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1998 Fluoride Abstracts. Part 1.

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http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9761592&dopt=Abstract

Neurotoxicol Teratol 1998 Sep-Oct;20(5):537-42

Influence of chronic fluorosis on membrane lipids in rat brain.

Guan ZZ, Wang YN, Xiao KQ, Dai DY, Chen YH, Liu JL, Sindelar P, Dallner G.

Department of Pathology, Guiyang Medical College, Guizhou, China. jialiul@public.gy.gz.cn

Brain membrane lipid in rats were analyzed after being fed either 30 or 100 ppm fluoride for 3, 5, and 7 months. The protein content of brain with fluorosis decreased, whereas the DNA content remained stable during the entire period of investigation. After 7 months of fluoride treatment, the total brain phospholipid content decreased by 10% and 20% in the 30 and 100 ppm fluoride groups, respectively. The main species of phospholipid influenced by fluorosis were phosphatidylethanolamine, phosphatidylcholine, and phosphatidylserine. The fatty acid and aldehyde compositions of individual phospholipid classes were unchanged. No modifications could be detected in the amounts of cholesterol and dolichol. After 3 months of fluoride treatment, ubiquinone contents in brain were lower; however, at 7 months they were obviously increased in both groups of fluoride treatment. The results demonstrate that the contents of phospholipid and ubiquinone are modified in brains affected by chronic fluorosis and these changes of membrane lipids could be involved in the pathogenesis of this disease.

PMID: 9761592 [PubMed - indexed for MEDLINE]

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http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9559097&dopt=Abstract

Biomed Environ Sci 1998 Mar;11(1):1-6

Actions of sodium fluoride on acetylcholinesterase activities in rats.

Zhao XL, Wu JH.

Department of Environmental Toxicology, Chinese Academy of Preventive Medicine, Beijing, China.

This study was carried out to observe the effects of sodium fluoride on acetylcholinesterase (AChE) activities in the cerebral synaptic membranes (SPM) and the peripheral red blood cells (RBC) of rats by in vivo and in vitro experiments. In the in vivo study, pregnant rats ingested ad libitum fluorinated drinking water (5, 15, 50 ppm F-) during their gestation and lactation. It was shown that the AChE activities of the SPM and peripheral RBCs in maternal rats exposed 5-50 ppm F- for 60 days were elevated significantly by 30.0-67.6% and 12.5-31.9% in a dose-dependent manner, respectively. The AChE activities of their offspring 80 days after birth were also increased (8.7-28.7% for SPM and 20.6-32.4% for RBC). In contrast, the AChE activities of SPM in vitro were inhibited by 5.0-50.0 mmol F-/L treatment in a time- and dose-dependent manner. Analysis with the Hanes plots suggested that the enzymesubstrate kinetics are consistent with a mixed type of inhibition.

PMID: 9559097 [PubMed - indexed for MEDLINE]

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http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9974025&dopt=Abstract

Khirurgiia (Sofiia) 1998;51(3):36-9

[The use of ketamine in an experimental model of generalized cerebral ischemia]

[Article in Bulgarian]

Vasilev D, Konstantinov S, Konstantinova Zh, Nachkov Ia, Karaivanova M, Stamenova P.

Thus far, a sufficiently effective cerebroprotective substances has not been discovered. Glutamate overproduction plays a key role in ischemic brain lesion. Ketamine is assigned to the group of commonly used clinical anesthetics, being also familiar as NMDA antagonist. Sodium fluoride-induced cerebral ischemia in mice is used as a model of circulatory ischemic lesion. As shown by the experimental data, simultaneous administration of NaF + ketamine has no effect whatsoever on the survivorship of animals, as compared to that in the control group treated with NaF alone. Beforehand treatment of mice with 150 mg/kg ketamine brings about considerable prolongation of the survival term (15 per cent of the animals survive for more than 2 hours). The inference is reached that ketamine is endowed with cerebroprotective activity largely attributable to glutamate antagonism at the level of ischemia involved neurons.

