Fluoride Action Network

Fluoride & Oxidative Stress

F.A.N. | July 2012 | By Michael Connett

A vast body of research demonstrates that fluoride exposure increases oxidative stress. Based on this research, it is believed that fluoride-induced oxidative stress is a key mechanism underlying the various toxic effects associated with fluoride exposure. It is also well established that fluoride’s toxic effects can be ameliorated by exposure to anti-oxidants. One implication of this research is that people with inadequate intake of anti-oxidants  (e.g., vitamin C, flavonoids) will be at increased risk of fluoride toxicity.

The research cited below includes:

1) A recent, comprehensive review on fluoride and oxidative stress research,
2) Studies finding increased oxidative stress among individuals with skeletal fluorosis,
3) Studies finding anti-oxidants can ameliorate fluoride toxicity.

1) Summary of Fluoride/Oxidative Stress Research:

“Oxidative stress is a recognized mode of action of fluoride exposure that has been observed in vitro in several types of cells and also in vivo in soft tissues such as the liver, kidney, brain, lung, and testes in animals and in people living in areas of endemic fluorosis. Fluoride is thought to inhibit the activity of antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase, and catalase. Moreover, fluoride can alter glutathione levels, often resulting in the excessive production of ROS at the mitochondrial level, leading to the damage of cellular components. It is known that excessive ROS production leads to macromolecule oxidation, resulting in free radical attack of membrane phospholipids with resulting membrane damage via induction of lipid peroxidation, mitochondrial membrane depolarization, and apoptosis. Antioxidant treatment consistently protects cells from the lipid peroxidation caused by fluoride exposure, suggesting that oxidative/nitrosative damage is the major mode of action of fluoride.”
SOURCE: Barbier O, et al. (2010). Molecular mechanisms of fluoride toxicity. Chem Biol Interact. 188(2):319-33.

2) Studies finding increased oxidative stress among Humans with Skeletal Fluorosis:

“The objective of the present study was to determine the plasma total oxidative status (TOS) and total antioxidant capacity (TAC) in patients with endemic fluorosis. A total of 79 (35 males and 44 females; mean age 44.0 ± 11.9 years) patients withendemic fluorosis and 55 (23 males and 32 females; mean age 48.3 ± 8.5 years) age-, sex- and body mass index-matched healthy controls were included in this study. The urine fluoride levels and plasma TOS and TAC levels were measured. The urine fluoride levels of fluorosis patients were significantly higher than control subjects as expected (1.91 ± 0.15 vs. 0.49 ± 0.13 mg/L, respectively; p < 0.001). TOS was significantly higher in fluorosis group than in control group (17.55 ± 3.82 vs. 15.06 ± 4.31 ?mol H(2)O(2) Eq/L, respectively; p = 0.001). TAC was significantly lower in fluorosis group than in control group (1.60 ± 0.36 vs. 1.82 ± 0.51 mmol Trolox Eq/L, respectively; p = 0.004). Oxidative stress index (OSI) was significantly higher influorosis group than in control group (11.5 ± 3.8 vs. 8.8 ± 3.7, respectively; p < 0.001). Correlation analysis in all the groups indicated that TAC was negatively correlated with urine fluoride (r = -0.25, p = 0.003), TOS was positively correlated with urine fluoride (r = 0.34, p < 0.001) and OSI was positively correlated with urine fluoride (r = 0.36, p < 0.001). The results of our study demonstrate that oxidative stress plays an important role in the pathogenesis of the endemic fluorosis.”
SOURCE: Varol E, et al. (2011). Evaluation of total oxidative status and total antioxidant capacity in patients with endemic fluorosis. Toxicology & Industrial Health Dec. 8 [Epub ahead of print].

“This study was conducted to find out the level of oxidative stress and effect of supplementation of vitamin C, D and Calcium on levels of SOD, serum and urinary fluoride in children residing in endemic fluorosis area. . . . The parameters selected were Super oxide dismutase, serum fluoride and urinary fluoride. The study was conducted on one hundred children, selected from four areas (25 from each area) consuming water containing 1.2, 2.4, 5.6 and 13.6 mg/l of fluoride. . . . The study indicated an increasing oxidative stress in cases of fluorosis with increasing drinking water fluoride concentration. Treatment with Calcium, Vitamin D and Vitamin C resulted a significant reduction in serum fluoride and SOD and increase in urinary fluoride.”
SOURCE: Ailani V, et al. (2009). Oxidative stress in cases of chronic fluoride intoxication. Indian Journal of Clinical Biochemistry 24 (4) 426-29.

