Excess fluoride in drinking water is an environmental issue of increasing worldwide concern, because of its adverse effect on human health. Skeletal fluorosis caused by chronic exposure to excessive fluoride is a metabolic bone disease characterized by accelerated bone turnover accompanied by aberrant activation of osteoblasts. It is not clear whether Wnt/β-catenin signaling, an important signaling pathway regulating the function of osteoblasts, mediates the pathogenesis of skeletal fluorosis. A cross-sectional case-control study was conducted in Tongyu County, Jilin Province, China showed that fluoride stimulated the levels of OCN and OPG, resulting in accelerated bone turnover in patients with skeletal fluorosis. To investigate the influence of fluoride on Wnt/β-catenin signaling pathway, 64 male BALB/c mice were allotted randomly to four groups and treated with deionized water containing 0, 55, 110 and 221 mg/L NaF for 3 months, respectively. The results demonstrated that fluoride significantly increased mouse cancellous bone formation and the protein expression of Wnt3a, phospho-GSK3β (ser 9) and Runx2. Moreover, partial correlation analysis indicated that there was no significant correlation between fluoride exposure and Runx2 protein levels, after adjusting for β-catenin, suggesting that β-catenin might play a crucial role in fluoride-induced aberrant osteogenesis. In vivo, viability of SaoS2 cells was significantly facilitated by 4 mg/L NaF, and fluoride could induce the abnormal activation of Wnt/β-catenin signaling, the expression of its target gene Runx2 and significantly increased Tcf/Lef reporter activity. Importantly, inhibition of β-catenin suppressed fluoride-induced Runx2 protein expression and the osteogenic phenotypes. Taken together, the present study provided in vivo and in vitro evidence reveals a potential mechanism for fluoride-induced aberrant osteoblast activation and indicates that β-catenin is the pivot molecule mediating viability and differentiation of osteoblasts and might be a therapeutic target for skeletal fluorosis.

Fluoride has been considered as a risk factor of cardiovascular disease due to its endothelial toxicology. However, the mechanism underlying the endothelial toxicity of fluoride has not been clearly illustrated. MiR-200c-3p was strongly linked with endothelial function and its level is increased in serum of fluorosis patients, but it is unclear the role of miR-200c-3p in the fluoride induced endothelial dysfunction. In this study, we confirmed that fluoride exposure induced the apoptosis of endothelial cells both in established rats model and cultured human umbilical vein endothelial cells (HUVECs). And miR-200c-3p was found to be upregulated in NaF treated HUVECs. Fluoride stimulation increased caspase-dependent apoptosis through miR-200c-3p upregulation, with repressing expression of its target gene Fas-associated phosphatase 1 (Fap-1), which functioned as Fas inhibitor. This resulted in activation of Fas-associated extrinsic apoptosis via interaction with increased Fas, Fadd, Cleaved Caspase-8 and Cleaved Caspase-3. The activation of Fas-associated extrinsic apoptosis was abrogated by miR-200c-3p inhibitor. Furthermore, the antiapoptotic effect of downregulated miR-200c-3p was restored by Fap-1 siRNA. These results suggested a determinant role of the miR-200c-3p/Fap-1 axis in fluoride induced endothelial apoptosis.

Studies have yet to evaluate the effects of water improvement on fluoride concentrations in drinking water and the corresponding health risks to Chinese residents in endemic fluorosis areas (EFAs) at a national level. This paper summarized available data in the published literature (2008–2016) on water fluoride from the EFAs in China before and after water quality was improved. Based on these obtained data, health risk assessment of Chinese residents' exposure to fluoride in improved drinking water was performed by means of a probabilistic approach. The uncertainties in the risk estimates were quantified using Monte Carlo simulation and sensitivity analysis. Our results showed that in general, the average fluoride levels (0.10–2.24 mg/L) in the improved drinking water in the EFAs of China were lower than the pre-intervention levels (0.30–15.24 mg/L). The highest fluoride levels were detected in North and Southwest China. The mean non-carcinogenic risks associated with consumption of the improved drinking water for Chinese residents were mostly accepted (hazard quotient < 1), but the non-carcinogenic risk of children in most of the EFAs at the 95th percentile exceeded the safe level of 1, indicating the potential non-cancer-causing health effects on this fluoride-exposed population. Sensitivity analyses indicated that fluoride concentration in drinking water, ingestion rate of water, and the exposure time in the shower were the most relevant variables in the model, therefore, efforts should focus mainly on the definition of their probability distributions for a more accurate risk assessment.

