The pathogenesis of endemic fluorosis: Research progress in the last 5 years.
ABSTRACT: Fluorine is one of the trace elements necessary for health. It has many physiological functions, and participates in normal metabolism. However, fluorine has paradoxical effects on the body. Many studies have shown that tissues and organs of humans and animals appear to suffer different degrees of damage after long-term direct or indirect exposure to more fluoride than required to meet the physiological demand. Although the aetiology of endemic fluorosis is clear, its specific pathogenesis is inconclusive. In the past 5 years, many researchers have conducted in-depth studies into the pathogenesis of endemic fluorosis. Research in the areas of fluoride-induced stress pathways, signalling pathways and apoptosis has provided further extensive knowledge at the molecular and genetic level. In this article, we summarize the main results.
Project description:To assess the effects of provided fluoride-safe drinking-water for the prevention and control of endemic fluorosis in China.A national cross-sectional study in China.In 1985, randomly selected villages in 27 provinces (or cities and municipalities) in 5 geographic areas all over China.Involved 81 786 children aged from 8 to 12 and 594 698 adults aged over 16.The prevalence of dental fluorosis and clinical skeletal fluorosis, the fluoride concentrations in the drinking-water in study villages and in the urine of subjects.The study showed that in the villages where the drinking-water fluoride concentrations were higher than the government standard of 1.2 mg/l, but no fluoride-safe drinking-water supply scheme was provided (FNB areas), the prevalence rate and index of dental fluorosis in children, and prevalence rate of clinical skeletal fluorosis in adults were all significantly higher than those in the historical endemic fluorosis villages after the fluoride-safe drinking-water were provided (FSB areas). Additionally, the prevalence rate of dental fluorosis as well as clinical skeletal fluorosis, and the concentration of fluoride in urine were found increased with the increase of fluoride concentration in drinking-water, with significant positive correlations in the FNB areas. While, the prevalence rate of dental fluorosis and clinical skeletal fluorosis in different age groups and their degrees of prevalence were significantly lower in the FSB areas than those in the FNB areas.The provision of fluoride-safe drinking-water supply schemes had significant effects on the prevention and control of dental fluorosis and skeletal fluorosis. The study also indicated that the dental and skeletal fluorosis is still prevailing in the high-fluoride drinking-water areas in China.
Project description:An observational study was conducted to determine dietary fluoride intake, diet, and prevalence of dental and skeletal fluorosis of school age children in three fluorosis endemic districts of the Ethiopian Rift Valley having similar concentrations of fluoride (F) in drinking water (~5 mg F/L). The duplicate plate method was used to collect foods consumed by children over 24 h from 20 households in each community (n = 60) and the foods, along with water and beverages, were analyzed for fluoride (F) content. Prevalence of dental and skeletal fluorosis was determined using presence of clinical symptoms in children (n = 220). Daily dietary fluoride intake was at or above tolerable upper intake level (UL) of 10 mg F/day and the dietary sources (water, prepared food and beverages) all contributed to the daily fluoride burden. Urinary fluoride in children from Fentale and Adamitulu was almost twice (>5 mg/L) the concentration found in urine from children from Alaba, where rain water harvesting was most common. Severe and moderate dental fluorosis was found in Alaba and Adamitulu, the highest severity and prevalence being in the latter district where staple foods were lowest in calcium. Children in all three areas showed evidence of both skeletal and non-skeletal fluorosis. Our data support the hypothesis that intake of calcium rich foods in addition to using rain water for household consumption and preparation of food, may help in reducing risk of fluorosis in Ethiopia, but prospective studies are needed.
Project description:Fluorosis is caused by excess of fluoride intake over a long period of time. Aberrant change in the Runt-related transcription factor 2 (RUNX2) mediated signaling cascade is one of the decisive steps during the pathogenesis of fluorosis. Up to date, role of fluoride on the epigenetic alterations is not studied. In the present study, global expression profiling of short noncoding RNAs, in particular miRNAs and snoRNAs, was carried out in sodium fluoride (NaF) treated human osteosarcoma (HOS) cells to understand their possible role in the development of fluorosis. qPCR and in silico hybridization revealed that miR-124 and miR-155 can be directly involved in the transcriptional regulation of Runt-related transcription factor 2 (RUNX2) and receptor activator of nuclear factor ?-B ligand (RANKL) genes. Compared to control, C/D box analysis revealed marked elevation in the number of UG dinucleotides and D-box sequences in NaF exposed HOS cells. Herein, we report miR-124 and miR-155 as the new possible players involved in the development of fluorosis. We show that the alterations in UG dinucleotides and D-box sequences of snoRNAs could be due to NaF exposure.
