燃煤污染型氟中毒患者氟暴露、骨相损伤程度与骨形成标志物的关系

慢性氟暴露是世界范围内的公共卫生问题之一.为研究燃煤污染型氟中毒患者中氟暴露、骨相损伤程度与骨形成标志物血清碱性磷酸酶(ALP)、骨钙素(BGP)之间的相关关系,以贵州省织金县荷花村(燃煤污染型地方性氟中毒病区)和安顺市张官村(非氟暴露村)为调查点,采集环境样品,采用氟离子选择电极法测定环境介质及食物中的氟含量.在知情同意的原则下,对295例氟暴露和85例非氟暴露调查对象进行氟斑牙、氟骨症诊断;收集其尿液及外周血,测定尿氟(UF)浓度、ALP活性和BGP含量.结果表明: 病区环境中大米、辣椒、玉米、饮水、黏土、菜土、煤以及室内外空气氟含量均明显高于对照区,但较以往报道数据降低;随着尿氟浓度的升高,ALP活性、BGP含量显著升高,氟骨症病情差异有统计学意义,氟斑牙病情差异无统计学意义;氟骨症病情与ALP活性、BGP含量呈正相关.表明燃煤污染型低氟暴露可引起人群的骨相损害,且ALP、BGP可用于评估氟骨症患者骨转换情况,在氟骨症的辅助诊断、疗效评估中有着一定的应用价值.     

The Relationship of PTH Bst BI Polymorphism, Calciotropic Hormone Levels, and Dental Fluorosis of Children in China

The aim of this study was to explore the association of parathyroid hormone (PTH) gene Bst BI polymorphism, calciotropic hormone levels, and dental fluorosis of children. A case-control study was conducted in two counties (Kaifeng and Tongxu) in Henan Province, China in 2005-2006. Two hundred and twenty-five children were recruited and divided into three groups including dental fluorosis group (DFG), non-dental fluorosis group (NDFG) from high fluoride areas, and control group (CG). Urine fluoride content was determined using fluoride ion selective electrode; PTH Bst BI were genotyped using PCR-RFLP; osteocalcin (OC) and calcitonin (CT) levels in serum were detected using radioimmunoassay. Genotype distributions were BB 85.3% (58/68), Bb 14.7% (10/68) for DFG; BB 77.6% (52/67), Bb 22.4% (15/67) for NDFG; and BB 73.3% (66/90), Bb 27.7% (24/90) for CG. No significant difference of Bst BI genotypes was observed among three groups (P > 0.05). Serum OC and urine fluoride of children were both significantly higher in DFG and NDFG than in CG (P < 0.05, respectively), while a similar situation was not observed between DFG and NDFG in high fluoride areas (P > 0.05). Serum OC level of children with BB genotype was significantly higher compared to those with Bb genotype in high fluoride areas (P < 0.05). However, no significant difference of serum CT or calcium (Ca) was observed. In conclusion, there is no correlation between dental fluorosis and PTH Bst BI polymorphism. Serum OC might be a more sensitive biomarker for detecting early stages of dental fluorosis, and further studies are needed.     

Protections against toxicity in the brains of rat with chronic fluorosis and primary neurons exposed to fluoride by resveratrol involves nicotinic acetylcholine receptors

Protection of Resveratrol (RSV) against the neurotoxicity induced by high level of fluoride was investigated. Sprague-Dawley (SD) rats and their offspring, as well as cultures of primary neurons were divided randomly into four groups: untreated (control); treated with 50 mg RSV/kg/ (once daily by gavage) or (20 M in the cultured medium); exposed to 50 ppm F⁻ in drinking water or 4 mmol/l in the cultured medium; and exposed to fluoride then RSV as above. The adult rats were treated for 7 months and the offspring sacrificed at 28 days of age; the cultured neurons for 48 h. For general characterization, dental fluorosis was assessed and the fluoride content of the urine measured (by fluoride-electrode) in the rates and the survival of cultured neurons monitored with the CCK-8 test. The spatial learning and memory of rats were assessed with the Morris water maze test. The levels of α7 and α4 nicotinic acetylcholine receptors (nAChRs) were quantified by Western blotting; and the activities of superoxide dismutase (SOD) and catalase (CAT), and the levels of malondialdehyde (MDA) and H₂O₂ assayed biochemically. The results showed that chronic fluorosis resulted in the impaired learning and memory in rats and their offspring, and more oxidative stress in both rat brains and cultured neurons, which may be associated the lower levels of α7 and α4 nAChR subunits. Interestingly, RSV attenuated all of these toxic effects by fluorosis, indicating that protection against the neurotoxicity of fluoride by RSV might be in mechanism involved enhancing the expressions of these nAChRs.     