PMID: 9974025 [PubMed - indexed for MEDLINE]

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http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9482250&dopt=Abstract

Neurochem Res 1998 Mar;23(3):377-84

Process formation in astrocytes: modulation of cytoskeletal proteins.

Padmanabhan J, Shelanski ML.

Department of Pathology, Taub Center for Alzheimer's Disease Research, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. jp88@columbia.edu

Studies on primary astrocytes cultured in vitro have shown that process formation involves changes in cytoskeletal proteins and release of tension on the substratum. Actin filament reorganization has previously been found to be the major cytoskeletal change occurring during process formation. These changes are relatively rapid with breakdown of the actin web and release of contacts occur within 15 min. of cyclic AMP treatment. The former is regulated by myosin light chain (MLC) and actin depolymerizing factor (ADF), with MLC involved in the initial release of contractile tension and ADF in both initial and longer term actin breakdown. Our results show that the dephosphorylation of MLC is due to the phosphorylation and inactivation of myosin light chain kinase (MLCK) in response to cyclic AMP. To further study the mechanisms underlying the process formation in astrocytes we used endothelin-1 (ET-1), a vasopeptide which has been shown to inhibit process formation in astrocytes and sodium fluoride which is a general phosphatase inhibitor. We observe an increase in phosphorylation of MLC on inhibition of process formation. To study the role of adhesion in process formation we used suspension cultures of astrocytes. Our results with the astrocytes in suspension suggest that the process formation in astrocytes is adhesion dependent and the changes in ADF and MLC occur only when there is process formation.

PMID: 9482250 [PubMed - indexed for MEDLINE]

[Note from FAN:
Definition of Astrocyte: one of the large neuroglia cells of nervous tissue. SEE ALSO NEUROGLIA. SYN Astroglia, macroglia. - Ref: Steadman's Concise Medical Distionary for the Health Professions. Illustrated 4th Edition. Editor JH Dirckx. 2001.

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Brain Res Mol Brain Res 1998 Jan;53(1-2):196-205

Glutathione depletion exacerbates impairment by oxidative stress of phosphoinositide hydrolysis, AP-1, and NF-kappaB activation by cholinergic stimulation.

Li X, Song L, Jope RS.

Department of Psychiatry and Behavioral Neurobiology University of Alabama at Birmingham, Birmingham, AL 35294-0017, USA.

Oxidative stress appears to contribute to neuronal dysfunction associated with Alzheimer's disease and other CNS neurodegenerative disorders. This investigation examined if oxidative stress might contribute to impairments in cholinergic receptor-linked signaling systems and if intracellular glutathione levels modulated responses to oxidative stress. To do this the activation of the AP-1 and NF-kappaB transcription factors and of the phosphoinositide second-messenger system was measured in human neuroblastoma SH-SY5Y cells after exposure to the oxidants H2O2 or diamide, with or without prior depletion of cellular glutathione. H2O2 concentration-dependently inhibited carbachol-stimulated AP-1 activation and this inhibition was potentiated in glutathione-depleted cells. Carbachol-stimulated NF-kappaB activation was unaffected by H2O2 unless glutathione was depleted, in which case there was a H2O2 concentration-dependent inhibition. Glutathione depletion also potentiated the inhibition by H2O2 of carbachol- or G-protein (NaF)-stimulated phosphoinositide hydrolysis, whereas phospholipase C activated by the calcium ionophore ionomycin was not inhibited. The thiol-oxidizing agent diamide also inhibited phosphoinositide hydrolysis stimulated by carbachol or NaF, and glutathione depletion potentiated the diamide concentration-dependent inhibition. Unlike H2O2, diamide also inhibited ionomycin-stimulated phosphoinositide hydrolysis. Activation of both AP-1 and NF-kappaB stimulated by carbachol was inhibited by diamide, and glutathione depletion potentiated the inhibitory effects of diamide. Thus, diamide inhibited a wider range of signaling processes than did H2O2, but glutathione depletion increased the susceptibility of phosphoinositide hydrolysis and of transcription factor activation to inhibition by both H2O2 and diamide. These results demonstrate that the vulnerability of signaling systems to oxidative stress is influenced by intracellular glutathione levels, indicating that cell-selective susceptibility to inhibition of signal transduction systems by oxidative stress can arise from cellular variations in antioxidant capacity.

