Membrane Exporters of Fluoride Ion.

Microorganisms contend with numerous and unusual chemical threats and have evolved a catalog of resistance mechanisms in response. One particularly ancient, pernicious threat is posed by fluoride ion (F-), a common xenobiotic in natural environments that causes broad-spectrum harm to metabolic pathways. This review focuses on advances in the last ten years toward understanding the microbial response to cytoplasmic accumulation of F-, with a special emphasis on the structure and mechanisms of the proteins that microbes use to export fluoride: the CLCF family of F-/H+ antiporters and the Fluc/FEX family of F- channels.

Systematic review of epidemiological and toxicological evidence on health effects of fluoride in drinking water.

INTRODUCTION: Fluoride is a naturally occurring substance that is also added to drinking water, dental hygiene products, and food supplements for preventing dental caries. Concerns have been raised about several other potential health risks of fluoride. OBJECTIVE: To conduct a robust synthesis of evidence regarding human health risks due to exposure to fluoride in drinking water, and to develop a point of departure (POD) for setting a health-based value (HBV) for fluoride in drinking water. METHODS: A systematic review of evidence published since recent reviews of human, animal, and in vitro data was carried out. Bradford Hill considerations were used to weigh the evidence for causality. Several key studies were considered for deriving PODs. RESULTS: The current review identified 89 human studies, 199 animal studies, and 10 major in vitro reviews. The weight of evidence on 39 health endpoints was presented. In addition to dental fluorosis, evidence was considered strong for reduction in IQ scores in children, moderate for thyroid dysfunction, weak for kidney dysfunction, and limited for sex hormone disruptions. CONCLUSION: The current review identified moderate dental fluorosis and reduction in IQ scores in children as the most relevant endpoints for establishing an HBV for fluoride in drinking water. PODs were derived for these two endpoints, although there is still some uncertainty in the causal weight of evidence for causality for reducing IQ scores in children and considerable uncertainty in the derivation of its POD. Given our evaluation of the overall weight of evidence, moderate dental fluorosis is suggested as the key endpoint until more evidence is accumulated on possible reduction of IQ scores effects. A POD of 1.56 mg fluoride/L for moderate dental fluorosis may be preferred as a starting point for setting an HBV for fluoride in drinking water to protect against moderate and severe dental fluorosis. Although outside the scope of the current review, precautionary concerns for potential neurodevelopmental cognitive effects may warrant special consideration in the derivation of the HBV for fluoride in drinking water.

Does fluoride exposure affect thyroid function? A systematic review and dose-response meta-analysis.

INTRODUCTION: Fluoride exposure may have various adverse health effects, including affecting thyroid function and disease risk, but the pattern of such relation is still uncertain. METHODS: We systematically searched human studies assessing the relation between fluoride exposure and thyroid function and disease. We compared the highest versus the lowest fluoride category across these studies, and we performed a one-stage dose-response meta-analysis for aggregated data to explore the shape of the association. RESULTS: Most retrieved studies (27 of which with a cross-sectional design) were conducted in Asia and in children, assessing fluoride exposure through its concentrations in drinking water, urine, serum, or dietary intake. Twenty-four studies reported data on thyroid function by measuring thyroid-related hormones in blood (mainly thyroid-stimulating-hormone - TSH), 9 reported data on thyroid disease, and 4 on thyroid volume. By comparing the highest versus the lowest fluoride categories, overall mean TSH difference was 1.05 µIU/mL. Dose-response curve showed no change in TSH concentrations in the lowest water fluoride exposure range, while the hormone levels started to linearly increase around 2.5 mg/L, also dependending on the risk of bias of the included studies. The association between biomarkers of fluoride exposure and TSH was also positive, with little evidence of a threshold. Evidence for an association between fluoride exposure and blood concentrations of thyroid hormones was less evident, though there was an indication of inverse association with triiodothyronine. For thyroid disease, the few available studies suggested a positive association with goiter and with hypothyroidism in both children and adults. CONCLUSIONS: Overall, exposure to high-fluoride drinking water appears to non-linearly affect thyroid function and increase TSH release in children, starting above a threshold of exposure, and to increase the risk of some thyroid diseases.