Enzymatic Activity of Glutathione S-Transferase and Dental Fluorosis Among Children Receiving Two Different Levels of Naturally Fluoridated Water

This study was conducted to measure the activity of the enzyme glutathione S-transferase (GST) in saliva and to compare the activity of this enzyme in children with and without dental fluorosis in communities with different concentrations of naturally fluoridated water. A total of 141 schoolchildren participated in this cross-sectional study. Children were selected from two communities: one with a low (0.4 ppm) and the other with a high (1.8 ppm) water fluoride concentration. Dental fluorosis was evaluated by applying the Thylstrup and Fejerskov Index (TFI) criteria. Stimulated saliva was obtained, and fluoride concentration and GST activity were measured. The GST activity was compared among children with different levels of dental fluorosis using multinomial logistic regression models and odds ratios (OR). The mean age of the children was 10.6 (±1.03) years. Approximately half of the children showed dental fluorosis (52.5 %). The average GST activity was 0.5678 (±0.1959) nmol/min/μg. A higher concentration of fluoride in the saliva was detected in children with a higher GST activity (p = 0.039). A multinomial logistic regression model used to evaluate the GST activity and the dental fluorosis score identified a strong association between TFI = 2–3 (OR = 15.44, p = 0.007) and TFI ≥ 4 (OR = 55.40, p = 0.026) and the GST activity level, compared with children showing TFI = 0–1, adjusted for age and sex. Schoolchildren with higher levels of dental fluorosis and a higher fluoride concentration in the saliva showed greater GST activity. The increased GST activity most likely was the result of the body’s need to inactivate free radicals produced by exposure to fluoride.     

Mineral content of water and food in fluorotic villages and prevalence of dental fluorosis

The fluoride (F), calcium (Ca), magnesium (Mg), zinc (Zn), copper (Cu), and phosphorus (P) content in potable water and food samples (cereals, pulses, and vegetables) from endemic and nonendemic villages for fluorosis were analyzed. It was found that the F content in water was significantly higher (p<0.01) in endemic villages (4.20±1.6 ppm) than control villages (0.63±0.15 ppm), whereas the Ca, Cu, and Mg contents were found to be significantly lower (p<0.05) in endemic villages compared to control villages. However, there was no significant difference in Zn and P contents between the villages. Foods (cereals, pulses, and vegetables) grown in endemic villages contained significantly higher (p<0.01) fluoride content as compared to control villages. There was no significant difference in Ca, Mg, P, and Zn contents in food grown in endemic and control villages. Copper content in cereals (p<0.05), pulses (p<0.01), and vegetables (p<0.01) in endemic villages was found significantly higher as compared to control villages. The overall prevalence of dental fluorosis in six endemic villages was 97.4% in boys and 96% in girls, which was significantly higher (p<0.01) than that of control villages, where it was 10.5% in boys and 8.3% in girls. The prevalence of dental fluorosis was positively correlated (r=0.125, p<0.01) to fluoride and negatively correlated to Ca and Cu content in drinking water in endemic villages.     

Appropriate uses of fluorides for children: guidelines from the Canadian Workshop on the Evaluation of Current Recommendations Concerning Fluorides.

