [F] after brushing with the F dentifrice was higher than after using the placebo. The average plaque [F] 1.0 h after brushing with the F dentifrice was higher than after using the placebo (p < 0.01), but the difference at 12 h was not significant. Plaque [Ca] and [F] were directly related under all experimental conditions (p = 0.0001). The relationships between plaque [Mg] and [F] were weaker and inconsistent. Based on these findings and reports in the literature it is concluded that, for persons whose drinking water is fluoridated, plaque [F] throughout much of the day is not significantly increased by the use of a fluoridated dentifrice. Instead they are directly related to plaque [Ca]. These findings offer at least a partial explanation for why fluoridated dentifrices and drinking water have similar cariostatic effects.

Background. Acute fluoride poisoning produces a clinical syndrome characterized by nausea, vomiting, diarrhea, abdominal pain, and paresthesias. In May 1992, excess fluoride in one of two public water systems serving a village in Alaska caused an outbreak of acute fluoride poisoning. Methods. We surveyed residents, measured their urinary fluoride concentrations, and analyzed their serum-chemistry profiles. A case of fluoride poisoning was defined as an illness consisting of nausea, vomiting, diarrhea, abdominal pain, or numbness or tingling of the face or extremities that began between May 21 and 23. Results. Among 47 residents studied who drank water obtained on May 21, 22, or 23 from the implicated well, 43 (91 percent) had an illness that met the case definition, as compared with only 6 of 21 residents (29 percent) who drank water obtained from the implicated well at other times and 2 of 94 residents (2 percent) served by the other water system. We estimated that 296 people were poisoned; 1 person died. Four to five days after the outbreak, 10 of the 25 case patients who were tested, but none of the 15 control subjects, had elevated urinary fluoride concentrations. The case patients had elevated serum fluoride concentrations and other abnormalities consistent with fluoride poisoning, such as elevated serum lactate dehydrogenase and aspartate aminotransferase concentrations. The fluoride concentration of a water sample from the implicated well was 150 mg per liter, and that of a sample from the other system was 1.1 mg per liter. Failure to monitor and respond appropriately to elevated fluoride concentrations, an unreliable control system, and a mechanism that allowed fluoride concentrate to enter the well led to this outbreak. Conclusions. Inspection of public water systems and monitoring of fluoride concentrations are needed to prevent outbreaks of fluoride poisoning

These studies were done to determine the effects of fluoride (F) on the structure and function of the canine gastric mucosa and the possible protective effects of 16,16-dimethyl-prostaglandin E2 (dmPGE2). A portion of the stomach with its vascular supply intact was mounted in a two-compartment chamber, one side of which contained a control solution. Minor effects were caused by exposure to 1 mmol/liter F. Both 5 and 10 mmol/liter F caused marked increases in the fluxes of water and Na, K, and H ions; mucus secretion; and tissue swelling and redness. The extent of these changes did not increase appreciably upon exposure to 50 or 100 mmol/liter F. Histological findings included marked thinning of the surface cell layer, reduced uptake of PAS stain, localized exfoliation and necrosis of surface cells, acute gastritis, and edema. It was concluded that: (1) the threshold F concentration for effects on the structure and function of the gastric mucosa was approximately 1 mmol/liter; (2) the maximum or near-maximum effects were caused by 10 mmol/liter F; (3) the effects persisted for at least 6 hr after the exposure; and (4) dmPGE2 (0.5 microg/ml) did not attenuate the effects induced by F.

Genetic factors influence the effects of fluoride (F) on amelogenesis and bone homeostasis but the underlying molecular mechanisms remain undefined. A label-free proteomics approach was employed to identify and evaluate changes in bone protein expression in two mouse strains having different susceptibilities to develop dental fluorosis and to alter bone quality. In vivo bone formation and histomorphometry after F intake were also evaluated and related to the proteome. Resistant 129P3/J and susceptible A/J mice were assigned to three groups given low-F food and water containing 0, 10 or 50 ppmF for 8 weeks. Plasma was evaluated for alkaline phosphatase activity. Femurs, tibiae and lumbar vertebrae were evaluated using micro-CT analysis and mineral apposition rate (MAR) was measured in cortical bone. For quantitative proteomic analysis, bone proteins were extracted and analyzed using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS), followed by label-free semi-quantitative differential expression analysis. Alterations in several bone proteins were found among the F treatment groups within each mouse strain and between the strains for each F treatment group (ratio greater than or equal to 1.5 or less than or equal to 0.5; p<0.05). Although F treatment had no significant effects on BMD or bone histomorphometry in either strain, MAR was higher in the 50 ppmF 129P3/J mice than in the 50 ppmF A/J mice treated with 50 ppmF showing that F increased bone formation in a strain-specific manner. Also, F exposure was associated with dose-specific and strain-specific alterations in expression of proteins involved in osteogenesis and osteoclastogenesis. In conclusion, our findings confirm a genetic influence in bone response to F exposure and point to several proteins that may act as targets for the differential F responses in this tissue.