Return to Submission of Objections to EPA's Final Rule on Sulfuryl fluoride
APPENDIX H.
FLUORIDE AND THE BRAIN.
March 23, 2004, Submission to US EPA
from Fluoride Action Network:
Objections and Request for a Hearing
RE: US EPA's January 23, 2004, Final Rule for Sulfuryl Fluoride.
The use of high doses increases the likelihood that potentially significant toxic effects will be identified. Findings of adverse effects in any one species do not necessarily indicate such effects might be generated in humans. From a conservative risk assessment perspective however, adverse findings in animal species are assumed to represent potential effects in humans, unless convincing evidence of species specificity is available.
-- Food and Agricultural Organization of the United Nations
Ref: January 23, 2004. Sulfuryl Fluoride; Pesticide Tolerance.
40 CFR Part 180 [OPP-2003-0373; FRL-7342-1]. Final Rule. Federal RegisterExcerpts from: Table 1.--Subchronic, Chronic, and Other Toxicity Study Guideline Type of Study NOAEL
mg/kg/dayLOAEL
mg/kg/dayBased on: None cited
2-Week inhalation study--rabbit30/30 (M/F) 90/90
(M/F)malacia (necrosis) in cerebrum, vacuolation of cerebrum
None cited
2-Week inhalation study--rabbit- 180/180
(M/F)malacia (necrosis) in cerebrum, vacuolation of cerebrum
(870.3100) 90-Day inhalation toxicity--rat 24/25 (M/F) 90/90
(M/F)malacia (necrosis) in cerebrum, vacuolation of cerebrum
(870.3100) 90-Day inhalation toxicity--rat - 180/180
(M/F)malacia (necrosis) in cerebrum, vacuolation of cerebrum
(870.3100) 90-Day inhalation toxicity--rat - 240/250
(M/F)vacuolation of caudate-putamen nucleus and white
fiber tracts of the internal capsule of the brain(870.3100) 90-Day inhalation toxicity--mouse 38/36 (M/F) 125/121
(M/F)miscroscopic lesions in caudate-putamen nucleus and external capsule of the brain (870.3150)
90-Day inhalation toxicity--dog25/26 (M/F) 50/51
(M/F)slight histopathology of the caudate nucleus of the basal ganglia (870.3150)
90-Day inhalation toxicity-- rabbit8.6/8.5 (M/F) 29/28
(M/F)vacuolation of white matter of the brain (F only) (870.3150) 90-Day inhalation toxicity-- rabbit - 86/85
(M/F)malacia (necrosis) and vacuolation of putamen, globus pallidus and internal and external capsules in the brain (870.4100)
Chronic toxicity--rodents3.5 for M
16 for F
14 for M
62 for F
histopathology in brain (vacuolation in cerebrum and
thalmus/hypothalmus)(870.4100)
1-Year chronic inhalation toxicity--dog5.0/5.1 (M/F) 50/51
(M/F)malacia (necrosis) in caudate nucleus of brain (870.4200)
18-Month carcinogenicity inhalation study--mouse25/25 (M/F) 101/101
(M/F)cerebral vacuolation in brain (870.4300)
2-Year combined chronic/
carcinogenicity--rat3.5 for M
16 for F
14 for M
62 for F
histopathology in brain (vacuolation in cerebrum and
thalmus/hypothalmus)
Ref: January 23, 2004. Sulfuryl Fluoride; Pesticide Tolerance.
40 CFR Part 180 [OPP-2003-0373; FRL-7342-1]. Final Rule. Federal RegisterExcerpts: Table 2.--Summary of Toxicological Dose and Endpoints for sulfuryl fluoride for Use in Human Risk Exposure Scenario Dose Used in Risk Assessment, Interspecies and Intraspecies and any Traditional UF Special FQPA SF and Level of Concern for Risk Assessment Study and Toxicological Effects
Chronic dietary (all populations)NOAEL = 8.5 mg/kg/day
UF = 3,000...
Chronic RfD = 0.003 mg/kg/day.Special FQPA SF = 1X
cPAD = chronic RfD/
Special FQPA SF = 0.003 mg/kg/day.Rabbit - 90-Day inhalation
LOAEL = 28 mg/kg/day based on vacuolation of white matter in the brain of females.
Short-term inhalation (1 to 30 days)Inhalation study
NOAEL = 30 mg/kg/day
(100 ppm; 0.42 mg/L).Residential LOC for MOE = 1,000 Occupational
LOC = 100Rabbit - 2-Week inhalation
LOAEL = 90 mg/kg/day (300 ppm; 1.25 mg/L) based on malacia (necrosis) and vacuolation in brain, inflammation of nasal tissue and trachea
Intermediate-term inhalation (1 to 6 months)Inhalation study
NOAEL = 8.5 mg/kg/day (100 ppm; 0.42mg/L).Residential LOC for MOE = 1,000
Occupational LOC for MOE = 100.Rabbit - 90-Day inhalation
LOAEL = 28 mg/kg/day (100 ppm; 0.42 mg/L) based on vacuolation of white matter in the brain of females.
Long-term inhalation (>6 months)Inhalation study
NOAEL = 8.5 mg/kg/day
(30 ppm; 0.13 mg/L).Residential LOC for MOE = 3,000
Occupational LOC for MOE = 300.
Rabbit - 90-Day inhalation
LOAEL = 28 mg/kg/day based on vacuolation of white matter in the brain of femalesNOTE: The following are some of the abstracts available on fluoride and the brain.
There is a considerable number of papers, not included below, on brain effects from
Aluminum fluoride, other inorganic fluroides, and G-proteins, and the brain. Some of
these are available at http://www.fluorideaction.org/abstracts.page.htm
This long-term (52 weeks), low dose rat study found that when rats were fed either aluminum fluoride (AlF3) or sodium fluoride (NaF) at a fluoride level of 1 ppm in doubly-distilled, deionized drinking water it led to kidney damage, brain damage, a greater uptake of aluminum into the brain, and the occurrence of beta amyloid plagues. Beta amyloid plaques are a classic marker for Alzheimer's Disease. The authors speculate that fluoride facilitates aluminum to cross the blood brain barrier (BBB) and for the NaF exposed rats, the fluoride facilitated the aluminum in the rat chow to cross the BBB. - EC.
Brain Res 1998 Feb 16;784(1-2):284-98
Chronic administration of aluminum-fluoride or sodium-fluoride to rats in drinking water: alterations in neuronal and cerebrovascular integrity.
Varner JA, Jensen KF, Horvath W, Isaacson RL.
Psychology Department, Binghamton University, Binghamton, NY, USA.
This study describes alterations in the nervous system resulting from chronic administration of the fluoroaluminum complex (AlF3) or equivalent levels of fluoride (F) in the form of sodium-fluoride (NaF). Twenty seven adult male Long-Evans rats were administered one of three treatments for 52 weeks: the control group was administered double distilled deionized drinking water (ddw). The aluminum-treated group received ddw with 0.5 ppm AlF3 and the NaF group received ddw with 2.1 ppm NaF containing the equivalent amount of F as in the AlF3 ddw. Tissue aluminum (Al) levels of brain, liver and kidney were assessed with the Direct Current Plasma (DCP) technique and its distribution assessed with Morin histochemistry. Histological sections of brain were stained with hematoxylin & eosin (H&E), Cresyl violet, Bielschowsky silver stain, or immunohistochemically for beta-amyloid, amyloid A, and IgM. No differences were found between the body weights of rats in the different treatment groups although more rats died in the AlF3 group than in the control group. The Al levels in samples of brain and kidney were higher in both the AlF3 and NaF groups relative to controls. The effects of the two treatments on cerebrovascular and neuronal integrity were qualitatively and quantitatively different. These alterations were greater in animals in the AlF3 group than in the NaF group and greater in the NaF group than in controls. Copyright 1998 Elsevier Science B.V.
Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi. 2003 Apr;21(2):102-4.
[Studies on fluoride concentration and cholinesterase activity in rat hippocampus]
[Article in Chinese]
Zhai JX, Guo ZY, Hu CL, Wang QN, Zhu QX.
School of Public Health, Anhui Medical University, Hefei 230032, China.
OBJECTIVE: To study the accumulation of fluoride in rat hippocampus and its effect on cholinesterase activity.
METHODS: Rats were subchronically exposed to NaF, and fluoride concentration and cholinesterase activity in rat hippocampus were determined.
RESULTS: Fluoride concentration in rat hippocampus was significantly correlated with the dosage of fluoride, and there were significant differences among high dosage group [(13.03 +/- 1.79) micro g/g], low dosage group [(9.83 +/- 0.92) micro g/g] and control [(8.27 +/- 1.11) micro g/g], P < 0.01. Acetylcholinesterase activities among three groups [(0.111 +/- 0.031) micro mol/mg, (0.143 +/- 0.025) micro mol/mg, (0.183 +/- 0.027) micro mol/mg] were also significantly different (P < 0.01), which was negatively correlated with fluoride concertration in rat hippocampus (r = -0.700, P < 0.01). The activity of butylcholinesterase in high dosage group [(0.041 +/- 0.010) micro mol/mg] was different from that of control [(0.067 +/- 0.025) micro mol/mg, P < 0.05], but the activity was not significantly related with fluoride concertration in rat hippocampus (r = -0.317, P = 0.094).
CONCLUSION: Fluoride may go through the blood-brain barrier and accumulate in rat hippocampus, and inhibit the activity of cholinesterase.
Indian J Exp Biol. 2002 May;40(5):546-54.
Neurotoxicity of fluoride: neurodegeneration in hippocampus of female mice.
Bhatnagar M, Rao P, Sushma J, Bhatnagar R.
Department of Zoology, M.L.S. University, Udaipur 313 001, India. mbhatnagar@yahoo.com
Light microscopic study of hippocampal sub-regions demonstrated significant number of degenerated nerve cell bodies in the CA3, CA4 and dentate gyrus(Dg) areas of sodium fluoride administered adult female mice. Ultrastructural studies revealed neurodegenrative characteristics like involution of cell membranes, swelling of mitochondria, clumping of chromatin material etc, can be observed in cell bodies of CA3, CA4 and dentate gyrus (Dg). Fluoride intoxicated animals also performed poorly in motor co-ordination tests and maze tests. Inability to perform well increased with higher fluoride concentration in drinking water.
Zhonghua Yu Fang Yi Xue Za Zhi. 2002 Jul;36(4):222-4.
[Studies on DNA damage and apoptosis in rat brain induced by fluoride]
[Article in Chinese]
Chen J, Chen X, Yang K, Xia T, Xie H.
Department of Environmental Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
OBJECTIVE: To explore the DNA damage effects and apoptosis in brain cells of rats induced by sodium fluoride.
METHODS: SD rats were divided into two groups, i.e. control group and fluoride treated group, which were injected intraperitoneally with distilled water and sodium fluoride (20 mg.kg(-1).d(-1)) respectively. On the hand, 5 mmol/L NaF were used in in vitro study. Single Cell Gel Electrophosis (SCGE or Comet Assay) was utilized to measured DNA damage and apoptosis was detected by the TUNEL method and Flow Cytometry (FCM).
RESULTS: The DNA damage in pallium neurons in rats of the fluoride group was much more serious compared with those of the control group, with the Ridit value being 0.351 and 0.639 respectively (P < 0.01) in vivo, and 0.384 4 and 0.650 1 respectively (P < 0.01) in vitro. TUNEL positive cells were found in pallium, hippocampus and cerebellar granule cells in rats of fluoride group, whereas those in the control group were rare. It was demonstrated by FCM results that the percentages of apoptotic cells both in pallium and hippocampus were significantly higher (P < 0.01) in rats of fluoride group (27.12 +/- 3.08, 34.97 +/- 5.46) than those in control group (4.63 +/- 0.98, 5.35 +/- 0.79), (P < 0.01).
CONCLUSION: Sodium fluoride could induce DNA damage and apoptosis in rats brain.
Fluoride 2002; 35(3):153-160.
Brain lipid peroxidation and antioxidant systems of young rats in chronic fluoride intoxication.