OBJECTIVE: To prevent fluorosis caused by excessive fluoride ingestion by revising recommendations for fluoride intake by children. OPTIONS: Limiting fluoride ingestion from fluoridated water, fluoride supplements and fluoride dentifrices. OUTCOMES: Reduction in the prevalence of dental fluorosis and continued prevention of dental caries. EVIDENCE: Before the workshop, experts prepared comprehensive literature reviews of fluoride therapies, fluoride ingestion and the prevalence and causes of dental fluorosis. The papers, which were peer-reviewed, revised and circulated to the workshop participants, formed the basis of the workshop discussions. VALUES: Recommendations to limit fluoride intake were vigorously debated before being adopted as the consensus opinion of the workshop group. BENEFITS, HARMS AND COSTS: Decrease in the prevalence of dental fluorosis with continuing preventive effects of fluoride use. The only significant cost would be in preparing new, low-concentration fluoride products for distribution. RECOMMENDATIONS: Fluoride supplementation should be limited to children 3 years of age and older in areas where there is less than 0.3 ppm of fluoride in the water supply. Children in all areas should use only a "pea-sized" amount of fluoride dentifrice no more than twice daily under the supervision of an adult. VALIDATION: These recommendations are almost identical to changes to recommendations for the use of fluoride supplements recently proposed by a group of European countries. SPONSORS: The workshop was organized by Dr. D. Christopher Clark, of the University of British Columbia, and Drs. Hardy Limeback and Ralph C. Burgess, of the University of Toronto, and funded by Proctor and Gamble Inc., Toronto, the Medical Research Council of Canada and Health Canada (formerly the Department of National Health and Welfare). The recommendations were formally adopted by the Canadian Dental Association in April 1993.     

Household water sources and their contribution towards fluoride consumption in Njoro Division,Nakuru District,Kenya

Fluoride is regarded as an essential element for the formation of healthy bones and teeth. However, high fluoride levels in drinking water have been associated with high incidences of dental fluorosis. A 1996–1997 study in Njoro Division, Nakuru District, established that the groundwater used for cooking and drinking, obtained from boreholes and wells, had fluoride levels much higher than the World Health Organisation recommended level of 0.7ppm.     

Effects of fluoride emissions from a modern primary aluminum smelter on a local population of white-tailed deer (Odocoileus virginianus)

The influence of fluoride emissions from a modern aluminum smelter on concentrations of skeletal fluoride and dental fluorosis in a resident population of white-tailed deer was studied. The smelter was located on Mount Holly Plantation in South Carolina, and concentrations of skeletal fluoride in the deer collected at Mount Holly increased approximately five-fold 3 yr after the operation began. Increases in skeletal fluoride of less than two-fold were observed in deer obtained from Medway Plantation which has its nearest boundary 1.6 km from the smelter site. No dental fluorosis was observed in deer collected at Medway Plantation, but mild dental fluorosis was observed in a significant number of deer collected at Mount Holly Plantation. The dental fluorosis that was observed was not associated with incisor wear or with fluoride-induced molar wear. Osteofluorosis of mandibles or metacarpals was not observed in any of the deer obtained from either plantation. The data obtained from this study indicated that the presence of a modern aluminum smelter caused a detectable increase in concentration of skeletal fluoride in the resident population of white-tailed deer, but that no adverse health effects were seen.     

Paleopathology of skeletal fluorosis

Skeletal fluorosis is one of a range of conditions causing excessive ossification and joint ankylosis in skeletons. It is rarely considered, however, in differential diagnoses of palaeopathological lesions. This paper considers the identification of skeletal fluorosis in a skeletal sample from the island of Bahrain, Arabian Gulf, dating to ca. 250 BC–AD 250. Approximately 4% of 255 adult skeletons in the sample have hyperostosic lesions resulting in joint ankylosis primarily of the lumbar vertebrae, as well as the major joints. These lesions most frequently occur among males in the 50+ age group. Chemical analysis on a small series of bone and dental samples confirmed the presence of high levels of fluoride, while staining of the teeth is evidence of dental fluorosis. The level of dental fluorosis is comparable with a naturally occurring fluoride level in water of between 1–2 ppm. The prevalence of hyperostosic lesions, however, appears higher than expected, and two possible reasons are suggested: confusion between a diagnosis of diffuse idiopathic skeletal hyperostosis and skeletal fluorosis on partial or less severely affected skeletons; and the presence of predisposing factors for skeletal fluorosis on the island in the past. Am J Phys Anthropol 109:465–483, 1999. © 1999 Wiley-Liss, Inc.     

