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Collection of latest fluoride abstracts I -- the G-protein, cytokine effects  Magnu-@aol.com
 Jun 08, 2003 20:12 PDT 


Arch Toxicol 1999 Aug;73(6):310-5

Inflammatory responses of rat alveolar macrophages following exposure to

Hirano S, Ando M, Kanno S.

Regional Environment Division, National Institute for Environmental Studies,
16-2 Onogawa, Tsukuba, Ibaraki 305-0053, Japan. seis-@nies.go.jp

Inhalation exposure to fluoride compounds has been associated with
respiratory failure. We have addressed effects of fluoride on alveolar
macrophages and
lung responses to intratracheally (i.t.) instilled fluoride in rats. I.t.
instillation of fluoride at doses of 200 and 400 microg F/rat caused
polymorphonuclear leukocyte (PMN) infiltration in the rat lung at 20 h
post-administration, while 100 microg fluoride did not recruit a significant
number of
PMNs in the alveolar space. Total RNA was extracted from the lung lavage
obtained from 5 h post i.t. instillation and mRNA levels of chemokines and
proinflammatory cytokines were semi-quantitatively evaluated by reverse
transcriptase-polymerase chain reaction (RT-PCR). I.t. instillation of
significantly enhanced mRNA expression of cytokines such as
(IL-1beta), tumor necrosis factor-alpha, cytokine-induced neutrophil
chemoattractant, and macrophage inflammatory proteins-1alpha and -2.
augmentation in IL-1beta mRNA expression was also examined by Northern
following in vitro exposure of alveolar macrophages to fluoride. However,
enhancement of IL-1beta mRNA expression following in vitro exposure to
fluoride was observed only at 500 microM, a dose higher than the 50% lethal
concentration (LC(50)). Non-specific adhesion of alveolar macrophages to the
dish was significantly increased following in vitro exposure to fluoride.
fluoride-induced non-specific adhesion was significantly reduced by
suggesting that beta(2) integrin played a role in the increase of adherence.
Those results suggest that fluoride activates alveolar macrophages, enhances
production of chemokines and proinflammatory cytokines, and causes PMN
infiltration in the lung.

PMID: 10447558 [PubMed - indexed for MEDLINE]



Scand J Work Environ Health 1999 Aug;25(4):326-34

Increased CD3 positive cells in bronchoalveolar lavage fluid after hydrogen
fluoride inhalation.

Lund K, Refsnes M, Sandstrom T, Sostrand P, Schwarze P, Boe J, Kongerud J.

Department of Thoracic Medicine, The National Hospital, University of Oslo,

OBJECTIVES: This study examined whether experimental hydrogen fluoride
exposure for 1 hour induces an inflammatory response in the lower
respiratory tract
that is detectable in bronchoalveolar lavage fluid.
METHODS: Nineteen healthy, nonsmoking men were exposed for 1 hour to
low (<0.6 mg/m3), intermediate (0.7-2.4 mg/m3), or high (2.5-5.2 mg/m3)
concentrations of hydrogen fluoride. Bronchoalveolar lavage was performed at
3 weeks before and 24 hours after the exposure. For 15 subjects differential
countings were performed.
RESULTS: There was a significant increase in the percentage of CD3 positive
cells in the bronchial portion for those exposed to "intermediate" and
concentrations. For the "high" exposure group the increase in the
bronchoalveolar portion was also significant. A significant correlation was
found between
the increase in the percentage of lymphocytes and CD3 positive cells in the
bronchoalveolar portion (Spearman's coefficient r=0.68, P=0.008).
and interleukin-6 increased significantly in the bronchial portion for those
exposed to "high" concentrations. There was a significant increase in
myeloperoxidase (P=0.005) for all the exposures, while there was a decrease
E-selectin (P=0.007).
CONCLUSIONS: Hydrogen fluoride may induce an inflammatory reaction in the
airways at concentrations that can occur in the ambient air in the primary
aluminum industry.

Publication Types: Clinical Trial

PMID: 10505658 [PubMed - indexed for MEDLINE]


Fluoride 2002; 35(4):244
XXVth ISFR Conference Abstract

Fluoride and aluminum: messengers of false information

Struneck‡ A.