Shivarajashankara YM et al.Summary: A study was made of the effect of fluoride on oxidative stress in rats during their early stages in life. Wistar albino rats were exposed to 30 ppm and 100 ppm fluoride (from sodium fluoride) in drinking water during the last one week of intrauterine life and then up to ten weeks after birth. Oxidative stress was evaluated by the assays of malondialdehyde and antioxidants in brain homogenates. Malondialdehyde (MDA), the marker of extent of lipid peroxidation, was elevated in the brain of rats treated with 100 ppm fluorde but was without change in rats treated at 30 ppm fluoride. Levels of total gluthathione, reduced glutathione (GSH), and ascorbic acid (vitamin C) were elevated in 30 ppm fluoride-treated rats, while these levels decreased in 100 ppm fluoride-treated rats. The activity of glutathione peroxidase (GSH-Px) was elevated significantly in both 30 ppm and 100 ppm fluoride-treated rats. Glutathione S-transferease (GST) activity in the brain increased with 30 ppm and 100 ppm fluoride, and greater elevation occurred in 30 ppm. These results suggest that fluoride enhances oxidative stress in the brain, thereby disturbing the antioxidant defense of rats Increased oxidative stress could be one of the mediating factors in the pathogenesis of fluoride toxicity in the brain.
-- Excerpts:
-- Introduction: Fluorosis, caused by long-term intake of high levels of fluoride, is characerized by clinical manifestations in bones and teeth (1). However, detrimental effecs of high-fluoride intake are also observed in soft tissues (2,3). In advanced stages of fluorosis, neurological manifestations such as paralysis of limbs, vertigo, spasticity in extremities, and impaired mental acuity, are observed in human beings (4). Fluoride accuulation was observed in the brain of rats exposed to chronic high-fluroide intake through drinking water (5). Intake of high levels of fluoride is known to cause structural changes (2,6), altered activities of enzymes (7), and metabolic lesions (8,9) in the brain of experimental animals.
-- Increased free radical generation and lipid peroxidation are proposed to mediate the toxic effects of fluoride on soft tissues (10-12). Earlier, we reported increased lipid peroxidation and disturbed antioxidant defense systems in brain, erythrocytes and liver of rats exposed to high-fluoride intake during the stages of life after weaning (13). There is, however a paucity of studies on the effect of fluoride intoxication during the early developing stages of life on oxidative stress. Recently, we observed increased lipid peroidation and altered levels of antioxidants in the blood of children with endemic skeletal fluorosis (14) and in the liver of young rats exposed to high levels of fluoride in drinking water during the early stages of life (15)...
Brain Res Dev Brain Res. 2002 Jan 31;133(1):69-75.
Ontogenetic development of the G protein-mediated adenylyl cyclase signalling in rat brain.
Ihnatovych I, Novotny J, Haugvicova R, Bourova L, Mares P, Svoboda P.
Department of Developmental Epileptology, Institute of Physiology, Academy of Sciences, Vijdenska 1083, 142 20 Prague 4, Czech Republic.
Maturation of the brain adenylyl cyclase (AC) signalling system was investigated in the developing rat cortex, thalamus and hippocampus. Expression of AC type II, IV and VI measured by Western blot dramatically increased in all tested brain regions during the first 3 weeks after birth and these levels were maintained in adulthood. AC type I did not change during ontogenesis. In parallel, AC enzyme activities were determined in order to obtain the functional correlates to the preceding structural (immunoblot) analyses of trimeric G proteins [Ihnatovych et al., Dev. Brain Res. (2002) in press]. Surprisingly, basal, manganese-, fluoride-, forskolin- and GTP-stimulated adenylyl cyclase developed similarly. The relatively low enzyme activities, which were determined at birth, progressively increased (about four times) to a clear maximum around postnatal day PD 12. This was followed by a progressive regression to adulthood so that activity of AC at PD 90 was comparable with the low neonatal level. The peak of AC activities at PD 12 was detected in all tested brain regions. Stimulatory (isoproterenol) effect on basal AC activity as well as inhibitory (baclofen) effect on forskolin-stimulated AC activity were unchanged between PD 12 and PD 90. Thus, comparison of results of the structural and functional analyses of adenylyl cyclase signalling system revealed a clear dissociation between the increase in the amount protein of various AC isoforms and the decrease of total G-protein mediated enzyme activities between PD 12 and adulthood. As none of the complex changes in trimeric G protein levels can explain this difference, the future research has to be oriented to identification of potential negative regulators of AC in the course of brain development. Among these, the newly discovered group of GTPase activating proteins, RGS, appears to be of primary importance because these proteins represent potent negative regulators of any G protein-mediated signalling in brain.
Wei Sheng Yan Jiu. 1999 Jul;28(4):210-2.
[Effect of fluoride exposure on synaptic structure of brain areas related to learning-memory in mice]
[Article in Chinese]
Zhang Z, Xu X, Shen X, Xu X.
Department of Biology, Zhejiang Normal University, Jinhua 321004, China.The learning-memory behavior was tested in mice on a Y-maze after drinking different concentration of sodium fluoride. The impairment on the structure of Gray 1 synaptic interface in the CA3 area of mice hippocampus were quantitatively analyzed by electron microscopy and computer image processing appliance. The main results are as follows: the learning ability of mice drinking high concentration of fluoride presented remarkable deterioration, the thickness of post-synaptic density (PSD) was decreased, and the width of synaptic cleft was remarkably increased. The results suggested that the impairment on the learning capability induced by fluorosis may be closely related with the pathological changes of synaptic structure in the brain of mice.
Arch Physiol Biochem. 1999 Feb;107(1):15-21.
Fluoride enhances the effect of aluminium chloride on interconnections between aggregates of hippocampal neurons.
van der Voet GB, Schijns O, de Wolff FA.
Toxicology Laboratory Leiden University Medical Center Leiden, The Netherlands.
The role of fluoride in aluminium neurotoxicity was studied using an in vitro system of cultured hippocampal neurons from foetal rats. Sodium fluoride (50 microM) and aluminium chloride (12.5 microM) were administered alone or in a specific combination (50 + 12.5 microM) in a 14-day culture in a chemically defined medium before staining of neurofilaments. Neuronal aggregates interconnected by neuritic fibers were detected light microscopically in control cultures. The aggregates and the fibers stained positive for neurofilament proteins. In cultures treated with aluminium chloride the development of the interconnecting fibers was affected, resulting in a fusion pattern of the aggregates. This phenomenon was enhanced when sodium fluoride was given together with aluminum chloride. It was concluded that aluminium interferes with the metabolism of the neuronal cytoskeleton and that this interference is potentiated by fluoride.
Neurotoxicol Teratol. 1995 Mar-Apr;17(2):169-77.
Neurotoxicity of sodium fluoride in rats
Mullenix PJ, Denbesten PK, Schunior A, Kernan WJ.Abstract of this report as cited in Dart Special at Toxnet. -
(they incorrectly cite 1994 as year of publication)Abstract: Fluoride (F) is known to affect mineralizing tissue, but its effects on the developing brain have not been considered. This study in Sprague-Dawley rats compares behavioral outcomes, body weight, plasma and brain F levels after sodium fluoride (NaF) exposures during late gestation, at weaning or in adults. For prenatal exposures, dams received 0.13 mg/kg NaF (s.c.) 2 or 3 times daily 4 hrs apart on gestational days 14-18 or 17-19. Control dams received s.c. saline. Weanlings were given drinking water with 0, 75, 100 or 125 ppm F for 6 or 20 wks, and adults at 3 mo received water containing 100 ppm F for 6 wks. Behavior was tested in a computer pattern recognition system that classified acts in a novel environment and quantified act initiations, total times and time structures. Prenatal weanling and adult exposures all caused sex- and dose-specific behavioral deficits with a common pattern. Males were most sensitive to prenatal day 17-19 exposure, while females were more sensitive to weanling and adult exposures. After weanling and adult exposures the severity of deficits increased with increasing F levels found in plasma and specific brain regions such as the hippocampus. The plasma levels associated with behavioral deficits in this rat model are similar to those found in humans ingesting 5 and 10 ppm F in drinking water, but they are much lower than the peaks found in children receiving topical applications of an acidulated phosphate fluoride (1.23% F) gel.
Fluoride 2000. Vol. 33 No. 1:17-26.
EFFECTS OF FLUORIDE ACCUMULATION ON SOME ENZYMES OF BRAIN AND GASTROCNEMIUS MUSCLE OF MICE
M Lakshmi Vani and K Pratap Reddy
Summary: This study reports accumulation of fluoride and altered activities of some enzymes involved in free-radical metabolism and membrane function in whole brain and gastrocnemius muscle of female mice treated with NaF (20mg/kg/body weight) for 14 days. The body weight and somatic index were decreased, whereas fluoride levels were significantly increased (p<0.01) in both brain and gastrocnemius muscle. The enzymes SOD, GST, and catalase decreased significantly (p<0.01) in contrast to XOD activity, which moderately increased. SDH, LDH, AlAT, AAT, and CPK activities and membrane-bound enzymes, viz Na + -K + , Mg ++ and Ca ++ ATPase and AChE were decreased significantly (p<0.01) in both brain and gastrocnemius muscle. The effect of fluoride on enzymes of muscle was comparatively larger, which corroborates the greater accumulation of fluoride in muscle than brain. This study therefore shows that both brain and muscle are affected by fluoride with inhibition of some enzymes associated with free-radical metabolism, energy production and transfer, membrane transport, and synaptic transmission, but with an enhanced activity of XOD.
Neuroscience 2003. 119(1):265-75
Excitatory gaba input directly drives seizure-like rhythmic synchronization in mature hippocampal CA1 pyramidal cells.
Fujiwara-Tsukamoto Y, Isomura Y, Nambu A, Takada M.
Department of System Neuroscience, Tokyo Metropolitan Institute for Neuroscience, 2-6 Musashidai, Fuchu, 183-8526, Tokyo, Japan
GABA, which generally mediates inhibitory synaptic transmissions, occasionally acts as an excitatory transmitter through intense GABA(A) receptor activation even in adult animals. The excitatory effect results from alterations in the gradients of chloride, bicarbonate, and potassium ions, but its functional role still remains a mystery. Here we show that such GABAergic excitation participates in the expression of seizure-like rhythmic synchronization (afterdischarge) in the mature hippocampal CA1 region. Seizure-like afterdischarge was induced by high-frequency synaptic stimulation in the rat hippocampal CA1-isolated slice preparations. The hippocampal afterdischarge was completely blocked by selective antagonists of ionotropic glutamate receptors or of GABA(A) receptor, and also by gap-junction inhibitors. In the CA1 pyramidal cells, oscillatory depolarizing responses during the afterdischarge were largely dependent on chloride conductance, and their reversal potentials (average -38 mV) were very close to those of exogenously applied GABAergic responses. Moreover, intracellular loading of the GABA(A) receptor blocker fluoride abolished the oscillatory responses in the pyramidal cells. Finally, the GABAergic excitation-driven afterdischarge has not been inducible until the second postnatal week. Thus, excitatory GABAergic transmission seems to play an active functional role in the generation of adult hippocampal after discharge, in cooperation with glutamatergic transmissions and possible gap junctional communications. Our findings may elucidate the cellular mechanism of neuronal synchronization during seizure activity in temporal lobe epilepsy.
Free full text article at http://www.jbc.org/cgi/reprint/M302130200v1.pdf
J Biol Chem 2003. Apr 3; [epub ahead of print]
Atypical effect of salts on the thermodynamic stability of human prion protein
Apetri AC, Surewicz WK.
Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44106.
Prion diseases are associated with the conversion of cellular prion protein, PrP(C), into a misfolded oligomeric form, PrP(Sc). Previous studies indicate that salts promote conformational conversion of the recombinant prion protein into a PrP(Sc)-like form. To gain insight into the mechanism of this effect, here we have studied the influence of a number of salts (sodium sulfate, sodium fluoride, sodium acetate and sodium chloride) on the thermodynamic stability of the recombinant human prion protein. Chemical unfolding studies in urea show that at low concentrations (below approximately 50 mM), all salts tested significantly reduce the thermodynamic stability of the protein. This highly unusual response to salts was observed for both the full-length prion protein as well as the N-truncated fragments huPrP90-231 and huPrP122-231. At higher salt concentrations, the destabilizing effect was gradually reversed, and salts behaved according to their ranking in the Hofmeister series. The present data indicate that electrostatic interactions play an unusually important role in the stability of the prion protein. The abnormal effect of salts is likely due to the ion-induced destabilization of salt bridges (Asp144-Arg148 and/or Asp147-Arg151) in the extremely hydrophilic helix 1. Contrary to previous suggestions, this effect is not due to the interaction of ions with the glycine-rich flexible N-terminal region of the prion protein. The results of this study suggest that ionic species present in the cellular environment may control the PrP(C) to PrP(Sc) conversion by modulating the thermodynamic stability of the native PrP(C) isoform.