PMID: 9473671 [PubMed - indexed for MEDLINE]

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http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9842373&dopt=Abstract

Am J Public Health 1998 Dec;88(12):1774-80

Health effects associated with sulfuryl fluoride and methyl bromide exposure among structural fumigation workers.

Calvert GM, Mueller CA, Fajen JM, Chrislip DW, Russo J, Briggle T, Fleming LE, Suruda AJ, Steenland K.

Division of Surveillance, Hazard Evaluations and Field Studies, Centers for Disease Control and Prevention, Cincinnati, Ohio, USA. jac6@cdc.gov

OBJECTIVES: This study assessed the health effects associated with occupational exposure to methyl bromide and sulfuryl fluoride among structural fumigation workers.
METHODS: A cross-sectional study of 123 structural fumigation workers and 120 referents in south Florida was conducted. Nerve conduction, vibration, neurobehavioral, visual, olfactory, and renal function testing was included.
RESULTS: The median lifetime duration of methyl bromide and sulfuryl fluoride exposure among workers was 1.20 years and 2.85 years, respectively. Sulfuryl fluoride exposure over the year preceding examination was associated with significantly reduced performance on the Pattern Memory Test and on olfactory testing. In addition, fumigation workers had significantly reduced performance on the Santa Ana Dexterity Test of the dominant hand and a nonsignificantly higher prevalence of carpal tunnel syndrome than did the referents.
CONCLUSIONS: Occupational sulfuryl fluoride exposures may be associated with subclinical effects on the central nervous system, including effects on olfactory and some cognitive functions. However, no widespread pattern of cognitive deficits was observed. The peripheral nerve effects were likely caused by ergonomic stresses experienced by the fumigation workers.

PMID: 9842373 [PubMed - indexed for MEDLINE]

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Environmental Toxicology & Pharmacology 1998; 6(3):187-191

• As cited and abstracted in Fluoride 1999; 32(2):120-121

Effects of sodium fluoride on locomotor behavior and a few biochemical parameters in rats

Paul V, Ekambaram P, Jayakumar AR

Univiversity of Madras, Dept Pharmacol & Environm Toxicol, Dr ALM Postgrad Inst Basic Med Sci, Taramani, Chennai, India

Spontaneous motor activity and motor coordination were tested in adult female rats after treating with sodium fluoride at 20 or 40 mg/kg dose level deaily for 60 days, using an activity chamber and a rota-rod apparatus, respectively. Total protein concentrations were determined in skeletal muscle, liver and serum of similarly treated animals. The activities of total cholinesterase and acetylcholinesterase were determined in the blood and in regions of the brain, respectively. Sodium fluoride treatment suppressed spontaneous motor activity, but no change was observed in the mtor coordination of these animals. Tissue and serum protein concentrations were decreased. Cholinesterase activity was decreased in the blood but not in the brain regions. A failure of sodium fluoride to impair motor coordination indicated that the neuromuscular function required for a forced task had not deteriorated in these animals, although skeletal muscles were deprived of protein and blood cholinesterase activity was suppressed. A suppression of spontaneous motor actiity suggests that fluoride has, by a central action, inhibited the motivation of these animals to exhibit locomotor behavior. A cholinergic mechanism through a change in the activity of acetylcholinesterase may not account for this effect, since sodium fluoride treatment did not alter the activity of this enzyme in the brain regions. However, an involvement of monoamines may be proposed in view of the previously reported findings that excessive fluoride intake has decreased the concentrations of 5-hydroxyindoleacetic acid and increased that of norepinephrine in rat brain.

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http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9879930&dopt=Abstract

Cell Biol Toxicol 1998 Dec;14(6):383-9

Cytotoxicity of sodium fluoride on human oral mucosal fibroblasts and its mechanisms.