Project description:Fluorine is a bone-seeking element ubiquitously present in the environment and widely used in many oral hygiene products. In humans, excessive intake of fluoride may cause dental and skeletal fluorosis. However, endemic fluorosis does not appear to develop in a proportion of individuals exposed to the same levels of fluoride. The mechanisms by which mammalian cells resist fluoride are still unclear. In this study, we developed strains of mouse L-929 cells resistant to different levels of fluoride. High-throughput RNA-sequencing analyses of the fluoride-resistant L-929 cells indicated that massive changes in global gene expression occurred, compared with the wild-type L-929 cells. The main biological processes and functions changed were associated with the extracellular region and matrix, response to stress, receptor binding, and signal transduction. This indicated that high doses of fluoride not only exerted stress on L-929 cells but also induced functional pathways that helped them adapt to the presence of fluoride or to expel it. These data should prove useful in identifying cellular processes or transporters/channels that play central roles in adaptation to or expulsion of fluoride in humans.
Project description:Background. The inconsistent prevalence of fluorosis for a given level of fluoride in drinking water suggests developmental defects of enamel (DDEs) other than fluorosis were being misdiagnosed as fluorosis. The imprecise definition and subjective perception of fluorosis indices could result in misdiagnosis of dental fluorosis. This study was conducted to distinguish genuine fluorosis from fluorosis-resembling defects that could have adverse health-related events as a cause using Early Childhood Events Life-grid method (ECEL). Methods. A study was conducted on 400 9-year-old children from areas with high, optimal and low levels of fluoride in the drinking water of Fars province, Iran. Fluorosis cases were diagnosed on the standardized one view photographs of the anterior teeth using Dean's and TF (Thylstrup and Fejerskov) Indices by calibrated dentists. Agreements between examiners were tested. Early childhood health-related data collected retrospectively by ECEL method were matched with the position of enamel defects. Results. Using both Dean and TF indices three out of four dentists diagnosed that 31.3% (115) children had fluorosis, 58.0%, 29.1%, and 10.0% in high (2.12-2.85 ppm), optimal (0.62-1.22 ppm), and low (0.24-0.29 ppm) fluoride areas respectively (p < 0.001). After matching health-related events in the 115 (31.3%) of children diagnosed with fluorosis, 31 (8.4%) of children had fluorosis which could be matched with their adverse health-related events. This suggests that what was diagnosed as fluorosis were non-fluoride related DDEs that resemble fluorosis. Discussion. The frequently used measures of fluorosis appear to overscore fluorosis. Use of ECEL method to consider health related events relevant to DDEs could help to differentiate between genuine fluorosis and fluorosis-resembling defects.
Project description:Fluorosis induced by exposure to high level fluoride is quite widespread in the world. The manifestations of fluorosis include dental mottling, bone damage, and impaired malfunction of soft tissues. However, the molecular mechanism of fluorosis has not been clarified until now. To explore the underlying mechanisms of fluorosis and screen out serum biomarkers, we carried out a quantitative proteomics study to identify differentially expressed serum proteins in Wistar rats treated with sodium fluoride (NaF) by using a proteomics approach of isobaric tagging for relative and absolute quantitation (iTRAQ). We fed Wistar rats drinking water that had 50, 150, and 250 mg/L of dissolved NaF for 24 weeks. For the experimental duration, each rat was given an examination of the lower incisors to check for the condition of dental fluorosis (DF). By the end of the treatment, fluoride ion concentration in serum and lower incisors were detected. The results showed that NaF treatment can induce rat fluorosis. By iTRAQ analysis, a total of 37 differentially expressed serum proteins were identified between NaF-treated and control rats. These proteins were further analyzed by bioinformatics, out of which two proteins were validated by enzyme-linked immunoadsorbent assays (ELISA). The major proteins were involved in complement and coagulation cascade, inflammatory response, complement activation, defense response, and wound response, suggesting that inflammation and immune reactions may play a key role in fluorosis pathogenesis. These proteins may contribute to the understanding of the mechanism of fluoride toxicity, and may serve as potential biomarkers for fluorosis.
Project description:The fluoride has volcanic activity and abundantly exists in environment combining with other elements as fluoride compounds. Recent researches indicated that the molecular mechanisms of intracellular fluoride toxicity were very complex. However, the molecular mechanisms underlying the effects on gene expression of chronic fluoride-induced damage is unknown, especially the detailed regulatory process of mitochondria. In the present study, we screened the differential expression ESTs associated with fluorosis by DDRT-PCR in rat liver. We gained 8 genes, 3 new ESTs, and 1 unknown function sequence and firstly demonstrated that microsomal glutathione S-transferase 1 (MGST1), ATP synthase H(+) transporting mitochondrial F(0) complex subunit C1, selenoprotein S, mitochondrial IF1 protein, and mitochondrial succinyl-CoA synthetase alpha subunit were participated in mitochondria metabolism, functional and structural damage process caused by chronic fluorosis. This information will be very helpful for understanding the molecular mechanisms of fluorosis.