Indian J Exp Biol 2002 May;40(5):546-54
Neurotoxicity of fluoride: neurodegeneration in hippocampus of female mice.
Bhatnagar M, Rao P, Sushma J, Bhatnagar R.
Department of Zoology, M.L.S. University, Udaipur 313 001, India. mbhatnagar@yahoo.com
Light microscopic study of hippocampal sub-regions demonstrated significant number of degenerated nerve cell bodies in the CA3, CA4 and dentate gyrus(Dg) areas of sodium fluoride administered adult female mice. Ultrastructural studies revealed neurodegenrative characteristics like involution of cell membranes, swelling of mitochondria, clumping of chromatin material etc, can be observed in cell bodies of CA3, CA4 and dentate gyrus (Dg). Fluoride intoxicated animals also performed poorly in motor co-ordination tests and maze tests. Inability to perform well increased with higher fluoride concentration in drinking water.
Fluoride 2002; 35(3):153-160
Brain lipid peroxidation and antioxidant systems of young rats in chronic fluoride intoxicationShivarajashankara YM (a), Shivashankara AR (a), Bhat PG (b), Rao SH (c)(a) For Correspondence: YM Shivarajashankara, Dept. of Biochemistry, MR Medical College, Gulbarga-585105, Karnataka, India. E-mail: shivrajsym@yahoo.com
(b) Dept. of Biochemistry, Kasturba Medical College, Karnataka, India
(c) Dept. of Biochemistry, KBN Institute of Medical Sciences, Karnataka, IndiaSummary: A study was made of the effect of fluoride on oxidative stress in rats during their early stages in life. Wistar albino rats were exposed to 30 ppm and 100 ppm fluoride (from sodium fluoride) in drinking water during the last one week of intrauterine life and then up to ten weeks after birth. Oxidative stress was evaluated by the assays of malondialdehyde and antioxidants in brain homogenates. Malondialdehyde (MDA), the marker of extent of lipid peroxidation, was elevated in the brain of rats treated with 100 ppm fluorde but was without change in rats treated at 30 ppm fluoride. Levels of total gluthathione, reduced glutathione (GSH), and ascorbic acid (vitamin C) were elevated in 30 ppm fluoride-treated rats, while these levels decreased in 100 ppm fluoride-treated rats. The activity of glutathione peroxidase (GSH-Px) was elevated significantly in both 30 ppm and 100 ppm fluoride-treated rats. Glutathione S-transferease (GST) activity in the brain increased with 30 ppm and 100 ppm fluoride, and greater elevation occurred in 30 ppm. These results suggest that fluoride enhances oxidative stress in the brain, thereby disturbing the antioxidant defense of rats Increased oxidative stress could be one of the mediating factors in the pathogenesis of fluoride toxicity in the brain.
Excerpt:
Introduction: Fluorosis, caused by long-term intake of high levels of fluoride, is characerized by clinical manifestations in bones and teeth (1). However, detrimental effecs of high-fluoride intake are also observed in soft tissues (2,3). In advanced stages of fluorosis, neurological manifestations such as paralysis of limbs, vertigo, spasticity in extremities, and impaired mental acuity, are observed in human beings (4). Fluoride accuulation was observed in the brain of rats exposed to chronic high-fluroide intake through drinking water (5). Intake of high levels of fluoride is known to cause structural changes (2,6), altered activities of enzymes (7), and metabolic lesions (8,9) in the brain of experimental animals.Increased free radical generation and lipid peroxidation are proposed to mediate the toxic effects of fluoride on soft tissues (10-12). Earlier, we reported increased lipid peroxidation and disturbed antioxidant defense systems in brain, erythrocytes and liver of rats exposed to high-fluoride intake during the stages of life after weaning (13). There is, however a paucity of studies on the effect of fluoride intoxication during the early developing stages of life on oxidative stress. Recently, we observed increased lipid peroidation and altered levels of antioxidants in the blood of children with endemic skeletal fluorosis (14) and in the liver of young rats exposed to high levels of fluoride in drinking water during the early stages of life (15)...
References:
1. Bhussry BR et al. (1970). Toxic effects of larer doses of fluoride. In: Fluorides and human health. Geneva: WHO; p 225-73.
2. Zhavoronkov AA (1977). Non-skeletal forms of fluorosis. Arch Pathol 39:83-91.
3. Monsour PA, Kruger BJ (1985). Effect of fluoride on soft tissues in vertebrates. Fluoride 1985; 18:53-61
4. Waldbott GL et al. (1978). Fluoridation: the great dilemma. Lawrence, Kansas: Coronado Press.
5. Mullenix PJ et al. (1995). Neurotoxicity of sodium fluoride in rats. Neurotoxicol Teratol 17:169-77.
6. Shivarajashankara YM et al, (2002). Histological changes in the brain of young fluoride-intoxicated rats. Fluoride 35:12-21.
7. Vani ML, Reddy KP (2000). Effect of fluoride accumulation on some enzymes of brain and gastrocnemius muscle of mice. Fluoride 33:17-26.
8. Shashi A (1992). Studies on alterations in brain lipid metabolism following experimental fluorosis. Fluoride 25:77-84.
9. Shashi A et al. (1994). Effect of long-term administration of fluoride on levels of proteins, free animo acid and RNA in rabbit brain. Fluoide 27:155-9.
10. Patel PD, Chinoy NJ (1998). Ifluence of fluoride on biological free radical reactions in ovary of mice ad its reversal. Fluoride 31:S27.
11. Rzeuski R et al. (1998). Interactions between fluoride and bilogical free radical reactions. Fluoride 31:43-5.
12. Sharma A, Chinoy NJ (1998). Role of free radicals in fluoride-induced toxicity in liver and kidney of mice and its reversal. Fluoride 31:S26.
13. Shivarajashankara YM et al. (2001). Effect of fluoride intoxication on lipid peroxidation and antioxidant systems in rats. Fluoride 34:108-13.
14. Shivarajashankara YM et al. (2001). Oxidative stress in children with endemic skeletal fluorsis. Fluoride 34:103-7.
15. Shivashankara AR et al. (2002). Lipid peroxidation and antioxidant defense systems in liver of rats in chronic fluoride toxicity. Bull Environ Contam Toxicol 68:612-6.
Neurotoxicol Teratol 2002 Nov-Dec;24(6):751-7
Chronic fluoride toxicity decreases the number of nicotinic acetylcholine receptors in rat brain.
Long YG, Wang YN, Chen J, Jiang SF, Nordberg A, Guan ZZ.
Department of Pathology, Guiyang Medical College, 550004, Guizhou, Guiyang, PR China
In order to investigate the molecular mechanism(s) underlying brain dysfunction caused by chronic fluorosis, neuronal nicotinic acetylcholine receptors (nAChRs) in the brain of rats receiving either 30 or 100 ppm fluoride in their drinking water for 7 months were analyzed in the present study employing ligand binding and Western blotting. There was a significant reduction in the number of [3H]epibatidine binding sites in the brain of rats exposed 100 ppm of fluoride, but no alteration after exposed to 30 ppm. On the other hand, the number of [125I]alpha-BTX binding sites was significantly decreased in the brains of rats exposed to both levels of fluoride. Western blotting revealed that the level of the nAChR alpha4 subunit protein in the brains of rats was significantly lowered by exposure to 100 ppm, but not 30 ppm fluoride; whereas the expression of the alpha7 subunit protein was significantly decreased by both levels of exposure. In contrast, there was no significant change in the level of the beta2 subunit protein in the brains of rats administered fluoride. Since nAChRs play major roles in cognitive processes such as learning and memory, the decrease in the number of nAChRs caused by fluoride toxicity may be an important factor in the mechanism of brain dysfunction in the disorder.
Full report availavle at: http://www.fluoride-journal.com/02-35-1/351-12.pdf
Fluoride 2002; 35(1):12-21
Histological changes in the brain of young fluoride-intoxicated rats
YM Shivarajashankara (a), AR Shivashankara (a), P Gopalakrishna Bhat (b), S Muddanna Rao (c), S Hanumanth Rao (d)(a) Dept. of Biochemistry, MR Medical Col-lege, Gulbarga-585105, Karnataka, India; E-mail: shivrajsym@yahoo.com.
(b) Dept. of Biochemistry, Kasturba Medical College, Manipal-576119, Karnataka, India.
(c) Dept. of Anatomy, Kasturba Medical College, Manipal-576119, Karnataka, India.
(d) Dept. of Biochemistry, KBN Institute of Medical Sciences, Gulbarga-585104, Karnataka, India.SUMMARY: Wistar albino rats were exposed to 30 or 100 ppm fluoride (as NaF) in drinking water during their fetal, weanling, and post-weaning stages until the age of ten weeks. Rats exposed to 30 ppm fluoride did not show any notable alterations in brain histology, whereas rats exposed to 100 ppm fluoride showed significant neurodegenerative changes in the hippocampus, amygdala, motor cortex, and cerebellum. Changes included decrease in size and number of neurons in all the regions, decrease in the number of Purkinje cells in the cerebellum, and signs of chromatolysis and gliosis in the motor cortex. These histological changes suggest a toxic effect of high-fluoride in-take during the early developing stages of life on the growth, differentiation, and subcellular organization of brain cells in rats.
Zhonghua Yu Fang Yi Xue Za Zhi 2002 Jul;36(4):222-224
Studies on DNA damage and apoptosis in rat brain induced by fluoride.
Chen J, Chen X, Yang K, Xia T, Xie H.
Department of Environmental Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
OBJECTIVE: To explore the DNA damage effects and apoptosis in brain cells of rats induced by sodium fluoride.
METHODS: SD rats were divided into two groups, i.e. control group and fluoride treated group, which were injected intraperitoneally with distilled water and sodium fluoride (20 mg.kg(-1).d(-1)) respectively. On the hand, 5 mmol/L NaF were used in in vitro study. Single Cell Gel Electrophosis (SCGE or Comet Assay) was utilized to measured DNA damage and apoptosis was detected by the TUNEL method and Flow Cytometry (FCM).
RESULTS: The DNA damage in pallium neurons in rats of the fluoride group was much more serious compared with those of the control guoup, with the Ridit value being 0.351 and 0.639 respectively (P < 0.01) in vivo, and 0.384 4 and 0.650 1 respectively (P < 0.01) in vitro. TUNEL positive cells were found in pallium, hippocampus and cerebellar granule cells in rats of fluoride group, whereas those in the control group were rare. It was demonstrated by FCM results that the percentages of apoptotic cells both in pallium and hippocampus were significantly higher (P < 0.01) in rats of fluoride group (27.12 +/- 3.08, 34.97 +/- 5.46) than those in control group (4.63 +/- 0.98, 5.35 +/- 0.79), (P < 0.01).
CONCLUSION: Sodium fluoride could induce DNA damage and apoptosis in rats brain.
Wei Sheng Yan Jiu 2001 May;30(3):144-6
[Effects of selenium on the damage of learning-memory ability of mice induced by fluoride]
[Article in Chinese]
Zhang Z, Shen X, Xu X.
College of Life and Environmental Science, Zhejiang Normal University, Jinhua 321004, China.
Sodium fluoride added with or without sodium selenite in deionized water was administered to male mice for 8 weeks. The influences of fluoride on learning-memory behavior were tested on Y-maze, and the ultrastructure of Gray I synaptic interface in the CA3 area hippocampus was quantitatively analyzed by electron microscopy and computer image processing appliance. The main results showed that the learning capability of mice drinking higher concentration of fluoride presented remarkable deterioration. The thickness of post-synaptic density (PSD) was decreased. The width of the synaptic cleft was remarkably increased. It was found that combined administration of fluoride and proper concentration of selenium could decrease the toxic effect of fluoride. There were synergetic toxicities if the concentration of selenium was too high. The results suggested that selenium might antagonize the neurotoxicity of fluoride on behavior and morphology.