Jeng JH, Hsieh CC, Lan WH, Chang MC, Lin SK, Hahn LJ, Kuo MY.

School of Dentistry, College of Medicine, National Taiwan University, Taipei.

Because sodium fluoride (NaF) is widely used for prevention of dental caries, pathobiological effects of NaF were investigated on human oral mucosal fibroblasts. The results showed that NaF was cytotoxic to oral mucosal fibroblasts at concentrations of 4 mmol/L or higher. Exposure of cells to NaF for 2 h also inhibited protein synthesis, cellular ATP level and functional mitochondrial activities in a dose-dependent manner. However, incubation of cells with NaF up to 12 mmol/L for 2 h depleted only 13% of cellular glutathione level. The IC50 of NaF on cellular ATP level was about 5.75 mmol/L. Preincubation of the cells with pyruvate and succinate did not protect cells from NaF-induced ATP depletion. At concentrations of 4 mmol/L, 8 mmol/L and 12 mmol/L, NaF inhibited 31%, 56% and 57% of mitochondrial functions, respectively, after 2 h incubation. No significant inhibition for NaF was found at concentrations lower than 2 mmol/L (40 ppm). These results indicate that NaF can be toxic to oral mucosal fibroblasts in vitro by its inhibition of protein synthesis, mitochondrial function and depletion of cellular ATP. Because of repeated and long-term usage of NaF, more detailed studies should be undertaken to understand its toxic effects in vitro and in vivo.

PMID: 9879930 [PubMed - indexed for MEDLINE]

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http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10684086&dopt=Abstract

Hua Xi Yi Ke Da Xue Xue Bao 1998 Sep;29(3):256-8, 268

[Effect of fluoride on proliferation and differentiation in rat and mouse embryo bud cell in vitro]

[Article in Chinese]

Zhang B, Wu D.

Department of Environmental Health, School of Public Health, Chengdu.

The effect of fluoride on differentiation and proliferation of rat and mouse embryo limb bud cell were studied with micromass cultures in vitro. Embryo limb bud cells of rat (13-day) and mouse (12-day) were subjected to culture for 5 days. The results showed that fluoride could inhibit differentiation of cells without affecting cells proliferation. The concentrations of 50% inhibition of cell differentiation (ID50) were 6.8 micrograms/ml(rat) and 7.3 micrograms/ml(mouse). The concentrations of 50% inhibitions of cell proliferation (IP50) were 44.1 micrograms/ml (rat) and 63.6 micrograms/ml (mouse). The IP/ID50 values 6.4(rat) and 8.7 (mouse) were both greater than 5. According to the assessment criteria of Flint and Cheng Wanrong, the fluoride may be an embryo limb bud cells specific inhibitor. It could have potent teratogenicity.

PMID: 10684086 [PubMed - indexed for MEDLINE]

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Full report at http://www.fluoride-journal.com/98-31-3/313-143.htm

Fluoride 1998; 31(3):143-148

Ameliorative role of amino acids on fluoride-induced alterations in mice (Part II): ovarian and uterine nucleic acid metabolism

D Patel and NJ Chinoy

Department of Zoology, School of Sciences, Gujarat University, Ahmedabad 380 009, India. Correspondence to Professor N J Chinoy.

This study is Part II of the earlier experiment reported in Fluoride 1996; 29(4):217-226

SUMMARY: Sodium fluoride (5 mg/kg body weight) was effective from the 45th day of treatment in causing a significant decline in DNA and RNA levels of mice ovary and uterus, indicating alterations in nucleic acid and protein metabolism in these organs. The oestrus cycle was irregular with prolonged duration of the diestrus stage which in turn severely affected the fertility rate in treated mice. The administration of amino acids glycine and glutamine, individually and in combination along with NaF, helped in maintaining the status quo of all parameters as compared to control, thus elucidating their ameliorative role.

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Full report available at http://www.fluoride-journal.com/98-31-4/314-203.htm

Fluoride 1998; 31(4):203-216

Amelioration of fluoride toxicity by Vitamins E and D in reproductive functions of male mice

NJ Chinoy * and A Sharma

*Address for correspondence. Reproductive Endocrinology and Toxicology Unit, UGC Department of Special Assistance and COSIST in Zoology, School of Sciences, Gujarat University, Ahmedabad 380009, India.