“In conclusion, we have found that the blood of adult males with skeletal fluorosis living in an endemic fluorosis area exhibited increased lipid peroxidation associated with significantly decreased activity of the free radical-scavenging enzymes CAT and GST.”
SOURCE: Kalyanalakshmi P, et al. (2007). Lipid peroxidation and antioxidant enzyme status of adult males with skeletal fluorosis in Andhra Pradesh, India. Fluoride 40: 42–45.

“Fluorosis caused by long-term intake of high fluoride levels is characterized by clinical bone and tooth manifestations. The adverse impact of high fluoride intake was also observed in soft tissues. Although fluorosis is irreversible it could be prevented by appropriate and timely interventions through the understanding of the process at biochemical and molecular levels. Increased production of reactive oxygen forms and lipid peroxidation are considered to play an important role in the pathogenesis of chronic fluoride toxicity. Saliva is a biological fluid of the human organism may be a reflection of the metabolic state. Salivary indices are clinical diagnostic indicators. The purpose of this investigation was to comparatively study the salivary antioxidative defense system, including glutathione, glutathione reductase, glutathione-S-transferase, and glucose-6-phosphate dehydrogenase in adult patients with fluorosis before and after complex antioxidative therapy. Analysis indicated that there was a negative correlation between the level of glutathione and the clinical characteristics of the disease in patients with fluorosis. There was a direct relationship between the activity of glutathione-S-transferase and the clinical manifestations in the patients. These results reflected dose-dependent fluoride intoxication and metabolic imbalance. The imbalanced salivary antioxidative defense system was in part corrected by complex antioxidative therapy.”
SOURCE: Gavriliuk LA, et al. (2007). [Impact of antioxidative therapy on the activity of salivary glutathione-dependent enzymes in patients with fluorosis]. [Article in Russian]. Klinicheskaia laboratornaia diagnostika. Abstract available at: http://www.researchgate.net/publication/6422976_Impact_of_antioxidative_therapy_on_the_activity_of_salivary_glutathione-dependent_enzymes_in_patients_with_fluorosis.

“This study was designed to evaluate adverse health effects in adolescents from chronic exposure to various water fluoride concentrations in three communities located in Northern Mexico: Ciudad Juarez, Samalayuca, and Villa Ahumada. In these communities the fluoride concentration in water averages 0.3, 1.0, and 5.3 mg/L, respectively. The residents of Villa Ahumada have been exposed to excessive levels of fluoride in drinking water since their birth. . . . Uric acid is one of the important antioxidants of plasma, and its level was lower in fluorotic adolescents, indicating that fluoride toxicity may involve a reduction on certain intrinsic scavengers resulting in an increased vulnerability to oxygen free radical toxicity.”
SOURCE: Ruiz-Payan A. (2006). Chronic effects of fluoride on growth, blood chemistry and thyroid hormones in adolescents residing in three communities in Northern Mexico. ETD Collection for University of Texas, El Paso.Paper AAI3214004. http://digitalcommons.utep.edu/dissertations/AAI3214004

“The status of lipid peroxidation (LPO) and antioxidants was studied in red cell blood lysates of male subjects, aged 41–50, living in an endemic fluorosis area, Vellore district, Tamil Nadu, India. The men were divided into four groups: 1) normal healthy individuals (n=10); 2) individuals with mild dental fluorosis (n=13); 3) individual with moderate dental fluorosis (n=8); 4) individuals with severe dental fluorosis (n=7). In the groups with dental fluorosis, the concentration of thiobarbituric acid reactive substances (TBARS) was higher in the red blood cell lysates along with a concomitant decrease in the levels of both enzymatic and nonenzymatic antioxidants. Statistical analysis of all the group data revealed that increased lipid peroxidation and altered antioxidant status induced by fluoride were strongly associated with the prevalence of dental fluorosis.”
SOURCE: Shanthakumari D, et al. (2006). Antioxidant defense systems in red blood cell lysates of men with dental fluorosis living in Tamil Nadu, India. Fluoride 39:231-39.