Full report available at: http://www.fluoride-journal.com/01-34-3/343-165.pdf
Fluoride 2001; 34(3 ):165-173
Effect of fluoride on thyroid function and cerebellar development in mice
Mahmoud Trabelsi (a), Fadhel Guermazi (b), Najiba Zeghal (c)(a) Synthesis and Physical-Organic Chemistry Laboratory, Faculty of Sciences-Sfax;
(b) Nuclear Medicine Service, CHU Habib Bourguiba-Sfax.
(c) For correspondence: Dr N Zeghal, Animal Physiology Laboratory, Department of Biology, FacultŽ des Sciences de Sfax-Route de la Soukra-Km 3.5, 3038 Sfax BP802, Tunisia. Email: Nejiba.Zghal@fss.rnu.tnSUMMARY: The effect of fluoride on murine thyroid function and cerebellar development was studied by administering NaF in drinking water (0.5 g/L) to pregnant and lactating mice, from the 15th day of pregnancy to the 14th day after delivery. Compared to a control group, the NaF-treated pups, at age 14 days, showed a 35% decrease in body weight, a 75% decrease in plasma free T4, and reductions in the cerebellar and cerebral protein concentrations by 27% and 17%, respectively. Consistent histological changes were present in the cerebellum of the treated mice with the external granular layer being markedly reduced or absent, the Purkinje cell bodies being poorly differenti-ated and arranged in a single layer at the surface of the internal granular layer, and with more apoptotic Purkinje cells being present.
J Epidemiol 2001 Jul;11(4):170-9
Regression analysis of cancer incidence rates and water fluoride in the U.S.A. based on IACR/IARC (WHO) data (1978-1992). International Agency for Research on Cancer.
Takahashi K, Akiniwa K, Narita K.
Department of Physical Medicine, Faculty of Medicine, University of Tokyo, Japan.
Age-specific and age-standardized rates (ASR) of registered cancers for nine communities in the U.S.A. (21.8 million inhabitants, mainly white) were obtained from IARC data (1978-82, 1983-87, 1988-92). The percentage of people supplied with "optimally" fluoridated drinking water (FD) obtained from the Fluoridation Census 1985, U.S.A. were used for regression analysis of incidence rates of cancers at thirty six sites (ICD-WHO, 1957). About two-thirds of sites of the body (ICD) were associated positively with FD, but negative associations were noted for lip cancer, melanoma of the skin, and cancers of the prostate and thyroid gland. In digestive organs the stomach showed only limited and small intestine no significant link. However, cancers of the oral cavity and pharynx, colon and rectum, hepato-biliary and urinary organs were positively associated with FD. This was also the case for bone cancers in male, in line with results of rat experiments. Brain tumors and T-cell system Hodgkin's disease, Non-Hodgkin lymphoma, multiple myeloma, melanoma of the skin and monocytic leukaemia were also correlated with FD. Of the 36 sites, 23 were positively significant (63.9%), 9 not significant (25.0%) and 4 negatively significant (11.1%). This may indicate a complexity of mechanisms of action of fluoride in the body, especially in view of the coexising positive and negative correlations with the fluoridation index. The likelihood of fluoride acting as a genetic cause of cancer requires consideration.
Full report available at http://www.fluoride-journal.com/01-34-2/342-108.pdf
Fluoride 2001; 34(2):108-113
Effect of fluoride intoxication on lipid peroxidation and antitoxidant systems in rats
YM Shivarajashankara (a), AR Shivashankara (a), P Gopalakrishna Bhat (b), S Hanumanth Rao (c)(a) YM Shivarajashankara, Dept. of Biochemistry, MR Medical Col-lege, Gulbarga-585 105, Karnataka, India; E-mail: shivrajsym@yahoo.com;
(b) Dept. of Biochemistry, Kasturba Medical College, Manipal-576 119, Karnataka, India;
(c) Dept. of Biochemistry, KBN Institute of Medical Sciences, Gulbarga-585 104, Karnataka, India.SUMMARY: The effect of fluoride intoxication on lipid peroxidation and anti-oxidant systems in the blood, brain, and liver of rats was studied. Twelve one-month-old albino rats were administered 100-ppm fluoride (as NaF) in their drinking water for four months. In the red blood cells the levels of malondial-dehyde (MDA) and glutathione (GSH) increased, along with the activity of glutathione peroxidase (GSH-Px), but the activity of superoxide dismutase (SOD) decreased. In the plasma the level of ascorbic acid increased while that of uric acid decreased. In the brain and liver, MDA and GSH levels increased, as did the activities of GSH-Px and glutathione S-transferase (GST). The level of ascorbic acid increased in the brain, but it decreased in the liver. These results suggest that fluoride enhances lipid peroxidation in the red blood cells, brain and liver of rats and causes increased or decreased enzyme activity associated with free radical metabolism.
Wei Sheng Yan Jiu 2000 Jul;29(4):216-7
[Effects of selenium and zinc on the DNA damage caused by fluoride in pallium neural cells of rats]
[Article in Chinese]
Chen J, Chen X, Yang K.
Department of Environmental Health, Tongji Medical University, Wuhan 430030, China.
To investigate the effects of fluoride on DNA damage as well as the effects of selenium and zinc against fluoride respectively or jointly in pallium neural cells of rats, single cell gel electrophoresis was used to detect the DNA damage of neural cells prepared in vitro. The results showed that the degree of DNA damage in the fluoride group and the selenium group were significantly greater than that in control group(P < 0.01). The damage in the fluoride group was even more serious. The damage in the fluoride + selenium group and fluoride + zinc group was slighter than that in the fluoride group but with no significant difference. The extent of DNA damage in the fluoride + selenium + zinc group was significantly slighter than that in the fluoride group(P < 0.05). It suggested that fluoride and selenium could induce DNA damage in pallium neural cells of rats respectively. Moreover, the joint antagonistic effect of selenium and zinc against fluoride was more obvious.• Note from FAN:
Definition of Pallium: - the central cortex with the subajacent white substance. SYN mantle [L. cloak]
- Ref: Steadman's Concise Medical Dictionary for the Health Professions. Illustrated 4th Edition. 2001. Ed. JH Dirckx. Lippincott Williams & Wilkins.
Full report available at: http://www.fluoride-journal.com/00-33-1/331-17.pdfFluoride 2000; 33(1):17-26
Effects of fluoride accumulation on some enzymes of brain and gastrocnemius muscle of mice
M Lakshmi Vani, K Pratap Reddy *
* For correspondence: Neurobiology Laboratory, Department of Zoology, Osmania University, Hyderabad - 500 007, Andhra Pradesh, India.SUMMARY: This study reports accumulation of fluoride and altered activities of some enzymes involved in free-radical metabolism and membrane function in whole brain and gastrocnemius muscle of female mice treated with NaF (20mg/kg/body weight) for 14 days. The body weight and somatic index were decreased, whereas fluoride levels were significantly increased (p<0.01) in both brain and gastrocnemius muscle. The enzymes SOD, GST, and catalase decreased significantly (p<0.01) in contrast to XOD activity, which moderately increased. SDH, LDH, AlAT, AAT, and CPK activities and membrane-bound enzymes, viz Na + -K + , Mg ++ and Ca ++ ATPase and AChE were decreased signifi-cantly (p<0.01) in both brain and gastrocnemius muscle. The effect of fluoride on enzymes of muscle was comparatively larger, which corroborates the greater accumulation of fluoride in muscle than brain. This study therefore shows that both brain and muscle are affected by fluoride with inhibition of some enzymes associated with free-radical metabolism, energy production and transfer, membrane transport, and synaptic transmission, but with an enhanced activity of XOD.
Chinese Journal of Endemiology 2000;19(4):262-3
- As cited and abstracted in Fluoride 2001; 34(1):80
Effects of high fluoride drinking water on the cerebral functions of mice
Sun Z-R, Liu F-Z, Wu L-N, et al.
For Correspondence: Department of Environmental Health, Tianjin Medical University, Tianjin 300070, China.Objective: To study the effects of high fluoride concentration in drinking water on the cerebral functions of mice.
Methods: Learning and memory abilities of high-fluoride exposed and control groups of mice were measured by behavior-toxicological test (Shuttle box Test), and the cholinesterase (ChE) activity in brain tissue homogenate of the mice was determined.
Results: Learning and memory abilities of high-fluoride exposed groups were significantly lower than that of the control group, while the brain ChE activities of high-fluoride exposed groups were significantly higher.
Conclusions: High fluoride concentration in drinking water can decrease the cerebral functions of mice. Fluoride is a neurotoxicant.
Chinese Journal of Endemiology 2000;19(2):96-8
- As cited and abstracted in Fluoride 2001; 34(1):82
Study of the mechanism of neurone apoptosis in rats from the chronic fluorosis
Lu X-H, Li G-S, Sun B
For Correspondence: Institute of Endemi c Diseases in Nornman Bethune University of Medical Sciences, Changchun 130021, ChinaObjective: Study the mechanism of action chronic fluorosis in neurones.
Methods: Terminal deoxyribo-nucleotide transferase-mediated dUTP-biotin nick end labeling (TUNEL) and flow cytometry (FCM) were used to observe changes of apoptosis in cerebral cells in chronic fluorosis in rats.
Results: TUNEL results show non-random expression of DAB positive stain apoptosis cells which appear only in the hippocampus CA4 region. FCM re-sults show that the percentage of DNA fragmentation increased markedly in the cerebral neurones of rats with chronic fluorosis but not in different cerebral regions.
Conclusions: There is a tendency for neurone apoptosis in chronic fluorosis in rats. It is most evident with changes in pathology. It is not likely that only one form of neurone damage exist in the process of chronic fluorosis. There are recessive changes and apoptosis in the process at the same time.
Zhonghua Yu Fang Yi Xue Za Zhi 2000 Nov;34(6):330-2
[Influence of free radical inducer on the level of oxidative stress in brain of rats with fluorosis]
[Article in Chinese]
Shao Q, Wang Y, Guan Z.
Department of Neurology, Guiyang Medical College, Guizhou 550004, China.
OBJECTIVE: To study changes in content of lipid peroxide and compositon of fatty acids in the brain of rats afflicated with chronic fluorosis after treatment with free radical inducer (ferric ion).
METHODS: Thirty-six Wistar rats were divided into three groups, fed with similar fodder and varied concentrations of fluoride in drinking water, and were killed five months after treatment. Lipid peroxidation was induced by ferric ions. Malondialdehyde content in brain was analysed by high-performance liquid chromatography; oxygen consumption was determined with an oxygen electrode and fatty acid composition was measured by gas chromatography in brain tissues of the rats.
RESULTS: In the brain tissues, content of malondialdehyde and oxygen consumption increased, composition of polyunsaturated fatty acids decreased and that of saturated fatty acids decreased after treatment with free radical inducer in the treated group, as compared with those in control group.
CONCLUSION: Over uptake of fluoride for a long term could cause potantial increase in the level of oxidative stress in the brain tissue.
Int J Dev Neurosci 1999 Jul;17(4):357-67
Fluoride-induced depletion of polyphosphoinositides in rat brain cortical slices: a rationale for the inhibitory effects on phospholipase C.
Sarri E, Claro E.
Departament de Bioquimica i de Biologia Molecular, Facultat de Medicina, Universitat Autonoma de Barcelona, Spain.
Fluoride, which is used commonly as a pharmacological tool to activate phosphoinositide-phospholipase C coupled to the heterotrymeric Gq/11 proteins, inhibited the phosphorylation of phosphatidylinositol (PtdIns) to polyphosphoinositides (PtdIns4P and PtdIns4,5P2) in membranes from rat brain cortex. Fluoride enhanced basal production of 3H-inositol phosphates in membranes prepared from brain cortical slices that had been prelabeled with [3H]inositol, but inhibited the stimulation elicited by carbachol in the presence of GTPgammaS. However in both cases fluoride depleted [3H]PtdIns4P content by 95%. The inhibitory effects of fluoride on the release of 3H-inositol phosphates in slices were not apparent in a pulse [3H]inositol-labeling strategy, but became dramatic in a continuous labeling protocol, particularly at long incubation times. Prelabeling slices with [3H]inositol in the presence of fluoride precluded polyphosphoinositide labeling, and eliminated phospholipase C responsiveness to carbachol under normal or depolarizing conditions, and to the calcium ionophore ionomycin. The lack of response of 3H-polyphosphoinositide-depleted slices to phospholipase C stimuli was not due to fluoride poisoning, unaccessibility of the [3H]inositol label to phospholipase C or desensitization of Gq/11, as the effect of carbachol and GTPgammaS was restored, in the presence of ATP, in membranes prepared from slices that had been labeled in the presence of fluoride. In conclusion, our data show that fluoride, at a concentration similar to that used to stimulate directly Gq/11-coupled phospholipase C, effectively blocks the synthesis of phospholipase C substrates from PtdIns.