Co-exposure to fluoride and sulfur dioxide induces abnormal enamel mineralization in rats via the FGF9-mediated MAPK signaling pathway.

Fluoride (F) and sulfur dioxide (SO2) contamination is recognized as a public health concern worldwide. Our previous research has shown that Co-exposure to F and SO2 can cause abnormal enamel mineralization. Ameloblastin (AMBN) plays a crucial role in the process of enamel mineralization. However, the process by which simultaneous exposure to F and SO2 influences enamel formation by regulating AMBN expression still needs to be understood. This study aimed to establish in vivo and in vitro models of F-SO2 Co-exposure and investigate the relationship between AMBN and abnormal enamel mineralization. By overexpressing/knocking out the Fibroblast Growth Factor 9 (FGF9) gene, we investigated the impact of FGF9-mediated Mitogen-Activated Protein Kinase (MAPK) signaling on AMBN synthesis to elucidate the mechanism underlying the induction of abnormal enamel mineralization by F-SO2 Co-exposure in rats. The results showed that F-SO2 exposure damaged the structure of rat enamel and ameloblasts. When exposed to F or SO2, gradual increases in the protein expression of FGF9 and phosphorylated p38 mitogen-activated protein kinase (p-P38) were observed. Conversely, the protein levels of AMBN, phosphorylated extracellular signal-regulated kinase (p-ERK), and phosphorylated c-Jun N-terminal kinase (p-JNK) were decreased. AMBN expression was significantly correlated with FGF9, p-ERK, and p-JNK expression in ameloblasts. Interestingly, FGF9 overexpression reduced the levels of p-ERK and p-JNK, worsening the inhibitory effect of F-SO2 on AMBN. Conversely, FGF9 knockout increased the phosphorylation of ERK and JNK, partially reversing the F-SO2-induced downregulation of AMBN. Taken together, these findings strongly demonstrate that FGF9 plays a critical role in F-SO2-induced abnormal enamel mineralization by regulating AMBN synthesis through the JNK and ERK pathways.

A comprehensive review of human health risks of arsenic and fluoride contamination of groundwater in the South Asia region.

The present study found that ∼80 million people in India, ∼60 million people in Pakistan, ∼70 million people in Bangladesh, and ∼3 million people in Nepal are exposed to arsenic groundwater contamination above 10 µg/L, while Sri Lanka remains moderately affected. In the case of fluoride contamination, ∼120 million in India, >2 million in Pakistan, and ∼0.5 million in Sri Lanka are exposed to the risk of fluoride above 1.5 mg/L, while Bangladesh and Nepal are mildly affected. The hazard quotient (HQ) for arsenic varied from 0 to 822 in India, 0 to 33 in Pakistan, 0 to 1,051 in Bangladesh, 0 to 582 in Nepal, and 0 to 89 in Sri Lanka. The cancer risk of arsenic varied from 0 to 1.64 × 1-1 in India, 0 to 1.07 × 10-1 in Pakistan, 0 to 2.10 × 10-1 in Bangladesh, 0 to 1.16 × 10-1 in Nepal, and 0 to 1.78 × 10-2 in Sri Lanka. In the case of fluoride, the HQ ranged from 0 to 21 in India, 0 to 33 in Pakistan, 0 to 18 in Bangladesh, 0 to 10 in Nepal, and 0 to 10 in Sri Lanka. Arsenic and fluoride have adverse effects on animals, resulting in chemical poisoning and skeletal fluorosis. Adsorption and membrane filtration have demonstrated outstanding treatment outcomes.

Dose dependence of prenatal fluoride exposure associations with cognitive performance at school age in three prospective studies.

