Bone Fluoride Accumulation Research Articles

Synthesis and evaluation of 6-[18F]fluoro-3-(pyridin-3-yl)-1H-indole as potential PET tracer for targeting tryptophane 2, 3-dioxygenase (TDO)

IntroductionThe increase in expression of tryptophan 2, 3-dioxygenases (TDO) and indoleamine 2,3-dioxygenase (IDO) have been reported as potential tumor biomarkers. TDO and IDO are enzymes that catalyze the first and rate-limiting step of the kynurenine pathway. Positron emitting tomography (PET) tracers investigating the kynurenine pathway may allow for the detection of different disease pathologies in vivo including cancer. However, current PET tracers being developed for TDO and IDO have suffered from either multi-step low yielding syntheses or de-fluorination of the tracer in vivo. ResultsTDO inhibitors based on 6-fluoroindole with C3 substituents are a class of small molecules that have been shown to bind to TDO effectively, restore tryptophan concentration and decrease the production of immunosuppressive metabolites. The compound 6-fluoro-3-(pyridine-3-yl)-1H-indole has been reported to have high in vitro affinity for TDO. Herein we report the fully automated radiosynthesis of 6-[18F]fluoro-3-(pyridine-3-yl)-1H-indole [18F]4 using a copper-mediated nucleophilic 18F-fluorination resulting in a non-corrected yield of 5 to 6% of the tracer with a radiochemical purity of >99% after 4 h. Small animal dynamic PET/CT imaging of [18F]4 intravenously injected into normal C57BL/6 mice revealed rapid accumulation in heart and brain, reaching maximum occupancy in heart (10.9% ID/g) and brain (8.1% ID/g) at 1.75 min and 2.25 min, respectively. Furthermore, these in vivo studies revealed no de-fluorination of the tracer, as evidence by the absence of [18F]fluoride accumulation in bone. ConclusionIn vitro studies demonstrate that 4 has good affinity for hTDO and the radiolabeled analogue [18F]4 can be synthesized with suitable radiochemical yields. [18F]4 demonstrates good uptake in the brain and the radiolabeled compound shows no de-fluorination in vivo in C57BL/6 mice.

When less is more: a comparison of models to predict fluoride accumulation in free-ranging kangaroos

Vegetation contaminated by industrial fluoride emissions can cause disease in herbivorous mammals. Spatially explicit exposure models offer a quantitative approach for evaluating and managing the potentially toxic effects of chronic fluoride consumption on wildlife. We monitored eastern grey kangaroos (Macropus giganteus) inhabiting a high-fluoride environment in the buffer zone of an aluminium smelter in southeastern Australia between 2010 and 2013. We measured fluoride levels at 19 pasture sites and determined the foraging range of 37 individual kangaroos. A series of generalised linear models were developed to estimate bone fluoride accumulation as a function of pasture exposure. Model outputs were compared to identify the most appropriate predictive tool for kangaroo bone fluoride accumulation relative to exposure. Accounting for age there was a negative association between bone fluoride concentration and distance of the central emission point from both the mean centre of foraging range and the point of death. The mean foraging range centre was the best predictor, with point of death just as suitable (and simpler), whereas more complex parameters such as monthly and cumulative fluoride exposure were poor predictors of bone fluoride concentration. The more complex dietary fluoride exposure estimates did not improve predictive capability compared with the simple, spatial models. We conclude that in actively managed wildlife populations, simple, locally validated models can provide estimates of bone fluoride accumulation sufficient to support decision-making.

Effect of dietary fluoride derived from Antarctic krill (Euphausia superba) meal on growth of yellowtail (Seriola quinqueradiata)

Yellowtail (Seriola quinqueradiata) is the most important cultured marine fish in Japan. Dietary fish meal for yellowtail in aquaculture was replaced with 0.0%, 15.4% and 100.0% Antarctic krill meal (KM0, KM15, and KM100) and with 0.0%, 15.4%, and 100.0% low-fluoride krill meal (LFK0, LFK15 and LFK100). The fish was fed to duplicate fish groups for 92d (KM trial) or 75d (LFK trial), and fish growth was monitored.Dietary fluoride (F−) concentrations (mgkg−1) were 110, 160, and 580 (KM0, KM15, and KM100, respectively) and 98, 120, and 190 (LFK0, LFK15, and LFK100, respectively). The growth during the experimental period, weight gain, feed intake, specific growth rate, and feed efficiency in fish fed the KM100 diet were markedly lower than the other experimental groups, which showed no marked differences in growth performance.After the experiment, dorsal muscle fluoride concentrations in each group were below the detectable limit (1mgkg−1), but vertebral bone fluoride concentrations increased with increasing proportion of KM to 655 (KM0), 870 (KM15), and 2150 (KM100) mgkg−1. With increasing LFK in the feed, vertebral bone fluoride concentrations (mgkg−1) increased slightly from 500 (LFK0) to 655 (LFK15), and 695 (LFK100). No histopathological changes were detected in the liver tissue in any experimental group.It has been reported that the fluoride bioavailability was reduced with increasing water hardness, however, the dietary fluoride derived from KM exoskeleton accumulates in vertebral bones of marine fish with growth inhibition, as has already been shown for freshwater fish. Vertebral bone fluoride concentrations in two krill-eating Antarctic marine fish in the wild were 33000mgkg−1 (Champsocephalus gunnari) and 15000mgkg−1 (Notothenia rossii), but they did not show any adverse effect of growth. Therefore, fish bone fluoride accumulation apparently depends on fish species rather than the salinity of the habitat. Consequently, krill exoskeleton must be removed during the processing of Antarctic krill if indeed these krill are to be used as fish feed. However, LFK can completely replace dietary fish meal without apparent adverse effects.