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.
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.
Zhonghua Yu Fang Yi Xue Za Zhi 1997 Nov;31(6):330-3
[Changes of coenzyme Q content in brain tissues of rats with fluorosis]
[Article in Chinese]
Wang Y, Guan Z, Xiao K.
Department of Scientific Research, Guiyang Medical College.Animal models with pathological damage caused by chronic fluorosis to a different extent were duplicated in Wistar rats by feeding them with 66.3 mg/L and 221 mg/L fluorine-containing water for three, five and seven months, respectively. Cholesterol, dolichol and coenzyme Q in animal brain tissues were determined by high performance liquid chromatography. Results showed that no significant difference of cholesterol and dolichol contents in brian tissues between rats with fluorosis and normal controls were detected. Coenzyme Q content of brain tissue in rats fed with fluorine-containing water decreased at early stage of fluorosis, but increased significantly at late stage. It is speculated that changes in content of coenzyme Q could correlate with changes in free radical levels induced by fluorine.
Zhonghua Yi Xue Za Zhi 1997 Aug;77(8):592-6
[Influence of experimental fluorosis on phospholipid content and fatty acid composition in rat brain]
[Article in Chinese]
Guan Z, Wang Y, Xiao K.
Guiyang Medical College.
OBJECTIVE: To investigate the pathogenesis of brain damage by fluoride intoxication, phospholipid content, and fatty acid composition in rat brain with fluorosis were annlysed.
METHODS: Wistar rats were fed with NaF in various amounts and time periods to produce the animal model with chronic fluorosis. Phospholipid content and fatty acids composition were analysed using high performance liquid chromatography and gas chromatography, respectively.
RESULTS: All animals fed with high amount of fluoride suffered from chronic fluorosis. The total brain phospholipid content was lower in the rat treated with fluoride, which mainly influenced phosphatidylethanolamine, phosphatidylcholin, and phosphatidylserine. No modifications were detected in fatty acid and aldehyde compositions of individual phospholipid classes.
CONCLUSION: The metabolism of brain phospholipid might be interfered by fluoride accumulated in brain tissue, which is related with the degeneration of neuron. The changes of brain phospholipid could be involved in the pathogenesis of chronic fluorosis.
Mol Cell Biochem 1997 Nov;176(1-2):317-26
Regulation of Ca2+ homeostasis by glucose metabolism in rat brain.
Nijjar M, Belgrave RL.
Department of Anatomy and Physiology, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, Canada.
In a previous communication we reported that glucose deprivation from KHRB medium resulted in a marked stimulation of Ca2+ uptake by brain tissue, suggesting a relationship between glucose and Ca2+ homeostasis in brain tissue. Experiments were carried out to investigate the significance of glucose in Ca2+ transport in brain cells. The replacement of glucose with either D-methylglucoside or 2-deoxyglucose, non-metabolizable analogues of glucose, resulted in stimulation of Ca2+ uptake just as by glucose deprivation. These data show that glucose metabolism rather than glucose transfer was necessary to stimulate Ca2+ uptake in brain tissue. Inhibition of glucose metabolism with either NaF, NaCN, or iodoacetate resulted in stimulation of Ca2+ uptake similar to that produced by glucose deprivation. These results lend further support for the concept that glucose metabolism is essential for Ca2+ homeostasis in brain. Anoxia promotes glucose metabolism through glycolytic pathway to keep up with the demand for ATP by cellular processes (the Pasteur effect). Incubation of brain slices under nitrogen gas did not alter Ca2+ uptake by brain tissue, as did glucose deprivation and the inhibitors of glucose metabolism. We conclude that glucose metabolism resulting in the synthesis of ATP is essential for Ca2+ homeostasis in brain. Verapamil and nifedipine which block voltage-gated Ca2+ channels, did not alter Ca2+ uptake stimulated by glucose deprivation, indicating that glucose deprivation-enhanced Ca2+ uptake was not mediated by Ca2+ channels. Tetrodotoxin which specifically blocks Na2+ channels, abolished Ca2+ uptake enhanced by glucose deprivation, but had no effect on Ca2+ uptake in presence of glucose (controls). These results suggest that stimulation of Ca2+ uptake by glucose deprivation may be related to Na2+ transfer via NaCa exchange in brain.
From Toxnet
FASEB J 1997 Feb;11(3):A406
Effects of fluoride and aluminum exposure to dams prior to and during gestation on mineral compositions of bone and selected soft tissues of female mice dams and pups.
Koh ET, Clarke SL
Univ. of Oklahoma Health Sci. Center, Oklahoma City, OK.Abstract: Sixty-four CD-1 female mice were assigned to onez of four water treatment groups: Control (distilled, deionized water) (C); Fluoride (50 ppm F as NaF) (F); Aluminum (100 ppm Al as AlCl3) (Al); and Al & F (50 ppm F & 100 ppm Al) (AlF). One-half of the animals in each group were mated. The study was terminated on the 5th days after parturition. Pregnancy and lactation (P & L) reduced tibia Al more than 50% in the C, F, and Al groups, and 34% in the AlF group. In contrast, brain Al increased 168% in the F group, and 260% to 350% in the remaining three groups. P & L decreased tibia calcium (Ca) between 10% and 20% in all four groups, whereas the kidney Ca reduction ranged from 21% to 24%. However, heart Ca increased a minimum of 11% in the F group and a maximum of 169% in the AlF group. A maximum reduction of tibia zinc by pregnancy was obtained in the AlF group, reflecting the lowest fetal zinc in the group. The study demonstrated that pregnancy and lactation may increase the need of Al, Ca, and zinc in the vital organs such as brain, heart and fetus. These extra requirements may be fulfilled at the expense of the bones and less active organs such as kidneys. The study suggests that Al may be essential during pregnancy and lactation for increased cell proliferation.
No abstract available on PubMed
Ann N Y Acad Sci 1997 Oct 15;825:152-66
Toxin-induced blood vessel inclusions caused by the chronic administration of aluminum and sodium fluoride and their implications for dementia.
Isaacson RL, Varner JA, Jensen KF.
Department of Psychology, Binghamton University, New York 13902-6000, USA. isaacson@binghamton.edu
Publication Types:
Review
Review, Tutorial
Exp Gerontol 1997 Jul-Oct;32(4-5):441-50
Age-related changes in axonal transport.
Frolkis VV, Tanin SA, Gorban YN.
Institute of Gerontology, Academy of Medical Sciences of Ukraine, Ukraine.
In rats the rate of axonal transport (AT) or radiolabeled material decreased in the ventral roots of the spinal cord and the vagal and hypoglossal nerves with aging. A maximum AT deceleration in old age was observed in the vagus. The uncoupling of oxidative phosphorylation, inhibition of glycolysis and hypoxia induced a greater AT deceleration in old rats as compared to adults. Small doses of sodium fluoride accelerated AT, and this correlated with a rise in cAMP levels in ventral roots. High doses of sodium fluoride decelerated AT more markedly in old rats. It was shown that anabolic hormones (sex steroids and thyroxine) accelerated AT in both adult and old rats, whereas insulin induced a rise in AT rate in only adults. The catabolic steroid, hydrocortisone decelerated AT. In old rats castration diminished AT, while thyroidectomy had no effect. It was also shown that hydrocortisone and testosterone were transported along axons, reached fibers of the skeletal muscles, and hyperpolarized the plasma membrane. In old age the latent period was extended. Following 73 to 74 days of irradiation, AT slowed down in all the nerves studied in both adult and old rats. Following irradiation hormonal effects on AT changed, for example, the stimulatory effect of estradiol became weak, especially in old rats. Changes in AT could be an important mechanism of disordering the growth of neurons and innervated cells in old age.
J Neurosci 1996 Oct 1;16(19):5914-22
Cholinergic stimulation of AP-1 and NF kappa B transcription factors is differentially sensitive to oxidative stress in SH-SY5Y neuroblastoma: relationship to phosphoinositide hydrolysis.
Li X, Song L, Jope RS.
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham 35294-0017, USA.
Oxidative stress appears to contribute to neuronal dysfunction in a number of neurodegenerative conditions, notably including Alzheimer's disease, in which cholinergic receptor-linked signal transduction activity is severely impaired. To test whether oxidative stress could contribute to deficits in cholinergic signaling, responses to carbachol were measured in human neuroblastoma SH-SY5Y cells exposed to H2O2. DNA binding activities of two transcription factors that are respondent to oxidative conditions, AP-1 and NF kappa B, were measured in nuclear extracts. H2O2 and carbachol individually induced dose- and time-dependent increases in AP-1 and NF kappa B. In contrast, when given together, H2O2 concentration dependently (30-300 microM) inhibited the increase after carbachol in AP-1. Carbachol's stimulation of NF kappa B was not inhibited except with a high concentration (300 microM) of H2O2, which was associated with impaired activation of protein kinase C. Lower concentrations of H2O2 (30-300 microM) inhibited carbachol-induced [3H]phosphoinositide hydrolysis, and this inhibition correlated (r = 0.95) with the inhibition of carbachol-induced AP-1. Activation [3H]phosphoinositide hydrolysis by the calcium ionophore ionomycin was unaffected by H2O2, indicating that phospholipase C and phosphoinositides were impervious to this treatment. In contrast, activation with NaF of G-proteins coupled to phospholipase C was concentration dependently inhibited by H2O2, indicating impaired G-protein function. These effects of H2O2 are similar to signaling impairments reported in Alzheimer's disease brain, which involve deficits in receptor- and G-protein-stimulated phosphoinositide hydrolysis, but not phospholipase C activity. Thus, these findings indicate that oxidative stress may contribute to impaired phosphoinositide signaling in neurological disorders in which oxidative stress occurs, and that oxidative stress can differentially influence transcription factors activated by cholinergic stimulation.
Fluoride 1994; 27(3):155-159
Effect of long-term administration of fluoride on levels of protein, free amino acids and RNA in rabbit brain
Shashi A (1), Singh JP (1), Thapar SP (2)(1) Department of Zoology, Punjabi University, Patiala 14702, India
(2) Department of Anatomy, Dayanand Medical Collee and Hospital, Ludhiana, IndiaSummary: Biochemical alterations in the brain produced during experimental fluorosis were studied. Albino rabbits of both sexes were administered sodium fluoride solutions in the concentrations of 5, 10, 20, and 50 mg/kg body wt/day by subcutaneous injection for 100 days. The control rabbits were given 1 cc distilled water/kg body weight/day for the same length of time. In fluoride treated rabbits the brain showed significant decline (P <0.001) in soluble, basic total protein and free amino acid levels. RNA content rapidly decreased (P <0.001) in the brains of experimental animals compared to the controls. However, in male animals treated with 5 and 10 mg fluoride no statistically significant differences in RNA content of brain were observed. The depletion of proteins produced degenerative changes in purkinje clles of the cerebellar cortex. These changes in the brain lead to paralysis of limbs in fluoridated animals.
Zhonghua Yu Fang Yi Xue Za Zhi 1994 Sep;28(5):264-6
[Effects of sodium fluoride on the activity of Ca2+Mg(2+)-ATPase in synaptic membrane in rat brain]
[Article in Chinese]
Zhao XL, Gao WH, Zhao ZL.
Department of Environment Health Ningxia Medical College, Yinchuan.
Effects of sodium fluoride on Ca2+Mg(2+)-ATPase activity of synaptic membrane in rat brain were studied with in vitro or in vivo methods. Concentrations of sodium fluoride of 0.3, 1.6, 8.0, 20.0 and 40.0 mmol/L can significantly inhibit the activity of the enzyme with proportions of 6.6%, 18.0%, 41.0%, 55.5% and 63.1%, respectively, and with a half inhibitory concentration of 14.8 mmol/L reflecting an obvious dose-effect and time effect relationship. Analysis of enzyme substrate kinetics showed the effect that sodium fluoride had was a non competitive inhibition. Activity of Ca2+Mg(2+)-ATPase on synaptic membrane in female rat brain showed a decreasing tendency after feeding with water fluorinated with 5, 15 and 50 mg/L of fluoride during their gestation and lactation for 50 days, and that in their newborn offsprings with 5 and 50 mg/L of fluoride was inhibited by 11.3 and 32.1%, respectively.