BACKGROUND: Fluoride may be a developmental neurotoxicant at elevated exposures. We merged new data from a prospective Odense Child Cohort (OCC) with results from two previous birth cohort studies from Mexico and Canada to characterize the dose-effect relationship in greater detail. METHODS: The OCC contributed 837 mother-child pairs to the total of >1500. We measured creatinine-adjusted urine-fluoride concentrations in maternal urine samples obtained during late pregnancy. Child IQ was determined at age 7 years using an abbreviated version of the Wechsler Intelligence Scales for Children. Findings from the three cohorts were used to calculate the joint benchmark concentration (BMC) and the lower confidence limit (BMCL) after adjustment for covariables. RESULTS: In the OCC, urine-fluoride concentrations varied between 0.08 and 3.04 mg/l (median 0.52 mg/l) but were not significantly associated with full-scale IQ at age 7 years (ß = 0.08; 95% confidence interval -1.14 to 1.30 for a doubling in exposure). No difference was apparent between boys and girls. In the OCC, the BMC was 0.92 mg/l, with a BMCL of 0.30 mg/l. The joint analysis of all three cohorts showed a statistically significant association between urine-fluoride and IQ, with a BMC of 0.45 mg/l (BMCL, 0.28 mg/l), slightly higher than the BMC previously reported for the two North American cohorts alone. CONCLUSIONS: As the BMCL reflects an approximate threshold for developmental neurotoxicity, the results suggest that pregnant women and children may need protection against fluoride toxicity.

Effects of water fluoridation on early embryonic development of zebrafish.

Fluoride has strong electronegativity and exposes diversely in nature. Water fluoridation is the most pervasive form of occurrence, representing a significant threat to human health. In this study, we investigate the morphometric and physiological alterations triggered by fluoride stimulation during the embryogenesis of zebrafish and reveal its putative effects of stage- and/or dose-dependent. Fluoride exhibits potent biological activity and can be extensively absorbed by the yolk sac, exerting significant effects on the development of multiple organs. This is primarily manifested as restricted nutrient utilization and elevated levels of lipid peroxidation, further leading to the accumulation of superoxide in the yolk sac, liver, and intestines. Moreover, pericardial edema exerts pressure on the brain and eye development, resulting in spinal curvature and reduced body length. Besides, acute fluoride exposure with varying concentrations has led to diverse teratogenic outcomes. A low dose of water fluoridation tends to induce abnormal development of the embryonic yolk sac, while vascular malformation is widely observed in all fluoride-treated groups. The effect of fluoride exposure on blood circulation is universally present, even in zebrafish larvae that do not exhibit obvious deformities. Their swimming behavior is also affected by water fluoridation, resulting in reduced activity and delayed reactions. In conclusion, this study provides valuable insights into the monitoring of environmental quality related to water fluoridation and disease prevention.

Integrative transcriptome and metabolome analysis of fluoride exposure induced developmental neurotoxicity in mouse brain.

Fluoride could cause developmental neurotoxicity and significantly affect the intelligence quotient (IQ) of children. However, the systematic mechanism of neuronal damage caused by excessive fluoride administration in offspring is largely unknown. Here, we present a comprehensive integrative transcriptome and metabolome analysis to study the mechanism of developmental neurotoxicity caused by chronic fluoride exposure. Comparing the different doses of fluoride treatments in two generations revealed the exclusive signature of metabolism pathways and gene expression profiles. In particular, neuronal development and synaptic ion transport are significantly altered at the gene expression and metabolite accumulation levels for both generations, which could act as messengers and enhancers of fluoride-induced systemic neuronal injury. Choline and arachidonic acid metabolism, which highlighted in the integrative analysis, exhibited different regulatory patterns between the two generations, particularly for synaptic vesicle formation and inflammatory factor transport. It may suggest that choline and arachidonic acid metabolism play important roles in developmental neurotoxic responses for offspring mice. Our study provides comprehensive insights into the metabolomic and transcriptomic regulation of fluoride stress responses in the mechanistic explanation of fluoride-induced developmental neurotoxicity.

Regulating effect of miR-132-3p on the changes of MAPK pathway in rat brains and SH-SY5Y cells exposed to excessive fluoride by targeting expression of MAPK1.