Project description:OBJECTIVES:The authors describe associations between dental fluorosis and fluoride intakes, with an emphasis on intake from fluoride in infant formula. METHODS:The authors administered periodic questionnaires to parents to assess children's early fluoride intake sources from beverages, selected foods, dentifrice and supplements. They later assessed relationships between fluorosis of the permanent maxillary incisors and fluoride intake from beverages and other sources, both for individual time points and cumulatively using area-under-the-curve (AUC) estimates. The authors determined effects associated with fluoride in reconstituted powdered infant formulas, along with risks associated with intake of fluoride from dentifrice and other sources. RESULTS:Considering only fluoride intake from ages 3 to 9 months, the authors found that participants with fluorosis (97 percent of which was mild) had significantly greater cumulative fluoride intake (AUC) from reconstituted powdered infant formula and other beverages with added water than did those without fluorosis. Considering only intake from ages 16 to 36 months, participants with fluorosis had significantly higher fluoride intake from water by itself and dentifrice than did those without fluorosis. In a model combining both the 3- to 9-months and 16- to 36-months age groups, the significant variables were fluoride intake from reconstituted powder concentrate formula (by participants at ages 3-9 months), other beverages with added water (also by participants at ages 3-9 months) and dentifrice (by participants at ages 16-36 months). CONCLUSIONS:Greater fluoride intakes from reconstituted powdered formulas (when participants were aged 3-9 months) and other water-added beverages (when participants were aged 3-9 months) increased fluorosis risk, as did higher dentifrice intake by participants when aged 16 to 36 months. CLINICAL IMPLICATIONS:Results suggest that prevalence of mild dental fluorosis could be reduced by avoiding ingestion of large quantities of fluoride from reconstituted powdered concentrate infant formula and fluoridated dentifrice.
Project description:There are no studies of oral health in relation to esophageal cancer in Africa, or of Eastern Africa's endemic dental fluorosis, an irreversible enamel hypo-mineralization due to early-life excessive fluoride intake. During 2014-18, we conducted a case-control study of squamous cell esophageal cancer in Eldoret, western Kenya. Odds ratios (AORs (95% confidence intervals)) were adjusted for design factors, tobacco, alcohol, ethnicity, education, oral hygiene and missing/decayed teeth. Esophageal cancer cases (N = 430) had poorer oral health and hygiene than controls (N = 440). Compared to no dental fluorosis, moderate/severe fluorosis, which affected 44% of cases, had a crude OR of 20.8 (11.6, 37.4) and on full adjustment was associated with 9.4-fold (4.6, 19.1) increased risk, whilst mild fluorosis (43% of cases) had an AOR of 2.3 (1.3, 4.0). The prevalence of oral leukoplakia and tooth loss/decay increased with fluorosis severity, and increased cancer risks associated with moderate/severe fluorosis were particularly strong in individuals with more tooth loss/decay. Using a mswaki stick (AOR = 1.7 (1.0, 2.9)) rather than a commercial tooth brush and infrequent tooth brushing also independently increased risk. Geographic variations showed that areas of high esophageal cancer incidence and those of high groundwater fluoride levels have remarkably similar locations across Eastern Africa. In conclusion, poor oral health in combination with, or as a result of, high-altitude susceptibility to hydro-geologically influenced dental fluorosis may underlie the striking co-location of Africa's esophageal cancer corridor with the Rift Valley. The findings call for heightened research into primary prevention opportunities of this highly fatal but common cancer.
Project description:Brick-tea type fluorosis is a public health concern in the north west area of China. The vitamin D receptor (VDR)-FokI polymorphism is considered to be a regulator of bone metabolism and calcium resorption. However, the association of VDR-FokI polymorphism with the risk of brick-tea type fluorosis has not been reported.A cross sectional, case control study was conducted in three provinces (Inner Mongolia, Qinghai and Sinkiang) in China. The fluoride content of Brick-tea water and urine was tested using the standards GB 1996-2005 and WS/T89-2006 (China), respectively. Skeletal fluorosis was diagnosed using the standard WS/192-2008 (China). The VDR-FokI polymorphism was detected by the Sequenom MassARRAY system.Compared with carriers of the CC genotype, participants with the CT/TT genotype had a significantly decreased risk of skeletal fluorosis (OR=0.761 (95% CI 0.580 to 0.997)), after adjustment for risk factors. When investigated among ethnic groups, the protective effect of the CT/TT genotype was limited in the Mongolian participants (OR=0.525 (95% CI 0.278 to 0.991)). Moreover, the interaction of VDR-FokI with risk factors was only found in Mongolian participants: the protective effect of the CT/TT genotype was limited to participants with >7.0?mg/day daily intake of tea fluoride (OR=0.085 (95% CI 0.009 to 0.851), participants with >3.2?mg/L urine fluoride (OR=0.103 (95% CI 0.017 to 0.633)) or participants aged 46-65 years (OR=0.404 (95% CI 0.177 to 0.922).Our data suggest that the CT/TT genotype of VDR-FokI may be a protective factor for brick-tea type skeletal fluorosis, and this effect is pronounced in Mongolian participants.