Magn Reson Imaging 1993;11(5):697-703
Uptake and life time of fluoride ion in rats by 19F-NMR.
Scarpa M, Vianello F, Rigo A, Viglino P, Bracco F, Battistin L.
Department of Biological Chemistry, University of Padova, Italy.
19F nuclear magnetic resonance (NMR) was utilized to obtain information on the uptake and half-life time of fluoride ion in rats. Changes in tissue fluoride level after acute loading were monitored over time in blood and tissue homogenates obtained from liver and brain. The rate of fluoride elimination from various tissues was roughly similar, following in all cases a first-order kinetic rate law. The F- concentration in brain was about 20% of that found in liver, indicating a reduced fluoride diffusion across the blood-brain barrier. In vivo F- spectra were obtained in rat brain in few minutes with a good signal-to-noise ratio; this confirms the possibility of extending the use of F- as a probe of biomolecules to in vivo applications.
Zhonghua Bing Li Xue Za Zhi 1992 Aug;21(4):218-20
[The effect of fluorine on the developing human brain]
[Article in Chinese]
Du L.
Department of Pathology, Guiyang Medical College.
Fifteen therapeutically aborted fetuses at the 5th-8th gestation month from the endemic fluorosis area were compared with those from the non-endemic area. Stereological study of the brains showed that the numerical density of volume of the neurons and the undifferentiated neuroblasts as well as the nucleus-cytoplasm ratio of the neurons were increased. The mean volume of the neurons was reduced. The numerical density of volume, the volume density and the surface density of the mitochondria were significantly reduced. The results showed that chronic fluorosis in the course of intrauterine fetal life may produce certain harmful effects on the developing brain of the fetus.
Fluoride 1992; 25(2):77-84
Studies on alterations in brain lipid metabolism following experimental fluorosis
A Shashi
Department of Zoology, Punjabi University, Patala 147002, India
Summary: The neurotoxic effect of fluoride on lipid content of brain was assessed in rabbits during experimental fluorosis. Sodium fluoride at 5, 10, 20 and 50 mg/kg body weight/day was injected subcutaneously for 100 days into 60 rabbits of both sexes. The control animals were given 1 cc distilled water/kg body weight/day for the same period. Biochemical studies showed hyperlipidemia, hyperphospholipidemia, and hypertriglyceridemia in the brain of treated animals of both sexes. The maximum increase in total lipids, phospholipids and triglycerides of brain occurred in animals treated with 50 mg NaF/kg. In male rabbits, the cholesterol content of brain rose suddenly (p<0.001) in the 5 mg fluoride group, followed by gradual decline in 10, 20 and 50 mg fluoride groups. In females, the cholesterol level rose (p<0.001) in animals of the 5, 10 and 20 mg fluoride groups and fell suddenly in the 50 mg fluoride group. Fluoride exerts an inhibitory effect on the free fatty acids in brain of both sexes. The relevance of these results in experimental fluorosis is discussed.
Res 1992 Jun 26;583(1-2):155-60
Beta-adrenergic receptor activity of cerebral microvessels in experimental diabetes mellitus.
Mooradian AD, Scarpace PJ.
St. Louis DVA Medical Center, MO.
The effect of diabetes mellitus on beta-adrenergic receptor number (B(max)), receptor-cyclase coupling and adenylate cyclase (AC) activity was determined in cerebral microvessels isolated from control and streptozotocin induced diabetic rats after 5 weeks of induction of diabetes. Scatchard analysis of [125I]iodocyanopindolol (ICYP) binding indicated that the B(max) (fmol/mg) in diabetic rat cerebral microvessels (63.8 +/- 4.8) (mean +/- S.E.M.) was not significantly different from the B(max) in control rats (56.5 +/- 6.9). Isoproterenol competition of [125I]ICYP binding sites indicated that the percentage of beta-receptors expressing high affinity binding was 53.9 +/- 0.45% in control rats and 47.5 +/- 2.3% in diabetic rats. The total isoproterenol-stimulated AC activity (pmol cAMP/mg) in diabetic rats (76.7 +/- 6.1) was significantly lower than that in control rats (118.4 +/- 11.2) (P less than 0.01). However, the net isoproterenol-stimulated AC activity (i.e. total minus GTP-stimulated AC activity) was not altered in diabetes. The net sodium fluoride (NaF) stimulated AC activity in diabetic rats (109.5 +/- 11.4) was significantly lower than the control rats (154.3 +/- 16.3) (P less than 0.05). It is concluded that diabetes mellitus in rats is associated with reduced post receptor activation of adenylate cyclase in cerebral microvessels while the beta-adrenergic receptor density, affinity and receptor-cyclase coupling are not significantly altered.
Exp Brain Res 1991;84(3):680-4
Brief exposure to the G-protein activator NaF/AlCl3 induces prolonged enhancement of synaptic transmission in area CAl of rat hippocampal slices.
Publicover SJ.
School of Biological Sciences, University of Birmingham, Edgbaston, UK.
Rat hippocampal slices were exposed briefly (12-15 min) to AlF4- (10 mmol/l NaF, 10 mumol/l AlCl3). The effect on synaptic transmission in area CAl was measured using extracellular electrodes placed in the stratum pyramidale and stratum radiatum. During fluoride exposure, both spike and EPSP amplitude fell to very low levels. Upon washout, spike amplitude recovered beyond control values, and in half of the preparations a prolonged enhancement of spike amplitude (greater than 2 h) occurred. Similar modulation of EPSP slope indicated that these charges were primarily synaptic. If Al3+ was omitted from the F(-)-containing saline, enhancement of spike amplitude, when observed, was brief (20-30 min) and no enhancement of EPSP slope was seen. Omission of Ca2+ from the AlF(4-)-containing saline also abolished any long-lasting enhancement of synaptic transmission, though population spike amplitude in most slices showed a brief (20-30 min) stimulatory response. In preparations in which LTP had previously been saturated, synaptic transmission was not enhanced by exposure to AlF4-. It is concluded that NaF/ACl3 exposure induces an LTP-like process by G-protein activation, which involves recruitment of processes involved in LTP, possibly including an enhancement of Ca(2+)-influx.
Brain Res 1990 Dec 24;537(1-2):93-101
Multiple actions of fluoride ions upon the phosphoinositide cycle in the rat brain.
Tiger G, Bjorklund PE, Brannstrom G, Fowler CJ.
Department of Pharmacology, University of Umea, Sweden.
The effects of sodium fluoride upon basal and agonist-stimulated inositol phospholipid breakdown have been investigated in rat brain miniprisms. NaF concentration dependently increased basal inositol phospholipid breakdown, with a maximum effect being seen at 20 mM. NaF reduced the inositol phospholipid breakdown responses to stimulation by carbachol, noradrenaline, serotonin and quisqualate, but not to the stimulation produced by raising the assay [K+] from 6 to 18 mM. More detailed study demonstrated NaF to have a 'levelling' effect, reducing all InsP/(Lipid + InsP) values greater than 0.15 (i.e. produced by carbachol at raised [K+], noradrenaline and by 50 mM K+) to about this value. Time-course experiments indicated that NaF treatment reduced the rate of carbachol-stimulated inositol phospholipid breakdown up to this InsP/(Lipid + InsP) level and thereafter blocked further breakdown. Inhibitory effects upon carbachol-stimulated inositol phospholipid breakdown were not seen with forskolin, sodium nitroprusside or 8BrcGMP. Under conditions where there is no de novo synthesis of phosphoinositides from [3H]myo-inositol, NaF reduced the total Lipid + InsP labelling by about 20%. NaF in addition inhibits the activity of Ins(1,4)P2-phosphatase in cerebral cortical homogenates. It is concluded that fluoride ions inhibit agonist-stimulated inositol phospholipid breakdown via actions not only on G-proteins but also on phosphoinositide-specific phospholipase C substrate availability.
Eur J Pharmacol 1990 Jan 23;188(1):51-62
Effect of monovalent ions upon G proteins coupling muscarinic receptors to phosphoinositide hydrolysis in the rat cerebral cortex.
Tiger G, Bjorklund PE, Cowburn RF, Garlind A, O'Neill C, Wiehager B, Fowler CJ.
Department of Pharmacology, University of Umea, Sweden.
It has been suggested that K+, Li+ and Fl- affect the function of G proteins coupled to signal transducing enzymes. Lithium, at concentrations which were found to reduce forskolin-stimulated adenylate cyclase activity, was without effect on either membrane [3H]phosphatidylinositol-4,5-bisphosphate ([3H]PIP2) hydrolysis measured in the absence or presence of 5'-guanylyl-imidodiphosphate (Gpp(NH)p), or (at greater than or equal to 2.3 mM Li+) upon the stimulation of rat cerebral cortical inositol phospholipid breakdown by either carbachol, noradrenaline or NaF measured at either 6 or 18 mM K+. The increase in assay [K+] greatly enhanced the inositol phospholipid response to carbachol but not to NaF. The inhibitory effect of carbachol upon forskolin-stimulated adenylate cyclase was not affected by raising the [K+] from 6 to 18 mM. At 6 mM K+ (both in the absence and presence of 15 microM AlCl3), the effects of carbachol and NaF upon inositol phospholipid breakdown were essentially additive, whereas at 18 mM K+, the breakdown response to carbachol (antagonised by pirenzepine with a pA2 value of 7.6) was similar in the absence and presence of NaF. It is concluded that in the rat cerebral cortex:
(a) Li+ does not affect the function of either the phosphoinositide-specific phospholipase C enzyme itself or the Gp coupled to this enzyme;
(b) the difference between the additivity between NaF and carbachol seen at different assay [K+] may reflect the K(+)-dependent changes in the tetrodotoxin-resistant and tetrodotoxin-sensitive pathways of carbachol stimulation of inositol phospholipid breakdown reported by Gurwitz and Sokolovsky (1987, Biochemistry 26, 633); and
(c) the effect of K+ on muscarinic receptor-coupled inositol phospholipid breakdown is not found for muscarinic receptors inhibitorily coupled to adenylate cyclase. Evidence is also presented to suggest that NaF affects the dephosphorylation of the formed [3H]inositol polyphosphates.
Biochem J 1990 Jun 15;268(3):733-7
Dual effect of fluoride on phosphoinositide metabolism in rat brain cortex.
Stimulation of phospholipase C and inhibition of polyphosphoinositide synthesis.
Claro E, Wallace MA, Fain JN.
Department of Biochemistry, University of Tennessee, Memphis 38163.
We have studied the effects of fluoride, guanosine 5'-[gamma-thio]triphosphate (GTP[S]) and carbachol on phospholipase C and polyphosphoinositide synthesis. The experimental system consisted of membranes from rat brain cortex, with exogenous [3H]phosphatidylinositol ([3H]PtdIns) as substrate. In such systems, we have not found evidence to support carbachol and/or GTP[S] stimulation of PtdIns phosphorylation. Fluoride inhibited synthesis of PtdIns4P and PtdIns(4,5)P2 from PtdIns. Consequently, under conditions where breakdown of polyphosphoinositides by phospholipase C was dependent on PtdIns kinase activity, fluoride inhibited activation by GTP[S] plus carbachol of phospholipase C. When conditions allowed direct breakdown of PtdIns and precluded PtdIns kinase activity, the stimulatory effects of fluoride and GTP[S] plus carbachol on phospholipase C activity were additive.
J Neurochem 1990 Apr;54(4):1426-32
Guanosine 5'-O-thiotriphosphate and sodium fluoride activate polyphosphoinositide hydrolysis in rat cortical membranes by distinct mechanisms.
Li PP, Sibony D, Warsh JJ.
Section of Biochemical Psychiatry, Clarke Institute of Psychiatry, Toronto, Ontario, Canada.