SUMMARY: Studies on the beneficial effects of vitamins E and D supplementation on functions of caput and cauda epididymides, their spermatozoa, vas deferens and seminal vesicle of sodium fluoride (NaF) treated (10 mg/kg body weight) male mice (Mus musculus) were carried out. The NaF treatment resulted in significant decrease in the body and epididymis weight but those of vas deferens and seminal vesicle were not affected. NaF treatment brought about alterations in epididymal milieu as elucidated by the significant decrease in levels of sialic acid and protein as well as activity of ATPase in epididymides. As a result, the sperm maturation process was affected leading to a significant decline in cauda epididymal sperm motility and viability. This caused a significant reduction in fertility rate. The cauda epididymal sperm count was also significantly reduced. The data obtained suggest that fluoride treatment induced significant metabolic alterations in the epididymides, vas deferens and seminal vesicles of mice. The withdrawal of NaF treatment (30 days) produced incomplete recovery. On the other hand, sup-plementation of vitamins E or D during the withdrawal period of NaF treated mice was found to be very beneficial in recovery of all NaF induced effects, thus elucidating their ameliorative role in recovery from toxic effects of NaF on the reproductive functions and fertility. On the whole, a combination of vitamins E and D treatment was comparatively more effective than that with vitamin E or D alone. Therefore, vitamin therapy could be beneficial for the amelioration of fluoride induced changes in reproductive functions.

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http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9449681&dopt=Abstract

Environ Health Perspect 1998 Mar;106(3):167-74

Comment in:

• Environ Health Perspect. 1998 Oct;106(10):A472-3.

The estrogenicity of bisphenol A-related diphenylalkanes with various substituents at the central carbon and the hydroxy groups.

Perez P, Pulgar R, Olea-Serrano F, Villalobos M, Rivas A, Metzler M, Pedraza V, Olea N.

Laboratory of Medical Investigation, Department of Radiology, School of Medicine, HUSC-University of Granada, Granada, Spain.

The chemical structure of hydroxylated diphenylalkanes or bisphenols consists of two phenolic rings joined together through a bridging carbon. This class of endocrine disruptors that mimic estrogens is widely used in industry, particularly in plastics. Bisphenol F, bisphenol A, fluorine-containing bisphenol A (bisphenol AF), and other diphenylalkanes were found to be estrogenic in a bioassay with MCF7 human breast cancer cells in culture (E-SCREEN assay). Bisphenols promoted cell proliferation and increased the synthesis and secretion of cell type-specific proteins. When ranked by proliferative potency, the longer the alkyl substituent at the bridging carbon, the lower the concentration needed for maximal cell yield; the most active compound contained two propyl chains at the bridging carbon. Bisphenols with two hydroxyl groups in the para position and an angular configuration are suitable for appropriate hydrogen bonding to the acceptor site of the estrogen receptor. Our data suggest that estrogenicity is influenced not only by the length of the substituents at the bridging carbon but also by their nature. Because diphenylalkane derivatives are widespread and their production and use are increasing, potential exposure of humans to estrogenic bisphenols is becoming a significant issue. The hazardous effects of inadvertent exposure to bisphenol-releasing chemicals in professional workers and the general populations therefore deserve investigation.

PMID: 9449681 [PubMed - indexed for MEDLINE]

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Full report available at: http://www.fluoride-journal.com/98-31-4/314-193.htm

Fluoride 1998; 31(4):193-202

The role of fluoride ions in glycosaminoglycans sulphation in cultured fibroblasts

Pawlowska-Goral K (a), Wardas M (b), Wardas W (a), and Majnusz U (a)

(a) Department of General and Analytical Chemistry,
(b) Department of Food and Nutrition, Faculty of Pharmacy, Silesian Academy of Medicine, 4 Jagiellonska Street, PL-41-200 Sosnowiec, Poland.