Influence of coffee on fluoride metabolism in rats

Concomitant intragastric administration of sodium fluoride and coffee resulted in a significantly higher (P less than 0.01) plasma fluoride level than intake of the same amount of fluoride with water. The same result was obtained when coffee was substituted with an equivalent amount of caffeine. Comparison of plasma fluoride levels by total area under the curve of plasma fluoride concentration versus time indicated an almost 2-fold difference. Although the mechanism(s) is not known, it appears that caffeine is responsible for the present observation. This finding could help explain the variations in the incidence of dental fluorosis among people living in optimally fluoridated communities.     

Investigation and mapping of fluoride-endemic areas and associated health risk—A case study of Agra,Uttar Pradesh,India

The present study aimed at identifying the fluoride-endemic areas in five different blocks in Agra district, Uttar Pradesh, India. A total of 365 groundwater samples from 73 villages were analyzed for establishing the concentration range of fluoride in drinking water. The fluoride level in the study area varied from 0.14 to 4.88 mg/L. Out of 73, the fluoride levels in 45 villages did not meet the permissible Word Health Organization standards. The Baroli Ahir block was found the highly fluoride-endemic area followed by Saiyan, Bichpuri, Achnera and Etmadpur. Chronic daily intake of fluoride in adults was 1.25 and 1.5 times higher than those in children and infants, respectively. The probability of dental fluorosis in infants was higher (42%) while adults were more prone to bone and skeletal fluorosis (60%). The hazard quotient analysis revealed that children were found to be at maximum risk followed by infants and adults. Sensitivity analysis revealed that the fluoride concentration is the major influencing parameter responsible for different types of fluorosis in various age groups.     

Fluoride and environmental health: a review

The relationship between environmental fluoride and human health has been studied for over 100 years by researchers from a wide variety of disciplines. Most scientists believe that small amounts of fluoride in the diet can help prevent dental caries and strengthen bones, but there are a number of adverse affects that chronic ingestion at high doses can have on human health, including dental fluorosis, skeletal fluorosis, increased rates of bone fractures, decreased birth rates, increased rates of urolithiasis (kidney stones), impaired thyroid function, and lower intelligence in children. Chronic occupational exposure to fluoride dust and gas is associated with higher rates of bladder cancer and variety of respiratory ailments. Acute fluoride toxicity and even death from the ingestion of sodium fluoride pesticides and dental products have also been reported. The distribution of fluoride in the natural environment is very uneven, largely a result of the geochemical behavior of this element. Fluorine is preferentially enriched in highly evolved magmas and hydrothermal solutions, which explains why high concentrations are often found in syenites, granitoid plutonic rocks, alkaline volcanic, and hydrothermal deposits. Fluoride can also occur in sedimentary formations that contain fluoride-bearing minerals derived from the parent rock, fluoride-rich clays, or fluorapatite. Dissolved fluoride levels are usually controlled by the solubility of fluorite (CaF₂); thus, high concentrations are often associated with soft, alkaline, and calcium-deficient waters. Although much is known about the occurrence and health effects of fluoride, problems persist in Third World countries, where populations have little choice in the source of their drinking water and food. However, even in developed nations, fluoride ingestion can exceed the recommended dose when sources other than drinking water are ignored.     

Systematic review of water fluoridation

ObjectiveTo review the safety and efficacy of fluoridation of drinking water.DesignSearch of 25 electronic databases and world wide web. Relevant journals hand searched; further information requested from authors. Inclusion criteria were a predefined hierarchy of evidence and objectives. Study validity was assessed with checklists. Two reviewers independently screened sources, extracted data, and assessed validity.Results214 studies were included. The quality of studies was low to moderate. Water fluoridation was associated with an increased proportion of children without caries and a reduction in the number of teeth affected by caries. The range (median) of mean differences in the proportion of children without caries was −5.0% to 64% (14.6%). The range (median) of mean change in decayed, missing, and filled primary/permanent teeth was 0.5 to 4.4 (2.25) teeth. A dose-dependent increase in dental fluorosis was found. At a fluoride level of 1 ppm an estimated 12.5% (95% confidence interval 7.0% to 21.5%) of exposed people would have fluorosis that they would find aesthetically concerning.ConclusionsThe evidence of a beneficial reduction in caries should be considered together with the increased prevalence of dental fluorosis. There was no clear evidence of other potential adverse effects.     