BACKGROUND: Although the changes of mitogen-activated protein kinase (MAPK) pathway in the central nervous system (CNS) induced by excessive fluoride has been confirmed by our previous findings, the underlying mechanism(s) of the action remains unclear. Here, we investigate the possibility that microRNAs (miRNAs) are involved in the aspect. METHODS: As a model of chronic fluorosis, SD rats received different concentrations of fluoride in their drinking water for 3 or 6 months and SH-SY5Y cells were exposed to fluoride. Literature reviews and bioinformatics analyses were used to predict and real-time PCR to measure the expression of 12 miRNAs; an algorithm-based approach was applied to identify multiply potential target-genes and pathways; the dual-luciferase reporter system to detect the association of miR-132-3p with MAPK1; and fluorescence in situ hybridization to detect miR-132-3p localization. The miR-132-3p inhibitor or mimics or MAPK1 silencing RNA were transfected into cultured cells. Expression of protein components of the MAPK pathway was assessed by immunofluorescence or Western blotting. RESULTS: In the rat hippocampus exposed with high fluoride, ten miRNAs were down-regulated and two up-regulated. Among these, miR-132-3p expression was down-regulated to the greatest extent and MAPK1 level (selected from the 220 genes predicted) was corelated with the alteration of miR-132-3p. Furthermore, miR-132-3p level was declined, whereas the protein levels MAPK pathway components were increased in the rat brains and SH-SY5Y cells exposed to high fluoride. MiR-132-3p up-regulated MAPK1 by binding directly to its 3'-untranslated region. Obviously, miR-132-3p mimics or MAPK1 silencing RNA attenuated the elevated expressions of the proteins components of the MAPK pathway induced by fluorosis in SH-SY5Y cells, whereas an inhibitor of miR-132-3p just played the opposite effect. CONCLUSION: MiR-132-3p appears to modulate the changes of MAPK signaling pathway in the CNS associated with chronic fluorosis.

Evaluation of fluoride exposure using disability-adjusted life years and health risk assessment in south-western Iran: A novel Monte Carlo simulation.

Consumption of fluoride-contaminated water is a worldwide concern, especially in developing countries, including Iran. However, there are restricted studies of non-single-value health risk assessment and the disease burden regarding fluoride intake nationwide. Prolonged exposure to excessive fluoride has been linked to adverse health effects such as dental and skeletal fluorosis. This can lead to under-mineralization of hard tissues, causing aesthetic concerns for teeth and changes in bone structure, increasing the risk of fractures. As such, we aimed to implement probability-based frameworks using Monte Carlo methods to explore the potential adverse effects of fluoride via the ingestion route. This platform consists of two sectors: 1) health risk assessment of various age categories coupled with a variance decomposition technique to measure the contributions of predictor variables in the outcome of the health risk model, and 2) implementing Monte Carlo methods in dose-response curves to explore the fluoride-induced burden of diseases of dental fluorosis and skeletal fractures in terms of disability-adjusted life years (DALYs). For this purpose, total water samples of 8053 (N=8053) from 57 sites were analyzed in Fars and Bushehr Provinces. The mean fluoride concentrations were 0.75 mg/L and 1.09 mg/L, with maximum fluoride contents of 6.5 mg/L and 3.22 mg/L for the Fars and Bushehr provinces, respectively. The hazard quotient of the 95th percentile (HQ>1) revealed that all infants and children in the study area were potentially vulnerable to over-receiving fluoride. Sobol' sensitivity analysis indices, including first-order, second-order, and total order, disclosed that fluoride concentration (Cw), ingestion rate (IRw), and their mutual interactions were the most influential factors in the health risk model. DALYs rate of dental fluorosis was as high as 981.45 (uncertainty interval: UI 95 % 353.23-1618.40) in Lamerd, and maximum DALYs of skeletal fractures occurred in Mohr 71.61(49.75-92.71), in Fars Province, indicated severe dental fluorosis but mild hazard regarding fractures. Residents of the Tang-e Eram in Bushehr Province with a DALYs rate of 3609.40 (1296.68-5993.73) for dental fluorosis and a DALYs rate of 284.67 (199.11-367.99) for skeletal fractures were the most potentially endangered population. By evaluating the outputs of the DALYs model, the gap in scenarios of central tendency exposure and reasonable maximum exposure highlights the role of food source intake in over-receiving fluoride. This research insists on implementing defluoridation programs in fluoride-endemic zones to combat the undesirable effects of fluoride. The global measures presented in this research aim to address the root causes of contamination and help policymakers and authorities mitigate fluoride's harmful impacts on the environment and public health.