SUMMARY: The purpose of this study was to evaluate sulphur incorporation (by 35S sulphate) into glycosaminoglycans (GAG) cultures of isolated cells, pericellular substance and medium, and into glycosaminoglycans present in sulphate fibroblasts with NaF added to the culture. In the study, primary cultures of fibroblasts were used, isolated by tissue trypsinization from mice livers. Fibroblasts were cultured with the addition of NaF ([FÐ] = 0.116á10-3 M/dm3 ) and the addition of NaF and [35S]-Na2SO4 (activity 35S = 30 µCi/cm3). Simultaneously with the experimental cultures, control cultures were also examined. The effect of FÐ ions on culture growth, protein content in fibroblasts, and their morphometric characteristics were evaluated. Three fractions were isolated from fibroblast cultures: cell, pericellular substance, and medium. From these fractions glycosaminoglycans were isolated. GAG obtained from fibroblasts were electrophoretically separated, resulting in heparan sulphate (HS), dermatan sulphate (DS), and chondroitin sulphates (CS). Even in low concentrations FÐ ions have a toxic effect on fibroblast cultures. Growth inhibition and decrease in size, accompanied by a change in shape, were observed. Under the same conditions fluoride ions significantly modified incorporation of35 S into fibroblasts and GAG from individual fractions of experimental cultures. Analysis of sulphated GAG content in the fibroblasts showed interference by FÐ ions, both in their synthesis and metabolism, as well as their diffusion. The results suggest a significant increase in synthesis intensity and/or the degree of DS sulphation and a decrease in the intensity of the process in relation to CS and HS.

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http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9862654&dopt=Abstract

Food Chem Toxicol 1998 Dec;36(12):1117-24

Testing the potential of sodium fluoride to affect spermatogenesis: a morphometric study.

Sprando RL, Collins TF, Black T, Olejnik N, Rorie J.

Division of Toxicological Research, Center for Food Safety Applied Nutrition, Food and Drug Administration, Beltsville, MD 20708, USA.

This study provides quantitative information on the effect of sodium fluoride (NaF) on the testes of F1 generation male rats exposed in utero and during lactation to NaF at one of four concentrations (25, 100, 175, 250 ppm). At weaning, the F1 generation males were exposed to NaF in their drinking water for 14 weeks, after which time testicular tissues were perfusion-fixed with glutaraldehyde and observed after being embedded in plastic. The seminiferous tubules comprised 89%, 87%, 88%, 88% and 88% of the total testis volume while the interstitial space occupied 9.3%, 11.2%, 10.2%, 9.8% and 9.9% of the total testis volume for the 0, 25, 100, 175 and 250 ppm NaF treatment groups, respectively. Statistically significant differences between control and NaF-treated rats were not observed with respect to absolute volume of the seminiferous tubules, interstitial space, Leydig cells, blood vessels boundary layer, lymphatic space, macrophages, tubular lumen or absolute tubular length and absolute tubular surface area, mean Sertoli cell nucleoli number per tubular cross-section, mean seminiferous tubule diameter and the mean height of the seminiferous epithelium. A statistically significant decrease in the absolute volume and volume percent of the lymphatic endothelium was observed in the 175 and 250 ppm NaF-treated groups and in the testicular capsule in the 100 ppm NaF-treated groups. The significance of this finding is unknown at the present time. Overall, the quantitative information obtained suggests that exposure to NaF at the doses used in the present study does not adversely affect testis structure or spermatogenesis in the rat.

PMID: 9862654 [PubMed - indexed for MEDLINE]

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Full report available at: http://endo.endojournals.org/cgi/content/full/139/2/551

Endocrinology 1998 Feb;139(2):551-8

Evidence that glucose metabolism regulates leptin secretion from cultured rat adipocytes.

Mueller WM, Gregoire FM, Stanhope KL, Mobbs CV, Mizuno TM, Warden CH, Stern JS, Havel PJ.

Department of Nutrition, School of Medicine, University of California, Davis 95616, USA.