“The present study aimed to assess lipid peroxidation and levels of antioxidant defense systems in the blood of children afflicted with skeletal fluorosis. . . . A close association between chronic fluoride toxicity and increased oxidative stress has been reported in humans and experimental animals. . . . The increased MDA levels in fluorotic children observed in this study are in accord with earlier findings.”
SOURCE: Shivarajashankara YM, et al. (2001). Oxidative stress in children with skeletal fluorosis. Fluoride 34:103-07.

“Red cells from humans exposed chronically to toxic levels of fluoride through drinking water showed significant increase in lipid peroxidation and membranous cholesterol and phospholipids.”
SOURCE: Kumari DS, Rao PR. (1991). Red cell membrane alterations in human chronic fluoride toxicity. Biochemistry International 23:639-48.

“In a new approach to an understanding of the genesis of nonskeletal and skeletal fluorosis, glutathione content in blood was investigated. Thirty cases of fluorosis and forty controls (20 from fluorotic and 20 from nonfluorotic areas) were studied. In fluorotic subjects, blood glutathione concentration was significantly elevated. . . . It appears that the persistent stress of the fluoride ion demands a protective redox maintainer and that glutathione fulfills that need.”
SOURCE: Jeji J, et al. (1985). Implication of glutathione in endemic fluorosis. Fluoride 18:117-19.

3) Human & ANimal Studies Finding that Anti-Oxidants can Ameliorate Fluoride Toxicity:

“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.”
SOURCE: Susheela AK, Bhatnagar M. (2002). Reversal of fluoride induced cell injury through elimination of fluoride and consumption of diet rich in essential nutrients and antioxidants. Mol Cell Biochem. 234-235(1-2):335-40.

“Oxidative and nitrosative stress is widely recognized as an important mediator of apoptosis in different cells and plays a pivotal role in the pathogenesis of several diseases. Epidemiologic data have indicated that certain dietary additives can provide an effective defense against oxidative stress, thus have a potential in the treatment of a variety of diseases. Flavonoids are a class of natural biological products that have evolved to protect plants from the oxidative damage. Fisetin (3,30,40,7-tetrahydroxyflavone) is a flavonoid found in fruits, vegetables, nuts and wine at concentrations of 2–160 lg/g with an average daily intake estimate of 0.4 mg. Fisetin is also added to nutritional supplements at very high concentrations and has a variety of pharmacological effects including antioxidant and anti-inflammatory activity acting mainly as a free radical scavenger. . . . Our study demonstrates, for the first time, that fisetin can attenuate fluoride- and dexamethasone-induced oxidative/nitrosative damage in osteoblast and hippocampal cell lines.”
SOURCE: Inkielewicz-Stepniak I, et al. (2012). Fisetin prevents fluoride- and dexamethasone-induced oxidative damage in osteoblast and hippocampal cells. Food Chem Toxicol. 50(3-4):583-89.

“The protective effects of quercetin against sodium fluoride induced oxidative stress were examined in rat’s liver. Rats were divided into five groups. The first group served as normal group that was treated with standard diet. The second group was intoxicated with sodium fluoride (600 ppm) through drinking water for 1 week. The third, fourth and fifth groups were treated with quercetin at a dose of 10 and 20 mg/kg and vitamin C (as the positive control) at a dose of 10 mg/kg intraperitoneally for 1 week before sodium fluoride intoxication, respectively. After 1 week, activities of superoxide dismutase and catalase, level of reduced glutathione and lipid peroxidation end product were determined in the homogenates of rat liver. The results of the present study suggested that quercetin protects rat liver from sodium fluoride induced oxidative stress, probably via its antioxidant activity.”
SOURCE: Nabavi SM, et al. (2012). In vivo protective effects of quercetin against sodium fluoride-induced oxidative stress in the hepatic tissue. Food Chemistry 132:931-35.