This meta-analysis systematically evaluated the effects of water improvement and defluoridation on fluorosis-endemic areas in North and South China. The study used PubMed, Embase, China National Knowledge Infrastructure, and Wanfang to retrieve relevant research studies published between January 2000 and October 2019. The data included water fluoride levels, dental fluorosis prevalence in children 8–15 years of age, urinary fluoride levels in children and adults, and skeletal fluorosis prevalence in adults. Fixed-effects and random-effects models were used in the meta-analysis. A total of 17 research articles met the inclusion criteria and had an average water improvement period of 15.8 years. With water improvement, water fluoride levels decreased from 2.72 mg/L to 0.54 mg/L (95% confidence intervals: −2.75, −1.58), which was below the standard for drinking water (1.5 mg/L). Additionally, after water improvement, the prevalence of dental fluorosis decreased from 54.5% to 36.2% (95% confidence intervals: 0.12, 0.31) in children, and the prevalence of skeletal fluorosis decreased from 13.7% to 4.2% (95% confidence intervals: 0.16, 0.40) in adults. Urinary fluoride levels decreased from 3.06 mg/L to 1.70 mg/L (OR = −2.03, 95% confidence intervals: −2.77, −1.30) in children and from 2.29 mg/L to 1.72 mg/L (OR = −0.57, 95% confidence intervals: 0.65, −0.49) in adults. The results showed that the prevalence of dental fluorosis and skeletal fluorosis and urinary fluoride levels were significantly reduced by water improvement. This study findings revealed that the effects of water improvement and defluoridation were greater in South China than in North China, and it is obviously related to the time of water improvement and reducing fluoride.

Release of fluoride from Quaternary sediments produces F-contaminated groundwater which threatens the health of millions of people worldwide. Despite the mechanisms of fluoride release from sediments are documented by numerous studies, it remains poorly understood that whether indigenous microbes participate in or not for the formation of F-rich groundwater by releasing fluoride from aquifer sediments. A microcosm-based approach, geochemistry and techniques of microbiology and molecular ecology were conducted together to investigate these mechanisms. Results show that microbes are abundant in high [F] groundwater containing at least 1129 operational taxonomic units (OTUs), and indigenous microbes can have an essential role in the mobilization of fluoride in sediments collected from aquifers in a typical fluorosis area in China. It also shows that for the sediments in this study, fluoride release (ca. 2 mg/L) is coupled with elevated concentrations of Ca (△ = 75 mg/L), Mg (△ = 33 mg/L), Al (△ = 0.2 mg/L) and Mn (△ = 1.4 mg/L). This suggests that the fluoride may source from the dissolution of F-bearing carbonate minerals and/or Al-Mn hydroxides in a local acidic environment. The findings provide additional insights into the biogeochemical circulation of fluoride in natural environment, especially in groundwater system and the development of effective strategies for the management of F-contaminated groundwater worldwide.

Fluoride is a well-known compound for its usefulness in healing dental caries. Similarly, fluoride is also known for its toxicity to various tissues in animals and humans. It causes skeletal fluorosis leading to osteoporosis of the bones. We hypothesized that when bones are affected by fluoride, the skeletal muscles are also likely to be affected by underlying molecular events involving myogenic differentiation. Murine myoblasts C2C12 were cultured in differentiation media with or without NaF (1 ppm-5 ppm) for four days. The effects of NaF on myoblasts and myotubes when exposed to low (1.5 ppm) and high concentration (5 ppm) were assessed based on the proliferation, alteration in gene expression, ROS production, and production of inflammatory cytokines. Changes based on morphology, multinucleated myotube formation, expression of MyHC1 and signaling pathways were also investigated. Concentrations of NaF tested had no effects on cell viability. NaF at low concentration (1.5 ppm) caused myoblast proliferation and when subjected to myogenic differentiation it induced hypertrophy of the myotubes by activating the IGF-1/AKT pathway. NaF at higher concentration (5 ppm), significantly inhibited myotube formation, increased skeletal muscle catabolism, generated reactive oxygen species (ROS) and inflammatory cytokines (TNF-α and IL-6) in C2C12 cells. NaF also enhanced the production of muscle atrophy-related genes, myostatin, and atrogin-1. The data suggest that NaF at low concentration can be used as muscle enhancing factor (hypertrophy), and at higher concentration, it accelerates skeletal muscle atrophy by activating the ubiquitin-proteosome pathway.

Excessive amounts of fluoride in drinking groundwater are harmful to human health, but the mechanisms responsible for fluoride enrichment in groundwater are not fully understood. Samples from two neighboring areas with endemic fluorosis were collected to test the hypothesis that there are distinctly different mechanisms responsible for the enrichment of fluoride in these groundwater. Hydrochemistry, stable isotopes and geochemical simulation were conducted together to investigate the fluoride spatial distribution and the diversity of responsible mechanisms. Our results showed that the spatial distributions of fluoride are different: I) high [F] in fresh shallow groundwater (SGQJ) and II) medium [F] in fresh to brackish deep groundwater (DGQJ) in the Qiji area; and III) medium [F] in brackish shallow groundwater (SGYH) and IV) low [F] in fresh deep groundwater (DGYH) in the Yanhu area. We also found that the fluoride concentration in groundwater is primarily controlled by the dissolution equilibrium of fluorite, as suggested by the correlation between [F] and [Ca]. However, there are other significant mechanisms: 1) for SGQJ, fluoride-bearing minerals (such as fluorite) dissolution, along with moderate evaporation, cation exchange and the more alkaline conditions are the driving factors; 2) for SGYH, the contributing factors are strong evaporation, the salt effect, dissolution of evaporites, gypsum and dolomite, bicarbonate-fluoride competition and anthropogenic activity; 3) for DGQJ, cation exchange, alkaline conditions and competitive adsorption are major factors; and 4) dolomite dissolution promotes the [F] increase in DGYH. Our findings suggest that the hydrogeochemical conditions play key roles in the enrichment of fluoride and that caution should be taken in the future when evaluating fluoride occurrence in groundwater, even in nearby areas.