NaF and guanosine 5'-O-thiotriphosphate [GTP(S)] stimulated the accumulation of [3H]inositol monophosphate ([3H]InsP) in rat brain cortical membranes, with half-maximal stimulation at 2 mM and 1 microM, respectively. Calcium also increased basal [3H]InsP formation over a range of concentrations from 10(-7) to 10(-4) M. The stimulatory effect of GTP(S) (30 microM) on [3H]InsP production was insensitive to Ca2+, whereas NaF-evoked [3H]InsP formation was dependent on Ca2+ concentrations. Guanosine 5'-O-thiodiphosphate significantly attenuated GTP(S)- but not NaF-stimulated [3H]InsP production. Coincubation of GTP(S) (30 microM) and submaximal concentrations of NaF (1 or 3 mM) stimulated [3H]InsP formation to a degree that was nearly additive with that produced by either drug alone. However, the resultant accumulation of [3H]InsP in the presence of maximally effective concentrations of GTP(S) and NaF was not different from that produced by NaF alone. Incubation of cortical membranes with GTP(S) and NaF for 1 min stimulated the accumulation of [3H]inositol bisphosphate (InsP2) but not [3H]InsP. [3H]InsP2 production elicited by GTP(S) was markedly enhanced by the muscarinic cholinergic agonist carbachol. In contrast, NaF-stimulated [3H]InsP2 formation was not potentiated by carbachol. Our findings of different characteristics of GTP(S) and fluoride activation of polyphosphoinositide (PPI) hydrolysis suggest that separate regulatory mechanisms are involved in these two modes of stimulation in brain membranes. Activation of PPI hydrolysis by fluoride may be mediated by a direct stimulation of PPI phosphodiesterase or by activating a putative guanine nucleotide regulatory protein at a location distinct from the GTP-binding site.
J Neurochem 1990 Apr;54(4):1130-5
Modulation of gamma-aminobutyric acid release in cerebral cortex by fluoride, phorbol ester, and phosphodiesterase inhibitors: differential sensitivity of acetylcholine release to fluoride and K+ channel blockers.
Gardiner IM, de Belleroche J.
Department of Biochemistry, Charing Cross and Westminster Medical School, London, England.
In this study we have used fluoride as a tool to investigate the involvement of G protein-coupled effector systems in the regulation of the depolarization-induced release of gamma-aminobutyric acid (GABA) from rat cerebral cortex. To distinguish among the activating effects of NaF on G proteins linked to different effectors, such as adenylate cyclase, polyphosphoinositide phospholipase C, and K+ channels, agents specific to these effectors have been used in parallel. NaF induced a marked dose-dependent facilitation of the K(+)-evoked release of [14C]GABA, with an EC50 of 1.26 mM, increasing release by 103% at 5 mM NaF. No effect on basal release was seen up to 3 mM NaF, and no modulation of [3H]acetylcholine (ACh) release was seen up to 5 mM NaF. Phorbol 12,13-diacetate (PDA) produced a similar dose-dependent facilitation of the K(+)-evoked release of [14C]GABA, potentiating the release of [14C]GABA by 50% at 10 microM PDA. The phosphodiesterase inhibitors, 3-isobutyl-1-methylxanthine (IBMX) and theophylline, inhibited the K(+)-evoked release of [14C]GABA, and IBMX reversed the NaF facilitation of GABA release in a dose-dependent manner (pA2 2.57). The K+ channel blocker (IA current) tetrahydroaminoacridine (THA), which markedly inhibits the K(+)-evoked release of [14C]GABA, also reversed the NaF facilitatory effect, but the release of [3H]ACh was less sensitive to the inhibitory effect of THA. On the other hand, the K+ channel blocker, tetraethylammonium, which has no effect on the release of [14C]GABA, caused a significant facilitation of K(+)-evoked release of [3H]ACh. From these studies, it is concluded that GABA release in cerebral cortex is subject to regulation by G protein-linked effector systems that are distinct from those affecting the release of [3H]ACh in cerebral cortex.
Zhonghua Bing Li Xue Za Zhi 1989 Dec;18(4):290-2
[Experimental study of behavior and cerebral morphology of rat pups generated by fluorotic female rat]
[Article in Chinese]
Liu WX.
In order to study the effects of fluoride on the central nervous system, 33-42-day old rat pups generated by three groups of female Wistar rats, which were given distilled water containing 0, 30 and 60 ppm NaF respectively beforehand as drinking water for 85 days, were used for behavior test and cerebral morphological examination. The results of behavior test showed that the latent period of pain reaction and that of conditioned reflex in the 30 ppm F and 60 ppm F groups were longer than that in the control group (P less than 0.05 or P less than 0.01). morphological examination of the pup brains showed that the nerve cell density of the 60 ppm F group was higher than that of the control group (P less than 0.05). Electronmicroscopically, mild degeneration of organelles of the nerve cells was observed in those brains of the 60 ppm F group.
Shikwa Gakuho 1989 Mar;89(3):607-26
[The rabbit thermo-regulatory system. Effects of high dose of sodium fluoride]
[Article in Japanese]
Machida H.
The mechanism of sodium fluoride (NaF) induced hypothermia was investigated on relations between the monoamine synthesis and metabolism in the rabbit brain. Five male rabbits per a group, weighing about 2.5kg and having rectal temperatures of 38.4 to 39.3 degrees C, were used in this experiment. The rectal temperature measurements were made by means of an electric thermometer for 5 hours at intervals of 15 or 30 minutes. Through this experiment, animals were housed in a room kept at 22 to 23 degrees C. The following drugs were used in this experiment: NaF (40 mg/kg i.v.), barbital sodium (0.1 g/kg s.c.), hexamethonium bromide (C6, 10 mg/kg i.v.), ergotamine tartrate (30 mg/kg s.c.), phenoxybenzamine hydrochloride (15 mg/kg i.v.), propranolol hydrochloride (5 mg/kg s.c.), pindolol (0.3 mg/kg s.c.), atropine sulfate (30 mg/kg s.c.), 2, 4-dinitrophenol (DNP, 20 mg/kg i.v.), l-DOPA (20 mg/kg i.v.), 5-HTP (20 mg/kg i.v.) Results
1. Intravenous injection of 30 mg/kg of NaF induced a drop of 0.66 degrees C in rectal temperature.
2. Pretreatment with 0.1 mg/kg of barbital sodium or 10 mg/kg of C6 prominently inhibited the NaF-induced hypothermia.
3. The alpha-blockade caused by ergotamine tartrate and phenoxybenzamine or the beta blockade by propranolol hydrochloride and pindolol resulted in an approximate 50% inhibition of maximum drop in body temperature induced by NaF administration. Both alpha- and beta-blockades caused by ergotamine tartrate and propranolol or by phenoxybenzamine and pindolol, however, made a remarkable inhibition of the NaF effect. Cholinergic blockade brought on by atropine sulfate, on the other hand, had no effect against NaF-induced hypothermia.
4. Bilateral splanchnicotomy completely inhibited drops in rectal temperature.
5. Intravenous injection of NaF 40 mg/kg failed to counteract the rise of rectal temperature caused by DNP 20 mg/kg.
6. Pretreatment with l-DOPA made a prominent inhibition of NaF-induced hypothermia. The inhibiting effects of 5-HTP, however, were slight.
7. Administration of NaF made a significant decrease in norepinephrine levels in the rabbit hypothalamus, but had no effect on 5-HT levels.
Biochem Biophys Res Commun 1988 Sep 15;155(2):664-9
Fluoride inhibits agonist-induced formation of inositol phosphates in rat cortex.
Godfrey PP, Watson SP.
Department of Clinical Pharmacology, Radcliffe Infirmary, Oxford, United Kingdom.
Sodium fluoride inhibited carbachol, 5-hydroxytryptamine and noradrenaline stimulated formation of inositol phosphates in rat cerebral cortex. For example, carbachol (1 mM) induced a 337% increase of inositol phosphates above basal in 30 min which was reduced to 69% in the presence of NaF (10 mM). The IC50 for NaF was approximately 1.5 mM and inhibition was mediated by a decrease in maxima of the carbachol dose response curve rather than a shift to the right. This inhibitory action was not mimicked by NaBr or NaI, or by agents which increase cAMP. Inhibition did not appear to result from a toxic action of NaF since it had no effect on the formation of inositol phosphates by high K+; moreover, in higher concentrations NaF stimulated phospholipase C activity. Since fluoride ions are known to activate G-proteins in the concentrations used in this study, these results may indicate the existence of a novel G-protein linked to receptor inhibition of phospholipase C.
Biochem J 1987 May 15;244(1):35-40
Guanine nucleotide and NaF stimulation of phospholipase C activity in rat cerebral-cortical membranes. Studies on substrate specificity.
Litosch I.
Department of Pharmacology, University of Miami School of Medicine, FL 33101.
Guanyl-5'-yl imidodiphosphate (p[NH]ppG) stimulated a rapid phospholipase C-mediated breakdown of exogenously added phosphatidylinositol 4,5-bisphosphate (PIP2) in rat cerebral-cortical membranes, with half-maximal activation at approx. 33 microM. NaF stimulated phospholipase C activity, with half-maximal activation at 0.5 mM. Stimulation of phospholipase C activity by NaF exhibited pH optima at approx. 5.5 and 7.0, with the stimulatory activity at pH 7.0 greater than that at pH 5.5. With p[NH]ppG, only stimulation at pH 7.0 was observed. Neither p[NH]ppG nor NaF stimulated hydrolysis of added phosphatidylinositol (PI) or phosphatidylinositol 4-phosphate (PIP). Mg2+ (0.5 mM) potentiated p[NH]ppG-stimulated breakdown of PIP2. Ca2+ increased basal and p[NH]ppG-stimulated breakdown of PIP2. PI breakdown was stimulated only by high Ca2+ concentrations and was unaffected by p[NH]ppG at any Ca2+ concentration examined. These results indicate that, in cerebral-cortical membranes, activation of phospholipase C by guanine nucleotides or fluoride directly increases a phospholipase C activity which specifically hydrolyses PIP2.
Zhonghua Bing Li Xue Za Zhi 1986 Dec;15(4):297-9
No Abstract available
[Morphology of the brain of the offspring of rats with chronic fluorosis]
[Article in Chinese]
Guan ZZ.
J Biol Chem 1986 Jan 15;261(2):631-7
The purified alpha subunits of Go and Gi from bovine brain require beta gamma for association with phospholipid vesicles.
Sternweis PC.
The purified G-proteins from bovine brain were examined for potential solubility in the absence of detergent. The isolated alpha o and alpha i subunits migrated through sucrose with rates consistent with the existence of monomeric species either in the presence or the absence of cholate. The beta gamma subunits or holo-G-proteins aggregated extensively if cholate was absent. Al3+, Mg2+, and F- prevented the aggregation of alpha o and alpha i caused by the addition of beta gamma and could also prevent the aggregation of alpha s when Gs was examined at higher temperature. The association of subunits with phospholipid vesicles was examined. Whereas beta gamma associated totally with phospholipid vesicles, purified alpha o showed little interaction. alpha o did bind to vesicles containing beta gamma (beta gamma vesicles) in a saturable fashion that indicated a stoichiometric association between the subunits. Treatment with guanosine 5'-(3-O-thio)triphosphate could partially dissociate alpha o that was bound to beta gamma vesicles. These data suggest that beta gamma may be an anchor for association of alpha subunits with membranes and that regulation by these proteins may not be limited to the plasma membrane. This possibility and its implications are discussed. The reversible association of alpha o to beta gamma vesicles may provide a very sensitive system for the study of the interactions between these subunits.
The distribution of fluoride in some Antartic seals.
Adelung D, Bossmann K, Rossler D.
As cited in: Canadian Water Quality Guidelines for the Protection of Aquatic Life: Inorganic Fluorides. Environment Canada, August 2001.
Adelung et al. (1985) examined tissue levels of three different Antartic seals, the crabeater seal (Lobodon carcinophagus), the Weddell seal (Leptochynotes weddelli) and the Fur seal (Arctocephaus tropicalis) which feed on krill. The tissue levels of inorganic fluorides in these three seal species were similar [to] those in non-krill-eating marine or terrestrial invertebrates. The soft tissue inorganic fluoride levels ranged from 2.3 to 9.1 mg F/g dw, with the lowest amounts found in adipose tissue, and the highest amounts in the brain. Levels in the blood were also low (0.006 mg F/g)... (page 33)
J Neurochem 1985 Feb;44(2):370-5
Alkenylhydrolase: a microsomal enzyme activity in rat brain.
Gunawan J, Debuch H.