Enduring fluoride health hazard for the Vesuvius area population: the case of AD 79 Herculaneum

Background

The study of ancient skeletal pathologies can be adopted as a key tool in assessing and tracing several diseases from past to present times. Skeletal fluorosis, a chronic metabolic bone and joint disease causing excessive ossification and joint ankylosis, has been only rarely considered in differential diagnoses of palaeopathological lesions. Even today its early stages are misdiagnosed in endemic areas.

Methodology/Principal Findings

Endemic fluorosis induced by high concentrations of fluoride in water and soils is a major health problem in several countries, particularly in volcanic areas. Here we describe for the first time the features of endemic fluorosis in the Herculaneum victims of the 79 AD eruption, resulting from long-term exposure to high levels of environmental fluoride which still occur today.

Conclusions/Significance

Our observations on morphological, radiological, histological and chemical skeletal and dental features of this ancient population now suggest that in this area fluorosis was already endemic in Roman times. This evidence merged with currently available epidemiologic data reveal for the Vesuvius area population a permanent fluoride health hazard, whose public health and socio-economic impact is currently underestimated. The present guidelines for fluoridated tap water might be reconsidered accordingly, particularly around Mt Vesuvius and in other fluoride hazard areas with high natural fluoride levels.     

Fluoride induces endoplasmic reticulum stress in ameloblasts responsible for dental enamel formation

The mechanism of how fluoride causes fluorosis remains unknown. Exposure to fluoride can inhibit protein synthesis, and this may also occur by agents that cause endoplasmic reticulum (ER) stress. When translated proteins fail to fold properly or become misfolded, ER stress response genes are induced that together comprise the unfolded protein response. Because ameloblasts are responsible for dental enamel formation, we used an ameloblast-derived cell line (LS8) to characterize specific responses to fluoride treatment. LS8 cells were growth-inhibited by as little as 1.9-3.8 ppm fluoride, whereas higher doses induced ER stress and caspase-mediated DNA fragmentation. Growth arrest and DNA damage-inducible proteins (GADD153/CHOP, GADD45alpha), binding protein (BiP/glucose-responsive protein 78 (GRP78), the non-secreted form of carbonic anhydrase VI (CA-VI), and active X-box-binding protein-1 (Xbp-1) were all induced significantly after exposure to 38 ppm fluoride. Unexpectedly, DNA fragmentation increased when GADD153 expression was inhibited by short interfering RNA treatment but remained unaffected by transient GADD153 overexpression. Analysis of control and GADD153(-/-) embryonic fibroblasts demonstrated that caspase-3 mediated the increased DNA fragmentation observed in the GADD153 null cells. We also demonstrate that mouse incisor ameloblasts are sensitive to the toxic effects of high dose fluoride in drinking water. Activated Ire1 initiates an ER stress response pathway, and mouse ameloblasts were shown to express activated Ire1. Ire1 levels appeared induced by fluoride treatment, indicating that ER stress may play a role in dental fluorosis. Low dose fluoride, such as that present in fluoridated drinking water, did not induce ER stress.     

Fluoride induces oxidative damage and SIRT1/autophagy through ROS-mediated JNK signaling