“Fluoride is a serious health hazard across several nations, and chronic intake of fluoride deranges the carbohydrate, lipid and antioxidant metabolism in general. As there are limited remedial measures to prevent fluorosis, we investigated the role of tamarind leaf as a food supplement in restoration of carbohydrate, lipid and antioxidant metabolism in fluoride-exposed albino rats. METHODS: Albino rats were exposed to fluoride (100 ppm sodium fluoride) through drinking water and fed diet supplemented with tamarind leaf powder (2.5, 5 and 10 g %) for 4 weeks. Carbohydrate, lipid and antioxidant profiles were investigated in both controls and fluoride-exposed animals. RESULTS: While 4-week exposure to fluoride elevated plasma glucose and lipid profiles, simulating diabetic and hyperlipidaemic conditions, the antioxidant defence mechanisms of fluoride-exposed rats were compromised, with elevation and decline in lipid peroxidation and high-density lipoprotein (HDL)-cholesterol, respectively. When the diet was supplemented with tender tamarind leaves (used in southern India as a replacement for tamarind or other sour food ingredients), significant improvements in carbohydrate and lipid profiles occurred as evidenced by decreased plasma glucose and lipid levels, lipid peroxidation, increased hepatic glycogen content, hexokinase activity and cholesterol excretion, with simultaneous improvement in antioxidant profiles of both hepatic and renal tissues. CONCLUSIONS: These findings are significant in view of the need for cost-effective approaches to tackle fluorosis as an environmental hazard and use of food supplements as ameliorative measures.”
SOURCE: Vasant RA, Narasimhacharya AV. (2012). Ameliorative effect of tamarind leaf on fluoride-induced metabolic alterations. Environ Health Prev Med. 2012 Mar 22. [Epub ahead of print]

“Curcumin is well known for its potent antioxidant activity. The result of numerous studies showed that antioxidants can protect against fluoride-induced toxicity. In the present study, protective effects of curcumin against sodium fluoride-induced toxicity in rat erythrocytes were evaluated. Curcumin (10 and 20 mg/kg) and vitamin C (10 mg/kg) were administrated intraperitoneally for 1 week followed by sodium fluoride (600 ppm) treatment for next week. Erythrocytes were isolated and superoxide dismutase and catalase activities as well as the levels of reduced glutathione, and lipid peroxidation were measured. The level of malondialdehyde in sodium fluoride treated rats (595.13 ± 20.23 nmol/g Hb) increased compared to the normal rats (315.44 ± 9.76 nmol/g Hb). Animals which were pretreated with curcumin at 20 mg/kg for 1 week prior to sodium fluoride intoxication showed significant reduction in the malondialdehyde level (320.22 ± 9.28 nmol/g Hb). Also, pretreated with curcumin (20 mg/kg) and vitamin C restored the superoxide dismutase and catalase activities and modified the level of reduced glutathione compared with control group (p > 0.01).”
SOURCE: Nabavi SF, et al. (2012). Cytoprotective effects of curcumin on sodium fluoride-induced intoxication in rat erythrocytes. Bull Environ Contam Toxicol. 88(3):486-90.

“The present study was aimed to evaluate curcumin as a potential natural antioxidant to mitigate the genotoxic effects of arsenic (As) and fluoride (F) in human peripheral blood lymphocytes. The study was divided into nine groups consisting of negative control, positive control treated with ethyl methane sulphonate (EMS; 1.93 mM) and curcumin control with onlycurcumin (1.7 microM) in blood culture. As (1.4 microM) and F (34 microM) were added alone as well as in combination, to the cultures, with and without curcumin. Cultures were analysed for chromosomal aberrations (both structural and numerical) and primary DNA damage via comet assay as the genotoxic parameters after an exposure duration of 24h. Results revealed thatcurcumin efficiently ameliorates the toxic effect of As and F by reducing the frequency of structural aberrations (>60%), hypoploidy (>50%) and primary DNA damage. In  conclusion, curcumin mitigates the genotoxic effects of the two well known water contaminants (As and F) effectively and efficiently at the given concentration in vitro.”
SOURCE: Tiwari H, Rao MV. (2010). Curcumin supplementation protects from genotoxic effects of arsenic and fluoride. Food Chem Toxicol. 48(5):1234-8.

“The effect of fluoride exposure during gestation and post gestation periods were studied to check the status of oxidant, antioxidant and macromolecular changes in CNS and ameliorative role of antioxidants. The pregnant Wistar albino rats were exposed to 50 and 150 ppm fluoride in drinking water and the pups born to them were used for experimentation. After postpartum, the pups were administered daily selected antioxidants through oral gavage. On 21st postnatal day pups were sacrificed and biochemical parameters were assessed. Fluoride exposure substantially increased the activity/levels of fluoride, LPO, protein oxidation, MAO-B, GOT, GPT and decreased protein thiols, RNA and total proteins in discrete regions of CNS. The findings evidenced fluoride induced dyshomeostasis caused on antioxidants, enzymes, macromolecules and governed the pathophysiological events leading to functional loss in a dose dependent manner. The administration of antioxidants remedied the disquiet caused by high fluoride exposure at extreme vulnerable periods of life.”
SOURCE: Basha PM, Madhusudhan N. (2010). Pre and post natal exposure of fluoride induced oxidative macromolecular alterations in developing central nervous system of rat and amelioration by antioxidants. Neurochem Res.35(7):1017-28.