Low Levels of p53 Mutations in Indian Patients with Osteosarcoma and the Correlation with Fluoride Levels in Bone

The pathogenesis of osteogenic sarcoma is not known. Recently, chronic fluoride exposure has been incriminated as having a possible etiologic role by causing a nonspecific osteoblast proliferation. We were interested in exploring the possible relationship between fluoride bone content and p53 mutations. We analyzed p53 mutations in various exons in tissue of osteosarcoma, and correlated the findings with the bone fluoride levels in Indian patients. We analyzed tissue samples from 20 osteosarcoma patients for possible genetic alterations including mutations, and we assessed the extent of fluoride accumulation in bone. Fragments displaying an altered electrophoretic mobility were confirmed as having mutated sequences. Mutation was observed in samples of two cases (10% incidence). Eighteen samples showed bone fluoride levels between 1000 and 27,000 ppm, whereas the 2 mutated samples showed fluoride levels of 64,000 and 89,000 ppm, respectively. The high levels of bone fluoride levels and the similarity of the mechanisms of action between fluoride-induced DNA damage and chemically-induced p53 mutations lead us to propose that high fluoride bone content might have been one of the major factors causing osteosarcoma.

Mandibular bone fluoride levels and occurrence of fluoride induced dental lesions in populations of wild red deer ( Cervus elaphus) from Central Europe

Mandibular bone fluoride concentrations as well as frequency and intensity of fluoride-induced dental lesions were studied in four red deer populations from Czechia and Germany exposed to different levels of environmental fluoride. The degree of fluorosis in the permanent cheek teeth was recorded by a scoring system and the individual mandibles assigned to one of three categories (unfluorosed, slightly to moderately fluorosed, and markedly to severely fluorosed) on the basis of the tooth scores. An increase in the frequency and severity of dental fluorosis was positively associated with an increase in bone fluoride level, which itself was significantly different between the four samples. In all samples, the rate of bone fluoride accumulation was higher in younger than in older deer. The results of this study show that frequency and intensity of dental fluorosis can be used as valid indicators of increased fluoride exposure of deer populations, and thus as a quick, easy, economic and reliable means of monitoring fluoride pollution in areas inhabited by wild deer.

Mandibular bone fluoride accumulation in wild red deer (Cervus elaphus L.) of known age.

Mandibular bone fluoride concentration and its relation to age were studied in a sample of 39 red deer of known age (between 2 and 18 years) from an area not exposed to increased fluoride deposition (Harz mountains, Germany). Bone fluoride level ranged from 208 to 1026 ppm dry weight and was positively correlated with age (r = 0.808, P < 0.001), the rate of skeletal fluoride accumulation being higher in younger individuals. This indicates that during the period of skeletal growth, fluoride uptake is more rapid than in later life when accumulation at a lower rate occurs during normal bone turnover. Bone fluoride levels found in the present sample are regarded as resulting from "normal" fluoride exposure in a recent central European red deer population.

Journal of Bone and Mineral Research

We have developed a localized noninvasive nuclear magnetic resonance (NMR) method for determining the accumulated bone fluoride content in human index fingers. Using a 27 MHz "split-ring" resonator probe, we measure the total fluoride (F) content within a 6.5 cm length of the distal end of the index finger from a calibrated determination of the intensity of the observed 19F free induction decay (FID) signal. Since fluoride impurities accumulate almost exclusively in bone mineral, the 19F resonance signal is broadened by rigid lattice magnetic dipole-dipole interactions, causing the FID signal to have a relatively short lifetime of approximately 75 microseconds. This short signal lifetime, plus the weakness of the signal strength prevents conventional magnetic resonance imaging equipment from observing the 19F in bone mineral. Nevertheless, we have achieved an in vivo sensitivity of +/- 0.5 mg fluoride in an observation period of 30 min. Assuming an index finger has between 0.25 and 0.5 g of bone calcium, this sensitivity is just sufficient to detect fluorides in the index finger of most adults whose bone fluoride concentration is greater than 2.0 mg fluoride/g calcium (0.8 mg/g ash weight). We are particularly interested in using this new NMR technique to monitor the rate of bone fluoride accumulation in osteoporotic patients receiving therapeutic levels of fluoride in their diets.

Bone fluoride concentrations after 16 years of drinking water fluoridation.

The fluoride content of 147 pieces of vertebral cancellous bone, collected at autopsy from long-term residents in Basle, Switzerland, was determined. A statistical analysis of the results sustained the hypothesis of age-dependent fluoride accumulation in bone. No differences were found between sexes. 4 cases with severe chronic pyelonephritis had definitely elevated fluoride values.

Fluoride accumulation in bone and the effect on their physical properties in guinea pigs given different levels of fluoridated water.

Guinea pigs were exposed to fluoridated water (2-20 ppm) for a period ranging from 15 to 42 weeks. The fluoride content of the bones increased in proportion to the concentration of fluoride in drinking water and the period of exposure. The rate constant of accumulation of fluoride in guinea pig bones was estimated to be 2.5 X 10(-2) week-1, with a half-life of plateau formation in the order of 28 weeks. This indicated that maximum accumulation of fluoride during a continuous exposure, or a computed complete elimination of fluoride after exposure, will take approximately four years. Although fluoridated water improved the weight gain of guinea pigs, no effect on physical properties of bones was observed. No other toxic effects of fluoride under these conditions were noted.