Circulating leptin secreted from adipocytes is correlated with fat mass and plasma insulin concentrations in humans and rodents. Plasma leptin, insulin, and glucose decrease during fasting and increase after refeeding; however, the underlying mechanisms regulating the changes of leptin secretion are not known. To investigate the role of insulin-stimulated glucose metabolism in the regulation of leptin secretion, we examined the effects of insulin and inhibitors of glucose transport and metabolism on leptin secretion from rat adipocytes in primary culture. Insulin (0.16-16 nM) increased leptin secretion over 96 h; however, the increase in leptin was more closely related to the amount of glucose taken up by the adipocytes (r = 0.64; P < 0.0001) than to the insulin concentration per se (r = 0.20; P < 0.28), suggesting a role for glucose transport and/or metabolism in regulating leptin secretion. 2-Deoxy-D-glucose (2-DG), a competitive inhibitor of glucose transport and phosphorylation, caused a concentration-dependent (2-50 mg/dl) inhibition of leptin release in the presence of 1.6 nM insulin. The inhibitory effect of 2-DG was reversed by high concentrations of glucose. Two other inhibitors of glucose transport, phloretin (0.05-0.25 mM) and cytochalasin-B (0.5-50 microM), also inhibited leptin secretion. Inhibition of leptin secretion by these agents was proportional to the inhibition of glucose uptake (r = 0.60 to 0.86; all P < 0.01). Two inhibitors of glycolysis, iodoacetate (0.005-1.0 mM) and sodium fluoride (0.1-5 mM), produced concentration-dependent inhibition of leptin secretion in the presence of 1.6 nM insulin. In addition, both 2-DG and sodium fluoride markedly decreased the leptin (ob) messenger RNA content of cultured adipocytes, but did not affect 18S ribosomal RNA content. We conclude that glucose transport and metabolism are important factors in the regulation of leptin expression and secretion and that the effect of insulin to increase adipocyte glucose utilization is likely to contribute to insulin-stimulated leptin secretion. Thus, in vivo, decreased adipose glucose metabolism may be one mechanism by which fasting decreases circulating leptin, whereas increased adipose glucose metabolism would increase leptin after refeeding.

PMID: 9449624 [PubMed - indexed for MEDLINE]

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http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9437512&dopt=Abstract

Bone 1998 Jan;22(1):39-43

Fluoride potentiates the osteogenic effects of IGF-I in aged ovariectomized rats.

Ammann P, Rizzoli R, Caverzasio J, Bonjour JP.

WHO Collaborating Center for Osteoporosis and Bone Diseases, Department of Internal Medicine, University Hospital, Geneva, Switzerland.

The molecular mechanisms whereby fluoride stimulates osteogenic cell proliferation are not clearly established. However, fluoride has been shown to enhance the protein tyrosine phosphorylation of various constituents of intracellular signaling cascades in osteoblastic cells following stimulation of growth factor receptors such as the insulin-like growth factor-I (IGF-I) receptor. Such in vitro findings provided the rationale for testing whether the administration of fluoride could enhance IGF-I effects on bone mass in vivo. Adult ovariectomized osteopenic rats were treated with sodium fluoride at a dose of 6 mg/kg per day in drinking water for 8 weeks in association with IGF-I either at a dose of 2 mg/kg per day, which is capable of increasing bone mass, or at a lower dose without detectable skeletal effects. Bone mineral density (BMD) and content (BMC) were evaluated by dual-energy X-ray absorptiometry at the levels of the lumbar spine and proximal, midshaft, and total tibia before and after 8 weeks of treatment. During this period, fluoride alone did not significantly influence BMD/BMC at any skeletal site. However, it potentiated the effect of the higher dose of IGF-I on bone mass at the level of the proximal tibia. When administered in combination with the lower dose of IGF-I, which per se did not modify bone mass, it appeared to sensitize tibial bone to the effects of IGF-I. These changes were associated with a concomitant increase in osteocalcin, taken as a reflection of bone formation. These results indicate that fluoride could potentiate the osteogenic effects of IGF-I on bone in adult ovariectomized rats.