Periploca forrestii Schltr. ameliorate liver injury caused by fluorosis in rat.

To investigate the impact of the ethanoic fractions of Periploca forrestii Schltr. (P. forrestii) in ameliorating the liver injury caused by fluoride ingestion and to explore the potential mechanisms. Initially, an in vitro fluorosis cell model was constructed using the human normal liver cell line (L-02) induced by fluoride. Cell viability was assessed using the CCK-8 assay kit. The lactate dehydrogenase (LDH) assay kit was utilized to measure LDH content in the cell supernatant, while the malonic dialdehyde (MDA) assay kit was employed to determine MDA levels within the cells. Subsequently, a fluorosis rat model was established, and LDH content in the cell supernatant was measured using the LDH assay kit. Various parameters, including MDA, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and reactive oxygen species (ROS) content within the cells, were detected using appropriate assay kits. Additionally, cell apoptosis rate was determined using the Annexin V-FITC/PI cell apoptosis assay kit. The protein expression levels of B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), Caspase-3, Cleaved Caspase-3, Caspase-9, and Cleaved Caspase-9 were analyzed through Western blotting. Compared to the model group, the ethanolic fraction D of P.forrestii (Fr.D) increased cell viability (P < 0.01) and decreased LDH and MDA levels (P < 0.01). In the high-dose Fr.D treatment group of fluoride-poisoned rats, serum ALT, AST, LDH and MDA levels significantly decreased (P < 0.01). Results from rat primary cells exhibited that the Fr.D administration group exhibited significantly higher cell survival rates than the fluoride group (P < 0.01). Similarly, primary rat cells treated with Fr.D showed enhanced cell viability (P < 0.05) and reduced apoptosis rate, LDH, MDA, SOD, GSH-Px, CAT, and ROS levels (P < 0.05) compared to the model group. Western blot analysis indicated that the Fr.D treatment group elevated the Bcl-2/Bax protein expression ratio and reduced Caspase-3 and Caspase-9 activation levels (P < 0.01) compared to the model group. The results suggest that components within the Fr.D from Periploca forrestii may alleviate fluoride-induced liver injury by potentially counteracting oxidative stress and cell apoptosis.

The fluoride exporter (CsFEX) regulates fluoride uptake/accumulation in Camellia sinensis under different pH.

Fluoride (F) can be absorbed from the environment and hyperaccumulate in leaves of Camellia sinensis without exhibiting any toxic symptoms. Fluoride exporter in C. sinensis (CsFEX) could transport F to extracellular environment to alleviate F accumulation and F toxicity, but its functional mechanism remains unclear. Here, combining with pH condition of C. sinensis growth, the characteristics of CsFEX and mechanism of F detoxification were further explored. The results showed that F accumulation was influenced by various pH, and pH 4.5 and 6.5 had a greater impact on the F accumulation of C. sinensis. Through Non-invasive Micro-test Technology (NMT) detection, it was found that F uptake/accumulation of C. sinensis and Arabidopsis thaliana might be affected by pH through changing the transmembrane electrochemical proton gradient of roots. Furthermore, diverse expression patterns of CsFEX were induced by F treatment under different pH, which was basically up-regulated in response to high F accumulation, indicating that CsFEX was likely to participate in the process of F accumulation in C. sinensis and this process might be regulated by pH. Additionally, CsFEX functioned in the mitigation of F sensitivity and accumulation strengthened by lower pH in Escherichia coli and A. thaliana. Moreover, the changes of H+ flux and potential gradient caused by F were relieved as well in transgenic lines, also suggesting that CsFEX might play an important role in the process of F accumulation. Above all, F uptake/accumulation were alleviated in E. coli and A. thaliana by CsFEX through exporting F-, especially at lower pH, implying that CsFEX might regulate F accumulation in C. sinensis.