Trace element profiling in the incrementally formed dentine of mammalian teeth can be applied to reconstruct temporal variation of incorporation of these elements into the tissue. Using an electron microprobe, this study analysed fluoride distribution in dentine of first and third mandibular molars of free-ranging eastern grey kangaroos inhabiting a high-fluoride area, to assess temporal variation in fluoride uptake of the animals. Fluoride content in the early-formed dentine of first molars was significantly lower than in the late-formed dentine of these teeth, and was also lower than in both, the early and the late-formed dentine of third molars. As early dentine formation in M1 takes place prior to weaning, this finding indicates a lower dentinal fluoride uptake during the pre-weaning compared to the post-weaning period. This is hypothetically attributed to the action of a partial barrier to fluoride transfer from blood to milk in lactating females and a low bioavailability of fluoride ingested together with milk. Another factor contributing to lower plasma fluoride levels in juveniles compared to adults is the rapid clearance of fluoride from blood plasma in the former due to their intense skeletal growth. The combined action of these mechanisms is considered to explain why in kangaroos from high-fluoride areas, the (early-formed) first molars are not affected by dental fluorosis while the (later-formed) third and fourth molars regularly exhibit marked to severe fluorotic lesions.

The trace element fluoride can be beneficial for oral health by preventing dental caries. However, fluoride is also known as an environmental pollutant. Fluoride pollution can lead to fluoride over-ingestion and can cause health issues, including dental fluorosis. Curcumin attenuated fluoride-induced toxicity in animal models, however the molecular mechanisms of how curcumin affects fluoride toxicity remain to be elucidated. We hypothesized that curcumin attenuates fluoride toxicity through modulation of Ac-p53. Here we investigated how curcumin affects the p53-p21 pathway in fluoride toxicity.LS8 cells were treated with NaF with/without curcumin. Curcumin significantly increased phosphorylation of Akt [Thr308] and attenuated fluoride-mediated caspase-3 cleavage and DNA damage marker γH2AX expression. Curcumin-mediated attenuation of caspase-3 activation was reversed by Akt inhibitor LY294002 (LY). However, LY did not alter curcumin-mediated γH2AX suppression. These results suggest that curcumin inhibited fluoride-mediated apoptosis via Akt activation, but DNA damage was suppressed by other pathways. Curcumin did not suppress/alter fluoride-mediated Ac-p53. However, curcumin itself significantly increased Ac-p53 and upregulated p21 protein levels to suppress cell proliferation in a dose-dependent manner. Curcumin suppressed fluoride-induced phosphorylation of p21 and increased p21 levels within the nuclear fraction. However, curcumin did not reverse fluoride-mediated cell growth inhibition. These results suggest that curcumin-induced Ac-p53 and p21 led to cell cycle arrest, while curcumin attenuated fluoride-mediated apoptosis via activation of Akt and suppressed fluoride-mediated DNA damage.By inhibiting DNA damage and apoptosis, curcumin may potentially alleviate health issues caused by fluoride pollution. Further studies are required to better understand the mechanism of curcumin-induced biological effects on fluoride toxicity.

In this study, a novel biosorbent is prepared from the pods of Bauhinia variegata is used for defluoridation of the fluoride contaminated water. It is an eco-friendly and economically feasible material. Comparison of adsorption capacity of Physically Treated Bauhinia (PTB) and Chemically Treated Bauhinia (CTB) are carried in this work. Characterization studies like SEM, EDS, FTIR, and XRD are executed to analyze surface morphology and functional groups in PTB and CTB. The experimental procedure was implemented in a batch process where the operating constraints such as dosage, pH, initial fluoride concentration, time, and temperature are varied to attain optimized efficiency. PTB and CTB yield an adsorption capacities of 10.90 mg/g and 15.45 mg/g respectively in the batch process. PTB adheres fluoride in monolayer formation whereas CTB forms multilayer adsorption. The adsorption process was described by the Pseudo first-order model to state the mechanism of physisorption. The negative values of thermodynamic parameters indicate spontaneity and favorable conditions for adsorption process. As CTB has a higher adsorption capacity than PTB, the batch study has been extended to column adsorption. Bed depth, initial fluoride concentration, and flow rate are the experimental variables used to acquire breakthrough curves. Simplified column models like Adam-Bohart, Thomas, and Yoon-Nelson models were analyzed. In column studies, Yoon-Nelson model fitted well in describing the process of adsorption. The maximum adsorption capacity acquired during the column process was found to be 1.176 mg/g with a bed depth of 5 cm and a flow rate of 5 ml/min. Thus, the innocuous and sustainable adsorbent is developed and serves as an excellent defluoridation agent.