PMID: 9437512 [PubMed - indexed for MEDLINE]

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Full report available at: http://www.fluoridealert.org/pesticides/Sodium.Fluoride.Blood.1998.pdf

Clin Chem 1998 Oct;44(10):2204-6

Addition of sodium fluoride to whole blood does not stabilize plasma homocysteine but produces dilution effects on plasma constituents and hematocrit.

Hughes MP, Carlson TH, McLaughlin MK, Bankson DD.

Department of Laboratory Medicine, University of Washington, Seattle 98195, USA. hughes@mail.labmed.washington.edu

PMID: 9761260 [PubMed - indexed for MEDLINE]

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http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9490002&dopt=Abstract

FEBS Lett 1998 Jan 30;422(2):185-8

Activation by sodium fluoride of drug-metabolizing enzymes in rat hepatoma-derived Fa32 cells.

Dierickx PJ.

Instituut voor Volksgezondheid, Afdeling Toxikologie, Brussel, Belgium. p.dierickx@iph.fgov.be

Protection against xenobiotic insult, including cancer chemoprotection, can be achieved by a variety of natural and synthetic compounds belonging to over 20 different classes of chemicals. They all induce or activate drug-metabolizing enzymes. The discovery of a new class of activator is currently reported. Sodium fluoride activated the phase I ethoxyresorufin-O-deethylase (to 240%) and pentoxyresorufin-O-depentylase (to 156%), and the phase II glutathione transferase to 120% of the basal activities in rat hepatoma-derived Fa32 cells. It is, therefore, a bifunctional enzyme activator. A time- and concentration-dependent activation was observed. A possible impact of the daily fluoride uptake from drinking water is suggested.

PMID: 9490002 [PubMed - indexed for MEDLINE]

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http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9459149&dopt=Abstract

Br J Cancer 1998;77(1):79-86

The anti-cancer drug 5-fluorouracil is metabolized by the isolated perfused rat liver and in rats into highly toxic fluoroacetate.

Arellano M, Malet-Martino M, Martino R, Gires P.

Biomedical NMR Group, IMRCP Laboratory, Universite Paul Sabatier, Toulouse, France.

We report the first demonstration of the biotransformation of the anti-cancer drug 5-fluorouracil (FU) into two new metabolites, alpha-fluoro-beta-hydroxypropionic acid (FHPA) and fluoroacetate (FAC), in the isolated perfused rat liver (IPRL) and in the rat in vivo. IPRL was perfused with solutions of pure FU at two doses, 15 or 45 mg kg(-1) body weight, and rats were injected i.p. with 180 mg of FU kg(-1) body weight. Fluorine-19 NMR analysis of perfusates from IPRL and rat urine showed the presence of the normal metabolites of FU and low amounts of FHPA (0.4% or 0.1% of injected FU in perfusates from IPRL treated with 15 or 45 mg of FU kg(-1) body weight, respectively; 0.08% of the injected FU in rat urine) and FAC (0.1% or 0.03% of injected FU in perfusates from IPRL treated with 15 or 45 mg of FU kg(-1) body weight, respectively; 0.003% of the injected FU in rat urine). IPRL was also perfused with a solution of alpha-fluoro-beta-alanine (FBAL) hydrochloride at 16.6 mg kg(-1) body weight dose equivalent to 15 mg of FU kg(-1) body weight. Low amounts of FHPA (0.2% of injected FBAL) and FAC (0.07%) were detected in perfusates, thus demonstrating that FHPA and FAC arise from FBAL catabolism. As FAC is a well-known cardiotoxic poison, and FHPA is also cardiotoxic at high doses, the cardiotoxicity of FU might stem from at least two sources. The first one, established in previous papers (Lemaire et al, 1992, 1994), is the presence in commercial solutions of FU of degradation products of FU that are metabolized into FHPA and FAC; these are formed over time in the basic medium necessary to dissolve the drug. The second, demonstrated in the present study, is the metabolism of FU itself into the same compounds.

PMID: 9459149 [PubMed - indexed for MEDLINE]

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