Fluoride-induced hypertension by regulating RhoA/ROCK pathway and phenotypic transformation of vascular smooth muscle cells: In vitro and in vivo evidence.

Fluoride exposure has been implicated as a potential risk factor for hypertension, but the underlying mechanisms remain unclear. This study investigated the role of the RhoA/ROCK signaling pathway in fluoride-induced hypertension. Male Wistar rats were divided into different groups and exposed to varying concentrations of sodium fluoride (NaF) or sodium chloride (NaCl) via drinking water. The rats' blood pressure was measured, and their aortic tissue was utilized for high-throughput sequencing analysis. Additionally, rat and A7r5 cell models were established using NaF and/or Fasudil. The study evaluated the effects of fluoride exposure on blood pressure, pathological changes in the aorta, as well as the protein/mRNA expression levels of phenotypic transformation indicators (a-SMA, calp, OPN) in vascular smooth muscle cells (VSMCs), along with the RhoA/ROCK signaling pathway (RhoA, ROCK1, ROCK2, MLC/p-MLC). The results demonstrated that fluoride exposure in rats led to increased blood pressure. High-throughput sequencing analysis revealed differential gene expression associated with vascular smooth muscle contraction, with the RhoA/ROCK signaling pathway emerging as a key regulator. Pathological changes in the rat aorta, such as elastic membrane rupture and collagen fiber deposition, were observed following NaF exposure. However, fasudil, a ROCK inhibitor, mitigated these pathological changes. Both in vitro and in vivo models confirmed the activation of the RhoA/ROCK signaling pathway and the phenotypic transformation of VSMCs from a contractile to a synthetic state upon fluoride exposure. Fasudil effectively inhibited the activities of ROCK1 and ROCK2 and attenuated the phenotypic transformation of VSMCs. In conclusion, fluoride has the potential to induce hypertension through the activation of the RhoA/ROCK signaling pathway and phenotypic changes in vascular smooth muscle cells. These results provide new insights into the mechanism of fluoride-induced hypertension.

Rutin mitigates fluoride-induced nephrotoxicity by inhibiting ROS-mediated lysosomal membrane permeabilization and the GSDME-HMGB1 axis involved in pyroptosis and inflammation.

Fluoride is known to induce nephrotoxicity; however, the underlying mechanisms remain incompletely understood. Therefore, this study aims to explore the roles and mechanisms of lysosomal membrane permeabilization (LMP) and the GSDME/HMGB1 axis in fluoride-induced nephrotoxicity and the protective effects of rutin. Rutin, a naturally occurring flavonoid compound known for its antioxidative and anti-inflammatory properties, is primarily mediated by inhibiting oxidative stress and reducing proinflammatory markers. To that end, we established in vivo and in vitro models. In the in vivo study, rats were exposed to sodium fluoride (NaF) throughout pregnancy and up until 2 months after birth. In parallel, we employed in vitro models using HK-2 cells treated with NaF, n-acetyl-L-cysteine (NAC), or rutin. We assessed lysosomal permeability through immunofluorescence and analyzed relevant protein expression via western blotting. Our findings showed that NaF exposure increased ROS levels, resulting in enhanced LMP and increased cathepsin B (CTSB) and D (CTSD) expression. Furthermore, the exposure to NaF resulted in the upregulation of cleaved PARP1, cleaved caspase-3, GSDME-N, and HMGB1 expressions, indicating cell death and inflammation-induced renal damage. Rutin mitigates fluoride-induced nephrotoxicity by suppressing ROS-mediated LMP and the GSDME/HMGB1 axis, ultimately preventing fluoride-induced renal toxicity occurrence and development. In conclusion, our findings suggest that NaF induces renal damage through ROS-mediated activation of LMP and the GSDME/HMGB1 axis, leading to pyroptosis and inflammation. Rutin, a natural antioxidative and anti-inflammatory dietary supplement, offers a novel approach to prevent and treat fluoride-induced nephrotoxicity.