“Oxidative damage to cellular components such as lipids and cell membranes by free radicals and other reactive oxygen species is believed to be associated with the development of degenerative diseases. Fluoride intoxication is associated with oxidative stress and altered anti-oxidant defense mechanism. So the present study was extended to investigate black berry anti-oxidant capacity towards superoxide anion radicals, hydroxyl radicals and nitrite in different organs of fluoride-intoxicated rats. The data indicated that sodium fluoride (10.3mg/kg bw) administration induced oxidative stress as evidenced by elevated levels of lipid peroxidation and nitric oxide in red blood cells, kidney, testis and brain tissues. Moreover, significantly decreased glutathione level, total anti-oxidant capacity and superoxide dismutase activity were observed in the examined tissues. On the other hand, the induced oxidative stress and the alterations in anti-oxidant system were normalized by the oral administration of black berry juice (1.6g/kg bw). Therefore it can be concluded that black berry administration could minimize the toxic effects offluoride indicating its free radical-scavenging and potent anti-oxidant activities.”
SOURCE: Hassan HA, Abdel-Aziz AF. (2010). Evaluation of free radical-scavenging and anti-oxidant properties of black berry against fluoride toxicity in rats. Food Chem Toxicol. 48(8-9):1999-2004.

“The antioxidative and cardioprotective properties of quercetin were investigated against sodium fluoride (NaF) induced oxidative stress in rat hearts. Experimental rats were divided into five groups. The first group served as the untreated (normal) control. The second group received NaF at a dose of 600 ppm through drinking water for 1 week, and served as the toxin control. The third and fourth groups were exposed to quercetin (at the dose of 10 and 20 mg kg(-1) intraperitoneally (i.p.) for 1 week) prior to NaF intoxication, and the fifth group was treated with vitamin C at a dose of 10 mg kg(-1) i.p., for 1 week prior to NaF intoxication and served as the positive control in the study. The activities of various antioxidant enzymes, superoxide dismutase and catalase, level of reduced glutathione and lipid peroxidation end product were determined in the cardiac tissues of all the experimental animals. NaF intoxication significantly altered all the indices related to the pro-oxidant-antioxidant status of the heart; treatment with the active constituents prior to NaF administration, however, prevented these alterations. The combined results suggest that quercetin protects rat hearts from NaF-induced oxidative stress, probably via its antioxidant properties.”
SOURCE: Nabavi SF, et al. (2010). Protective effect of quercetin against sodium fluoride induced oxidative stress in rat’s heart. Food Funct. 3(4):437-41.

“Fluorides, when taken in amounts exceeding the standard therapeutic dosage, are regarded as toxic substances. Recent studies show that fluorides may affect the oxidoreductive processes of cells. The aim of the following study is to investigate the effect of antioxidative vitamins A and E and coenzyme Q on the morphological picture of the lungs and pancreata of rats exposed to high doses of sodium fluoride. The study was performed on 18 female rats, which were divided into 3 groups: a control group and 2 experimental groups. The control group received distilled water and standard fodder. Experimental groups I and II both received sodium fluoride (2.5mg/rat/24h). In addition, animals in group II received vitamin A (250 IU/rat/24h), vitamin E (3mg/rat/24h), and coenzyme Q (200 microg/rat/24h). The experiment was conducted for a period of 35 days. Upon dissection, lungs and pancreata were taken for histopathological examination. Pathomorphological evaluations of the removed organs were performed using paraffin preparations, stained with hematoxylin and eosin. The aldolase activity in the pancreata was measured using colorimetric methods and the protein concentration by the Lowry method. In the case of group I, pathomorphological examinations of the lungs revealed the appearance of erythrorrhagia, hyperaemia, necrosis of epithelium cells, numerous macrophages in interalveolar septa, infiltrations in the area of blood vessels and emphysematous blebs. Focal vacuolar degeneration cells and inflammatory infiltrations appeared only in pancreata. The results confirmed that the administration of vitamins A and E and coenzyme Q has a counteracting influence upon the degenerative changes seen in the examined organs.”
SOURCE: Stawiarska-Pieta B, et al. (2009). The effect of antioxidative vitamins A and E and coenzyme Q on the morphological picture of the lungs and pancreata of rats intoxicated with sodium fluoride. Food Chem Toxicol. 47(10):2544-50.