Rat brain microsomes have the capacity to liberate radioactive free aldehydes from 1-[1-14C]alk-1'-enyl-sn-glycero-3-phosphoethanolamine (lysoplasmalogen). Glycerophosphoethanolamine was found using 1-alk-1'-enyl-sn-glycero-3-phospho-[3H]ethanolamine. The ratio of both products released by lysoplasmalogenase action was 1:1. Another enzymic activity could be demonstrated, which hydrolyzes lysoplasmalogen at the hydrophilic part of the molecule, a lysophospholipid phosphodiesterase. Thus, 1-[1-14C]alk-1'-enylglycerol was detected as well as [3H]ethanolamine, again in a molar ratio, from the respective labeled substrates. This enzyme possesses nearly the same affinity toward the substrate as lysoplasmalogenase. Whereas the lysophospholipid phosphodiesterase is totally inhibited in the presence of NaF or EDTA, lysoplasmalogenase activity is not affected by these reagents. 1-[1-14C]Alk-1'-enylglycerol acts also as substrate for lysoplasmalogenase, which liberates radioactive aldehydes at the same rate as from lysoplasmalogen. Because the apparent Km and Vmax values are nearly identical for both substrates, the enzyme activities are inhibited in the same way, and the pH optimum is about 7.2 in both cases, it is concluded that both substrates were attacked by the same enzyme. The enzyme does not differentiate between a substrate substituted at the sn-3 position of glycerol and one that is not. It requires only a free OH group at the sn-2 position. Phosphoethanolamine phosphatase activity was also determined under our experimental conditions.
Acta Physiol Pol 1984 May-Jun;35(3):199-206
Effect of certain agents on subcellular cAMP level in different areas of rat brain.
Janiszewska G, Lachowicz L, Wojtkowiak R.
The influence was studied in vitro of certain agents (adenosine, ADP, ATP, theophylline, together with F- ions) on the cAMP concentrations in the nuclear (N) and mitochondrial (M) fractions from different areas of rat brain. F- ions caused a slight decrease of the cAMP concentrations in nuclear fractions of the thalamus with hypothalamus and a marked decrease of this cyclic nucleotide in M fractions from the cerebral cortex. After incubation with adenosine and F- ions a distinct decrease of cAMP level was observed in N fractions from the midbrain and thalamus with hypothalamus and in mitochondrial fractions obtained from all the investigated regions. The incubation with ATP and F- ions resulted in a distinct decrease of cAMP values in the nuclear fractions from all regions. The concentrations of cAMP in the mitochondria of the midbrain and thalamus with hypothalamus incubated with ATP and F- ions increased 2-3 times. The incubation of the nuclear fraction with theophylline and F- ions caused an increase of cAMP concentration in the cortex and a decrease of cAMP values in the midbrain. The level of cAMP after the incubation with theophylline and fluoride on the mitochondrial fraction is increased in the cortex and decreased in the thalamus with hypothalamus.
Neuropharmacology 1984 Apr;23(4):445-7
Fluoride-stimulated adenylate cyclase activity in rat brain following chronic treatment with psychotropic drugs.
Andersen PH, Klysner R, Geisler A.
Chronic treatment with imipramine and reserpine increased fluoride-stimulated activity of adenylate cyclase in homogenates of cerebral cortex and "limbic" forebrain of the rat. Concomitant treatment with lithium counteracted this effect, while lithium alone had no effect on the activity of adenylate cyclase.
Biochem Int 1983 Jan;6(1):81-91
Separation and properties of a regulatory GTPase activity associated with the adenylate cyclase system in rat brain synaptic plasma membranes.
Enomoto K, Asakawa T.
A GTPase activity having a Km value of 0.5 microM was present in synaptic plasma membranes from rat brain. The activity was inhibited 63% and 24% by NaF and cholera toxin respectively and solubilized from the membranes together with the adenylate cyclase activity. Upon gel chromatography, the solubilized GTPase activity was co-eluted with the GTP-binding regulatory protein of adenylate cyclase. A similar GTPase activity was also associated with the regulatory protein from myelin. The regulatory protein fraction enhanced the activity of the catalytic unit of adenylate cyclase in the presence of 5'-guanylylimidodiphosphate but inhibited the adenylate cyclase activity by 70% in the presence of GTP. These results indicate the possible involvement of the GTPase activity in the regulation of the adenylate cyclase activity.
Comp Biochem Physiol B 1983;76(4):869-73
Comparative inhibition profiles of human brain and mouse liver L-hexonate dehydrogenase.
Schofield PJ, Comerford MJ, de Jongh KS.
The inhibition profiles of mouse liver and human brain hexonate dehydrogenase were compared. In general, the pattern for fluoride, lithium, phenobarbital, hydroxylamine and iodoacetate inhibition is similar. Contrary to previous findings, the mouse liver enzyme is potently inhibited by cupric and mercuric ions in sub-millimolar concentrations. The human brain enzyme is also inhibited by these cations. Inhibition of both enzymes by thiol-blocking agents (p-chloromercuribenzoate, iodoacetate) and enzyme protection by the first substrate NADPH but not by the second substrate, glucuronate suggests that both enzymes contain thiol groups essential for catalytic activity.
J Neurosci Methods 1983 Apr;7(4):317-28
An application of neutron activation analysis to small biological samples: simultaneous determination of thirty elements in rat brain regions.
Chan AW, Minski MJ, Lai JC.
Thirty elements in 7 rat brain regions were determined by instrumental neutron activation analysis (INAA). The samples were irradiated by thermal neutrons using 3 different sets of conditions, depending on the nuclear characteristics of the elements. Analysis of the resulting radionuclides was by gamma-ray spectrometry using a high resolution Ge(Li) detector and Nuclear Data 6600 multichannel analyzer, which was fully computerized to give quantitative results for the gamma-ray spectra. This paper demonstrates the use of INAA for small biological samples and to show its potential elements, 7 rat brain regions are listed. It is interesting to note that certain elements, e.g. fluorine and potassium showed high and low regional differences respectively, and hypothalamus and hippocampus had higher elemental concentrations than other brain regions. However, since this paper is essentially an analytical one, no attempt is made to assess these data, which are preliminary, and the possible functional role of these elements will be discussed elsewhere.
Brain Res 1981 Aug 10;218(1-2):267-77
Distribution and different activation of adenylate cyclase by NaF and of guanylate cyclase by NaN3 in neuronal and glial cells separated from rat cerebral cortex.
Nanba T, Ando M, Nagata Y, Kitajima S, Nakazawa K.
Distribution of adenylate cyclase and guanylate cyclase activities in neuronal perikarya and glial cells separated from rat brain, and cellular differences in activation between of adenylate cyclase by NaF and of guanylate cyclase by NaN3 have been studied. Adenylate cyclase activity was higher in the glial cells than in the neuronal fraction, while guanylate cyclase activity was equally detected in both cell fractions. Adenylate cyclase was mainly derived from the particulate fraction of both brain cell homogenates, whereas the major portion of guanylate cyclase activity was found in their soluble rather than in the particulate fractions. Although bulk-separated neurons and glial cells almost failed to change intracellular cyclic nucleotide levels in response to some putative neurotransmitters, activation of adenylate cyclase by NaF was found to be greater in neuronal than in glial cell fractions, and was observed more clearly in the soluble than in the particulate fractions. Sodium azide greatly increased guanylate cyclase in the particulate fraction, but did not affect it considerably in the soluble one. Addition of catalase to the reaction mixture together with NaN3 further stimulated guanylate cyclase both int he soluble and the particulate fractions. These results suggest that adenylate cyclase and guanylate cyclase without intimate coupling to the transmitter-receptor system, but with activation by NaF or NaN3, may be distributed ubiquitously in the cells separated from rat cerebral cortex.
Fluoride 1979; 12(4):209-210
Book Review
Proiswodstwennyj Fljuoros [Industrial Fluorosis]
[Russian]
NA Bogdanow and EW Gembizkij
Medizina, Leningrad 1975, 95 pp., 24 tables, 10 figures
Excerpt from Review:
... Chapter 2 deals with the usual features of chronic fluoride intoxication. It refers to the literature, particuarly with reference to chronic changes in addition to those of the skeletal system. The authors quote primarily authors of the U.S.S.R., with a predominance of early publications... Chronic inflamatory changes of the skin, the eyes and the upper respiratory tract (chronic rhinitis, laryngitis and pharynigitis) are reported; moreover functional disturbances of the central nervous systems ("astheno-vegetative syndrome and diffuse damage of the CNS"), circulatory disturbances (bradycardia, hypotension and changes in the EKG), gastric and intestinal disorders, damage to liver and kidneys and dysfunction of endocrine organs, particularly of the thyroid, the parathyroid and the adrenal cortex. In the conclusion of this chapter alterations of the mineral metabolism are discussed...
Adv Cyclic Nucleotide Res 1978;9:85-99
Calcium-dependent regulation of brain adenylate cyclase.
Brostrom MA, Brostrom CO, Breckenridge BM, Wolff DJ.
The adenylate cyclase activity of a particulate preparation of rat cerebral cortex is comprised of two contributing components, only one of which requires a CDR for activity. The CDR-dependent component was inhibited by high ratios of Mg2+ to Ca2+, responded in a biphasic manner (activation then inhibition) to increasing free Ca2+ concentrations, was inhibited by 0.1 to 0.4 mM chlorpromazine, and was activated by 1 to 100 micrometer cocaine. This enzyme form, which represented approximately 80% of tge basal activity of a cortex homogenate, was stable during pretreatment of homogenates at 45 degrees C but was completely deactivated by the removal of CDR during the preparation of the particulate fraction. Adenylate cyclase activity that did not depend on CDR was unaffected by the removal of CDR during the preparation of the particulate fraction, had elevated activity at high ratios of Mg2+ to Ca2+, was inhibited by Ca2+, was unaffected by 0.1 to 0.4 mM chlorpromazine and was slightly inhibited by 1 to 100 micrometer cocaine, and was not stable during pretreatment of homogenates at 45 degrees. The CDR-dependent component of adenylate cyclase activity was activated by 5 mM NaF to varying degrees depending on the concentration of CDR present in the assay. NaF decreased the concentration of CDR required to produce half-maximal velocity obtained at optimal concentrations of CDR. Activation by NaF required the presence of Ca2+ and was immediately and completely reversed by EGTA. In contrast, the component that did not respond to CDR was activated four- to fivefold by NaF. This activation was not influenced by Ca2+ or CDR and was not reversed by EGTA. The observed effects of effects of divalent cations on the CDR-dependent enzyme are discussed in relation to the cation-binding properties of CDR. The relationship of the CDR-dependent form of adenylate cyclase to other forms of this enzyme remains to be determined.
Folia Histochem Cytochem (Krakow) 1974;12(1):37-44
Histochemical studies on the effect of sodium fluoride on metabolism in Purkinje's cells.
Czechowicz K, Osada A, Slesak B.Definition: Purkinje cell - a large densely branching neuron that is the characteristic cell of the cerebellar cortex
Endocrinol Exp 1975 Jun;9(2):149-55 =
Sodium fluoride-induced changes in the hypothalamic neurosecretory system of the spotted owlet, Athene brama Temminck.
Singh KB, Dominic CJ.
Administration of 10 or 20 mg of sodium fluoride (NaF) induced depletion of neurosecretory material (NSM) from the neurons of the supraoptic (SON) and paraventricular (PVN) nuclei in spotted owlet (Athene brama Temminck). The residual NSM in the perikarya was aranged in caplike paranuclear positions. The NSM in the hypothalamo-hypophysial tract, the zona externa of the anterior median eminence (ME) and in the neural lobe (NL) showed only a partial lossmthe effects of NaF administration on the HNS of the spotted owlet are similar to those induced by such stimulators of ADH secretion as hypertonic saline, morphine and formalin. Hence the histological changes induced by NaF administration in the HNS of the spotted owlet are presumably indicative of increased neurosecretory activity resulting in the augmented secretion of ADH. It is suggested that NaF, like other stressful agents, is a stimulator of ADH secretion.
Br J Pharmacol 1973 Jul;48(3):505-15
The relation of adenyl cyclase to the activity of other ATP utilizing enzymes and phosphodiesterase in preparations of rat brain; mechanism of stimulation of cyclic AMP accumulation by NaF.
Katz S, Tenenhouse A.
J Biol Chem 1971 Jan 10;246(1):62-8
Adenyl cyclase of rat cerebral cortex. Activation of sodium fluoride and detergents.
Perkins JP, Moore MM.