Fluoride exposure confers NRF2 activation in hepatocyte through both canonical and non-canonical signaling pathways.

Due to the high abundance in the Earth's crust and industrial application, fluoride is widely present in our living environment. However, excessive fluoride exposure causes toxicity in different organs. As the most important detoxification and excretion organ, liver is more easily involved in fluoride toxicity than other organs, and oxidative stress is considered as the key mechanism related with fluoride hepatotoxicity. In this study, we mainly investigated the role of nuclear factor erythroid-derived 2-like 2 (NRF2, a core transcription factor in oxidative stress) in fluoride exposure-induced hepatotoxicity as well as the related mechanism. Herein, liver cells (BNL CL.2) were treated with fluoride in different concentrations. The hepatotoxicity and NRF2 signaling pathway were analyzed respectively. Our results indicated that excessive fluoride (over 1 mM) resulted in obvious toxicity in hepatocyte and activated NRF2 and NRF2 target genes. The increased ROS generation after fluoride exposure suppressed KEAP1-induced NRF2 ubiquitylation and degradation. Meanwhile, fluoride exposure also led to blockage of autophagic flux and upregulation of p62, which contributed to activation of NRF2 via competitive binding with KEAP1. Both pharmaceutical activation and genetic activation of NRF2 accelerated fluoride exposure-induced hepatotoxicity. Thus, the upregulation of NRF2 in hepatocyte after fluoride exposure can be regarded as a cellular self-defense, and NRF2-KEAP1 system could be a novel molecular target against fluoride exposure-induced hepatotoxicity.

Could fluoride be considered a genotoxic chemical agent in vivo? A systematic review with meta-analysis.

The goal of this study was to perform systematic review (SR) to investigate the scientific literature regarding the genotoxicity effects of fluoride exposure (FE). The search of databases used for this study was PubMed/Medline, SCOPUS and Web of Science. The quality of included studies was assessed using the EPHPP (Effective Public Health Practice Project). A total of 20 potentially relevant studies were selected for evaluating the genotoxicity induced by fluoride. Few studies have revealed that FE induces genotoxicity. A total of 14 studies demonstrated negative results whereas 6 studies did not. After reviewing the twenty studies, 1 was classified as weak, 10 were considered moderate and 9 were considered strong, according to the EPHPP. Taken together, it has been established that genotoxicity of fluoride is limited.

Prevalence and risk factors of dental fluorosis among children aged 8-12 years in Shandong province of China.

This study was to investigate the prevalence and severity of children's dental fluorosis (DF) in Shandong and identified the potential risk factors for DF. A total of 87 villages in Shandong were investigated to calculate the prevalence of DF and Community Fluorosis Index (CFI) in 2018-2019. Six hundred and seventy children were enrolled to identify the potential risk factors using univariate and multivariate logistic regressions. Goodman-Kruskal Gamma was used to explore the factors related to the severity of DF. In 87 villages, 1249 of 8700 (14.36%) children still have DF. The prevalence of DF in most villages was below 40% in 2018-2019. Water fluorine concentration when selected for the study and urinary fluorine concentration were related to the risk of DF (P < 0.001). Some eating habits, like lower frequency of eating fresh vegetables, eggs, and beans, were associated with the risk of DF (P < 0.001). The high water fluorine concentration, and lower frequency of eating fresh vegetables, eggs, and beans were also related to the severity of DF (P < 0.001). DF in children in Shandong province is still a common endemic disease. This study tries to provide a useful guide for the prevention and control of DF.

Health risk assessment in an area of dental fluorosis disease from high fluoride drinking water: a case study from southeastern Türkiye.

This study focuses on identifying fluoride (F‒) concentrations and its health risk assessment (HRA) in drinking water sources in south-eastern Türkiye. Groundwater quality was assessed using some graphical approaches such as Schoeller and Piper diagrams and GIS mapping. Average daily exposure dosages through oral and dermal contact exposure routes were considered to determine the potential health risk of F‒ in groundwater. Groundwater samples were taken from 53 points in spring, summer, autumn, and winter seasons. The results showed that the average annual F‒ concentrations in water resources in the study area were 0.26‒3.62 mg/L. According to the HRA results, the highest F‒ health risk in this region was observed in children, followed by teenagers and adults. This study indicated that there is a strong relationship between the high health risk (4.28 > 3.5) in children and dental fluorosis caused by high F‒ concentration in groundwater.