“Vitamin E reduced brain fluoride level and tissue oxidative stress but had no effect on arsenic.”
SOURCE: Flora SJS, et al. (2009). Co-exposure to arsenic and fluoride on oxidative stress, glutathione linked enzymes, biogenic amines and DNA damage in mouse brain. Journal of the Neurological Sciences 285: 198–205.

“Administration of antioxidants during fluoride exposure significantly overcame cardiac fluoride toxicity and therefore may be a therapeutic strategy for fluorotic victims.”
SOURCE: Basha M, Sujitha N. (2009). Chronic fluoride toxicity and myocardial damage: Antioxidant offered protection in second generation rats. Toxicology International 18:99.

“High fluoride intake may affect biological systems by increasing free radicals, which may enhance lipid peroxidation levels of the tissues, thus leading to oxidative damage. Caffeic acid phenethyl ester (CAPE), a component of honeybee propolis, protects tissues from reactive oxygen species mediated oxidative stress in ischemia-reperfusion and toxic injuries. Several studies suggest that supplementation with anti-oxidant can influence fluoride induced tissue damage. The aims of this study was to investigate the possible role of malondialdehyde (MDA) levels and activity of superoxide dismutase (SOD) and catalase (CAT), in the pathogenesis of fluoride-induced endometrial damage and to demonstrate the effect of CAPE, the potent antioxidant, in decreasing the toxicity. . . . Fluoride administration increased MDA levels (p<0.05), decreased SOD (p<0.05) and CAT (p<0.05) activities. CAPE co-administration with fluoride treatments caused significantly decreased MDA levels (p<0.05), increased SOD (p<0.05) and CAT (p<0.05) activities in endometrial tissue when compared with F alone. Diffuse apoptosis in glandular epithelium and stromal cells was found by TUNEL method in endometrial tissues of rats treated with fluoride. The severity of these lesions was reduced by administration of CAPE. In conclusion, our study demonstrated that MDA may play an important role in the pathogenesis of fluoride-induced oxidative endometrial damage. CAPE may have protective aspects in this process by its antioxidant and anti-inflammatory effect.”
SOURCE: Guney M, et al. (2007). Protective effect of caffeic acid phenethyl ester (CAPE) on fluoride-induced oxidative stress and apoptosis in rat endometrium. Environ Toxicol Pharmacol. 24(2):86-91.

“Fluoride is a strong, hard anion and cumulative toxic agent. The effect of fluoride intoxication on lipid peroxidation in endometrial tissue and the protective effects of combinations of vitamins E and C in rats were studied. Additionally, the apoptotic changes in endometrial tissue were examined. Experimental groups were as follows: control group; a group treated with 100 mg/l fluoride (F group); and a group treated with 100 mg/l fluoride plus vitamins E and C (F+Vit group). The F and F+Vit groups were treated orally with fluoride for 30 days. Vitamins E and C were injected simultaneously at doses of 50 mg/kg day i.m. and 20 mg/kg day body weight i.p. Extensive formation of DNA strand breaks, the typical biochemical feature of apoptosis, was detected with the use of the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick and labeling (TUNEL) method. Malondialdehyde (MDA) levels were determined in uterine tissue of rats. Fluoride caused a significant increase in MDA levels (an important marker of lipid peroxidation) in the fluoride group compared with the controls (p<0.05). Vitamins E and C significantly reduced the fluoride-induced lipid peroxidation in the F+Vit group compared with the F group (p<0.05). Diffuse apoptosis in glandular epithelium and stromal cells was found in endometrial tissues of F treated rats by TUNEL method. The severity of these lesions was reduced by the administration of vitamins. From these results, it can be concluded that subchronic fluoride administration causes endometrial apoptosis, and lipid peroxidation may be a molecular mechanism involved in fluoride-induced toxicity. Furthermore, treatment with a combination of vitamins E and C reduced endometrial apoptosis caused by fluoride.”
SOURCE: Guney M, et al. (2007). Effect of fluoride intoxication on endometrial apoptosis and lipid peroxidation in rats: role of vitamins E and C. Toxicology. 231(2-3):215-23.