Fluoride is an effective caries prophylactic, but at high doses can also be an environmental health hazard. Acute or chronic exposure to high fluoride doses can result in dental enamel and skeletal and soft tissue fluorosis. Dental fluorosis is manifested as mottled, discolored, porous enamel that is susceptible to dental caries. Fluoride induces cell stress, including endoplasmic reticulum stress and oxidative stress, which leads to impairment of ameloblasts responsible for dental enamel formation. Recently we reported that fluoride activates SIRT1 and autophagy as an adaptive response to protect cells from stress. However, it still remains unclear how SIRT1/autophagy is regulated in dental fluorosis. In this study, we demonstrate that fluoride exposure generates reactive oxygen species (ROS) and the resulting oxidative damage is counteracted by SIRT1/autophagy induction through c-Jun N-terminal kinase (JNK) signaling in ameloblasts. In the mouse-ameloblast-derived cell line LS8, fluoride induced ROS, mitochondrial damage including cytochrome-c release, up-regulation of UCP2, attenuation of ATP synthesis, and H2AX phosphorylation (γH2AX), which is a marker of DNA damage. We evaluated the effects of the ROS inhibitor N-acetylcysteine (NAC) and the JNK inhibitor SP600125 on fluoride-induced SIRT1/autophagy activation. NAC decreased fluoride-induced ROS generation and attenuated JNK and c-Jun phosphorylation. NAC decreased SIRT1 phosphorylation and formation of the autophagy marker LC3II, which resulted in an increase in the apoptosis mediators γH2AX and cleaved/activated caspase-3. SP600125 attenuated fluoride-induced SIRT1 phosphorylation, indicating that fluoride activates SIRT1/autophagy via the ROS-mediated JNK pathway. In enamel organs from rats or mice treated with 50, 100, or 125 ppm fluoride for 6 weeks, cytochrome-c release and the DNA damage markers 8-oxoguanine, p-ATM, and γH2AX were increased compared to those in controls (0 ppm fluoride). These results suggest that fluoride-induced ROS generation causes mitochondrial damage and DNA damage, which may lead to impairment of ameloblast function. To counteract this impairment, SIRT1/autophagy is induced via JNK signaling to protect cells/ameloblasts from fluoride-induced oxidative damage that may cause dental fluorosis.     

Reversal of fluoride induced cell injury through elimination of fluoride and consumption of diet rich in essential nutrients and antioxidants

The objective of the present communication is to address the issues concerning reversal of fluoride induced cell injury and disease (i.e. fluorosis) through the elimination of fluoride and consumption of a diet containing essential nutrients and antioxidants. Humans afflicted with fluorosis, as a result of consuming fluoride contaminated water or food, have been investigated. Hospital based diagnostic procedure for early detection of fluorosis, through retrieval of history, clinical complaints, testing of blood, urine and drinking water for fluoride using ion selective electrode technology, along with X-ray of the forearm have been carried out. Confirmed cases of fluorosis were introduced to an intervention protocol consisting of (1) provision of safe drinking water with fluoride levels less than 1 mg/L and (2) counselling on nutritional supplementation with focus on adequate intake of calcium, vitamins C, E and antioxidants. The patients were monitored at frequent intervals up to one year and the results are reported. With a standardized early diagnosis, elimination of fluoride intake and supplementation of a diet rich in essential nutrients and antioxidants, we have shown that the fluorosis can be reversed.     

Reversal of fluoride induced cell injury through elimination of fluoride and consumption of diet rich in essential nutrients and antioxidants

The objective of the present communication is to address the issues concerning reversal of fluoride induced cell injury and disease (i.e. fluorosis) through the elimination of fluoride and consumption of a diet containing essential nutrients and antioxidants. Humans afflicted with fluorosis, as a result of consuming fluoride contaminated water or food, have been investigated. Hospital based diagnostic procedure for early detection of fluorosis, through retrieval of history, clinical complaints, testing of blood, urine and drinking water for fluoride using ion selective electrode technology, along with X-ray of the forearm have been carried out. Confirmed cases of fluorosis were introduced to an intervention protocol consisting of (1) provision of safe drinking water with fluoride levels less than 1 mg/L and (2) counselling on nutritional supplementation with focus on adequate intake of calcium, vitamins C, E and antioxidants. The patients were monitored at frequent intervals up to one year and the results are reported. With a standardized early diagnosis, elimination of fluoride intake and supplementation of a diet rich in essential nutrients and antioxidants, we have shown that the fluorosis can be reversed.     