A GIS approach for groundwater quality evaluation with entropy method and fluoride exposure with health risk assessment.

This study used the entropy water quality index to analyse the suitability of groundwater for human consumption as well as the hazard index to identify the probable non-carcinogenic dangers among children, women, and men in Nawada, Bihar (India). A total of 75 groundwater samples were taken from hand pumps and tube/bore wells in the pre-monsoon of 2017, and they were evaluated for various physicochemical characteristics. The region's groundwater major cations and anions are dominated by Ca2+ > Mg2+ and [Formula: see text] > Cl- > [Formula: see text] > NO3- > F > [Formula: see text]. Fluoride, chloride, and hardness exceeded WHO and BIS safe standards. Calcium, sodium, magnesium, sulphate, and chloride showed positive correlations, indicating water-rock interactions and mineral leaching and dissolution. Ionic cross-plots reveal that the dissolution of carbonate minerals was the primary source of calcium and magnesium in the groundwater. Also, silicate weathering contributed to these ions in the groundwater. The entropy water quality index (EWQI) found that 79% of groundwater samples were drinkable, whereas 21% were not consumable. The eastern, western, and some southern study areas have the worst drinking water quality. The main source of fluoride toxicity in people is groundwater. For all sampling locations, the HQ fluoride was calculated to be in the ranges of 0.04-3.69 (male), 0.04-3.27 (female), and 0.05-4 (children), indicating a considerably greater risk than the permissible levels (> 1). The fluoride-based non-carcinogenic risks are 27%, 20%, and 21% for children, women, and men, respectively. Children have higher risks from polluted water than adults, according to the non-carcinogenic health risk assessment. This study establishes a standard for regional and global scientific studies that help decision-makers and planners determine the quality of groundwater and fluoride risk and management.

Mediation of mitochondrial DNA copy number and oxidative stress in fluoride-related bone mineral density alteration in Chinese farmers.

Excessive fluoride can adversely affect bone mineral density (BMD). Oxidative stress and mitochondrial dysfunction are crucial mechanisms of health damage induced by fluoride. Here, a cross-sectional survey involving 907 Chinese farmers (aged 18-60) was carried out in Tongxu County in 2017, aiming to investigate the significance of mitochondrial DNA copy number (mtDNAcn) and oxidative stress in fluoride-related BMD change. Concentrations of urinary fluoride (UF), serum oxidative stress biomarkers, including total antioxidant capacity (T-AOC), total superoxide dismutase (T-SOD), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA), as well as relative mtDNAcn in peripheral blood were determined. The multivariable linear model and mediation analysis were performed to assess associations between UF, oxidative stress, and relative mtDNAcn with BMD. Results showed that GSH-Px levels increased by 6.98 U/mL [95% confidence interval (CI) 3.41-10.56)] with each 1.0 mg/L increment of UF. After stratification, the T-AOC, relative mtDNAcn, and BMD decreased by 0.04 mmol/L (-0.08 ~ -0.01), 0.29-unit (-0.55 ~ -0.04), and 0.18-unit (-0.33 ~ -0.03) with every 1.0 mg/L elevation of UF in the excessive fluoride group (EFG, adults with UF > 1.6 mg/L), respectively. Furthermore, T-AOC and relative mtDNAcn were favorably related to the BMD in the EFG (ß = 0.82, 95%CI 0.16-1.48 for T-AOC; ß = 0.11, 95%CI 0.02-0.19 for relative mtDNAcn). Mediation analysis showed that relative mtDNAcn and T-AOC mediated 15.4% and 17.1% of the connection between excessive fluoride and reduced BMD, respectively. Findings suggested that excessive fluoride was related to lower BMD in adults, and the decrement of T-AOC and relative mtDNAcn partially mediate this relationship.