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Note: The following is a limited selection of abstracts from 1994
to present.
•
Due to length, we present this as a separate section
• Click here to return to the 4-part Brain
section (see effects for Suffuryl fluoride) for fluorine &
organofluorine pesticides.
•
When time allows more information will be added.
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.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9518651&dopt=Abstract
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.
PMID: 9518651 [PubMed - indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14761523&dopt=Abstract
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.
PMID: 14761523 [PubMed - in process]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12622200&dopt=Abstract
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.
PMID: 12622200 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12411198&dopt=Abstract
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.
PMID: 12411198 [PubMed - indexed for MEDLINE]
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)...
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11850065&dopt=Abstract
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.
PMID: 11850065 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11938978&dopt=Abstract
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.
PMID: 11938978 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10455554&dopt=Abstract
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.
PMID: 10455554 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7760776&dopt=Abstract
Neurotoxicol Teratol. 1995 Mar-Apr;17(2):169-77.
Neurotoxicity
of sodium fluoride in rats
Mullenix
PJ, Denbesten PK, Schunior A, Kernan WJ.
Abstract: Fluoride
(F) is known to affect mineralizing tissues, but effects upon the
developing brain have not been previously considered. This study
in Sprague-Dawley rats compares behavior, 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 injections (SC) of 0.13 mg/kg NaF or saline on gestational
days 14-18 or 17-19. Weanlings received drinking water containing
0, 75, 100, or 125 ppm F for 6 or 20 weeks, and 3 month-old adults
received water containing 100 ppm F for 6 weeks. 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. Fluoride exposures caused sex- and dose-specific
behavioral deficits with a common pattern. Males were most sensitive
to prenatal day 17-19 exposure, whereas females were more sensitive
to weanling and adult exposures. After fluoride ingestion,
the severity of the effect on behavior increased directly with plasma
F levels and F concentrations in specific brain regions.
Such association is important considering that plasma levels in
this rat model (0.059 to 0.640 ppm F) are similar to those reported
in humans exposed to high levels of fluoride.
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.
http://www.fluoride-journal.com/00-33-1/331-17.pdf
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.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12763087&dopt=Abstract
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.
PMID: 12763087 [PubMed - in process]
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.
PMID: 12676939 [PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12622200&dopt=Abstract
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.
PMID: 12622200 [PubMed - in process]
Fluoride 2002;
35(3):153-160
Brain
lipid peroxidation and antioxidant systems of young rats
in chronic fluoride intoxication
Shivarajashankara
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,
India
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.
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.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12460657&dopt=Abstract
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.
PMID: 12460657 [PubMed - in process]
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.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12411198&dopt=Abstract
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.
PMID: 12411198 [PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11850065&dopt=Abstract
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.
PMID: 11850065 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12525083&dopt=Abstract
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.
PMID: 12525083 [PubMed - in process]
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.tn
SUMMARY: 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.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11512573&dopt=Abstract
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.
PMID: 11512573 [PubMed - indexed for MEDLINE]
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.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12520922&dopt=Abstract
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.
PMID: 12520922 [PubMed - in process]
•
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.pdf
Fluoride 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, China
Objective: 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.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11860941&dopt=Abstract
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.
PMID: 11860941 [PubMed - in process]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10479070&dopt=Abstract
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.
PMID: 10479070 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9761592&dopt=Abstract
Neurotoxicol Teratol
1998 Sep-Oct;20(5):537-42
Influence of chronic fluorosis on membrane lipids in rat
brain.
Guan
ZZ, Wang YN, Xiao KQ, Dai DY, Chen YH, Liu JL, Sindelar P, Dallner
G.
Department of Pathology, Guiyang Medical College, Guizhou, China.
jialiul@public.gy.gz.cn
Brain membrane lipid in rats were analyzed after being fed either
30 or 100 ppm fluoride for 3, 5, and
7 months. The protein content of brain with fluorosis decreased,
whereas the DNA content remained stable during the entire period
of investigation. After 7 months of fluoride
treatment, the total brain phospholipid content decreased by 10%
and 20% in the 30 and 100 ppm fluoride
groups, respectively. The main species of phospholipid influenced
by fluorosis were phosphatidylethanolamine, phosphatidylcholine,
and phosphatidylserine. The fatty acid and aldehyde compositions
of individual phospholipid classes were unchanged. No modifications
could be detected in the amounts of cholesterol and dolichol. After
3 months of fluoride treatment, ubiquinone
contents in brain were lower; however, at 7 months they were obviously
increased in both groups of fluoride
treatment. The results demonstrate that the
contents of phospholipid and ubiquinone are modified in brains affected
by chronic fluorosis and these changes of membrane lipids could
be involved in the pathogenesis of this disease.
PMID: 9761592 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9559097&dopt=Abstract
Biomed Environ Sci 1998
Mar;11(1):1-6
Actions of sodium fluoride on acetylcholinesterase
activities in rats.
Zhao
XL, Wu JH.
Department of Environmental Toxicology, Chinese Academy of Preventive
Medicine, Beijing, China.
This study was carried out to observe the
effects of sodium fluoride on acetylcholinesterase (AChE) activities
in the cerebral synaptic membranes (SPM) and the peripheral red
blood cells (RBC) of rats by in vivo and in vitro experiments.
In the in vivo study, pregnant rats ingested ad libitum fluorinated
drinking water (5, 15, 50 ppm F-) during
their gestation and lactation. It was shown that the AChE activities
of the SPM and peripheral RBCs in maternal rats exposed 5-50 ppm
F- for 60 days were elevated significantly
by 30.0-67.6% and 12.5-31.9% in a dose-dependent manner, respectively.
The AChE activities of their offspring 80 days after birth were
also increased (8.7-28.7% for SPM and 20.6-32.4% for RBC). In
contrast, the AChE activities of SPM in vitro were inhibited by
5.0-50.0 mmol F-/L treatment in a time- and dose-dependent manner.
Analysis with the Hanes plots suggested that the enzymesubstrate
kinetics are consistent with a mixed type of inhibition.
PMID: 9559097 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9863064&dopt=Abstract
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.
PMID: 9863064
[PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9772465&dopt=Abstract
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.
PMID: 9772465 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9406177&dopt=Abstract
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.
PMID: 9406177 [PubMed - indexed for MEDLINE]
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.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9369984&dopt=Abstract
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
PMID: 9369984
[PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9315448&dopt=Abstract
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.
PMID: 9315448 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8815874&dopt=Abstract
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.
PMID: 8815874 [PubMed - indexed for MEDLINE]
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, India
Summary: 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.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7842887&dopt=Abstract
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.
PMID: 7842887 [PubMed - indexed for MEDLINE]
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