许家窑人幼年个体的釉质发育缺陷

上世纪70年代在许家窑-侯家窑地点发现的人类化石对了解东亚中晚更新世过渡时期古人类的形态演化起到了重要作用。除形态特征外,针对许家窑人病理表现也开展过相关研究,其中许家窑人幼年个体前部牙齿上出现的黄色小坑被认为是患有氟斑牙病的证据,且可能代表世界范围内该牙病的最早实例。然而,经电子显微镜和显微断层扫描显示,这些黄色小坑或凹陷是釉质发育不良表现,而不是代表个体患有氟斑牙病后牙齿受咀嚼压力而产生的物理破损。同步辐射扫描显示,许家窑幼年个体前部牙齿釉质密度均匀,没有出现浅层釉质矿化减小的现象,不支持该个体因釉质矿化过程受影响而患有典型氟斑牙的结论。尽管如此,后部牙齿上大量坑状的釉质缺陷和坑状缺陷底部的加重生长线特征不排除是个体氟摄入过量而影响釉质形成的分泌期而导致的。除表面坑状釉质缺陷外,许家窑幼年个体恒齿不同部位的釉质内部出现缺失（空间结构一般为圆球状）。缺失主要集中在浅层区域,沿齿尖-齿颈方向的密集程度变化与釉质发育不良位置具有一定相关性。釉质内部缺失有时互连并与釉质表面垂直。以上特征显示釉质内部缺失是釉质形成过程受影响所致,且影响因素和发生机理可能与釉质发育不良的类似。许家窑幼年个体不同牙齿在外部釉质缺陷和内部釉质缺失密集程度上的差别可能反映的是个体在发育过程中所需应对的外界扰动因素程度不同。未来研究可对包含许家窑人化石的堆积物中以及许家窑人牙齿中的氟含量进行测定,以进一步研究许家窑人个体的生活环境中是否有过量的氟以及许家窑人是否摄入了过量氟元素,从而对许家窑人的牙齿发育缺陷机理有一个进一步的了解。     

Extract of Ginkgo biloba leaves attenuates neurotoxic damages in rats and SH-SY5Y cells exposed to a high level of fluoride

BackgroundPotential protection against the neurotoxic damages of high levels of fluoride on rats and SH-SY5Y cells by extract of Ginkgo biloba leaves, as well as underlying mechanisms, were examined.MethodsThe rats were divided randomly into 4 groups, i.e., control, treatment with the extract (100 mg/kg body weight, gavage once daily), treatment with fluoride (50 ppm F^- in drinking water) and combined treatment with both; SH-SY5Y cells exposed to fluoride and fluoride in combination with the extract or 4-Amino-1,8-naphthalimide (4-ANI), an inhibitor of poly (ADP-ribose) polymerase-1 (PARP-1). Spatial learning and memory in the rats were assessed employing Morris water maze test; the contents of fluoride in brains and urine by fluoride ion-selective electrode; cytotoxicity of fluoride was by CCK-8 kit; the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and the content of malondialdehyde (MDA) by appropriate kits; the level of 8-hydroxydeoxyguanosine (8-OHdG) was by ELISA; the content of ROS and frequency of apoptosis by flow cytometry; the expressions of phospho-histone H2A.X_(Ser139), PARP-1, poly (ADP-ribose) (PAR) and Sirtuin-1 (SIRT1) by Western blotting or immunofluorescence.ResultsThe rats with prolong treatment of fluoride exhibited dental fluorosis, the increased contents of fluoride in brains and urine and the declined ability of learning and memory. In the hippocampus of the rats and SH-SY5Y cells exposed to fluoride, the levels of ROS, MDA, apoptosis, 8-OHdG and the protein expressions of histone H2A.X_(Ser139), PARP-1 and PAR were all elevated; the activities of SOD and GSH-Px and the protein expression of SIRT1 reduced. Interestingly, the treatment of Ginkgo biloba extract attenuated these neurotoxic effects on rats and SH-SY5Y cells exposed to fluoride and the treatment of 4-ANI produced a neuroprotective effect against fluoride exposure.ConclusionGinkgo biloba extract attenuated neurotoxic damages induced by fluoride exposure to rats and SH-SY5Y cells and the underlying mechanism might involve the inhibition of PARP-1 and the promotion of SIRT1.