Charles Univ. Prague, Faculty of Sciences, Dept. of Physiology and
Developmental Biology, Vinicna 7, 128 00 Prague 2, Czech Republic. E-mail:

Intensive laboratory research on the mechanisms of signal transduction has
produced experimental data that could change our understanding of the action
fluoride at the cellular level. After reflecting on these laboratory
we suggest that some of pathological changes are not produced by fluoride
alone but by the synergistic action of fluoride and aluminum. Heterotrimeric
G-proteins mediate the transfer of information from heptahelical receptors
effector molecules. The discovery of aluminofluoride complexes (AlFx) as a
class of phosphate analogues has been followed by demonstrations of their
usefulness in laboratory investigations and their pharmacological efficacy.
complexes interact with all known G-protein-activated effector enzymes.
take part in an enormous variety of biological signaling systems, helping
control almost all important life processes. The family of cell-surface
that require coupling to G-protein transducers for functional signaling is
vast and diverse. AlFx may clone or potentiate the action of numerous
extracellular signals. It appears probable that we will not find any
process which is not potentially influenced by AlFx. The aluminofluoride
acts as the first messenger triggering processes of neurotransmission and
potentiating the action of various hormones. It is evident that AlFx are
species that
convey false information, which is then amplified by processes of signal
transmission. Many human diseases have their origin in the malfunctioning of
signaling components. Pharmacologists estimate that up to 60% of all
medicines used
today exert their effects through a G-protein signaling pathway. The
synergistic action of fluoride and aluminum in the environment, water, and
food can
thus evoke multiple pathological symptoms. AlFx might induce alterations in
homeostasis, metabolism, growth, and differentiation in living organisms. An
awareness of the health risks of this new ecotoxicological phenomenon, an
increasing load of aluminum ions and fluoride, would undoubtedly contribute
significantly to reducing the risk of a decrease in intelligence of children
and adults,
and many other disorders in the 21 st century.



J Gen Virol 2002 Dec;83(Pt 12):3055-3066

Role of G protein and protein kinase signalling in influenza virus budding
MDCK cells.

Hui EK, Nayak DP.

Department of Microbiology, Immunology and Molecular Genetics, Jonsson
Comprehensive Cancer Center (JCCC), UCLA School of Medicine, Los Angeles, CA
90095-1747, USA.

Recently, we have shown that influenza virus budding in MDCK cells is
regulated by metabolic inhibitors of ATP and ATP analogues (Hui & Nayak,
290, 329-341, 2001 ). In this report, we demonstrate that G protein
stimulators such as sodium fluoride, aluminium fluoride, compound 48/80 and
mastoparan stimulated the budding and release of influenza virus. In
contrast, G
protein signalling blockers such as suramin and NF023 inhibited virus
Furthermore, in filter-grown lysophosphatidylcholine-permeabilized
virus-infected MDCK cells, membrane-impermeable GTP analogues, such as
5'-O-(3-thiotriphosphate) or 5'-guanylylimidodiphosphate caused an increase
in virus
budding, which could be competitively inhibited by adding an excess of GTP.
These results suggest that the G protein is involved in the regulation of
influenza virus budding. We also determined the role of different protein
kinases in
influenza virus budding. We observed that specific inhibitors or activators
protein kinase A (H-89 and 8-bromoadenosine 3',5'-cyclic monophosphate) or
protein kinase C (bisindolylmaleimide I and Ro-32-0432) or of
phosphatidylinositol 3-kinase (LY294002 and wortmannin) did not affect
influenza virus
budding. However, the casein kinase 2 (CK2) inhibitor
5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole decreased virus budding. We
further observed an increase in
the CK2 activity during the replication cycle of influenza virus, although
Western blot analysis did not reveal any increase in the amount of CK2
in virus-infected cells. Also, in digitonin-permeabilized MDCK cells, the
introduction of CK2 substrate peptides caused a down-regulation of virus
These results suggest that CK2 activity also regulates influenza virus

PMID: 12466482 [PubMed - as supplied by publisher]



Yakugaku Zasshi 2002 Aug;122(8):507-25

[Fundamental and applied studies on transport and metabolism of electrolytes
and glucose--aim to contact with molecular biology]

[Article in Japanese]

Suketa Y.

University of Shizuoka School of Pharmaceutical Sciences, 52-1 Yada,
422-8526, Japan. ysuk-@theia.ocn.ne.jp

The authors' research focuses on polyuria, natriuresis, glucosuria,
and renal calcification in occupational lead poisoning and endemic
Changes in electrolyte mobilization and in glucose metabolism and transport
following the administration of lead compounds or fluoride were examined to
elucidate these mechanisms. The results suggest fundamental approaches to
mechanism of aging and life style diseases. Our results show that:
1) Natriuresis and polyuria in lead poisoning and fluorosis are due to a
decrease in renal Na/K-ATPase activity;
2) Renal calcification in fluorosis is due to stimulation of parathyroid
function and activation of the renal phosphatidylinositol cascade;
3) Glycemia in fluorosis is due to elevation of renal and hepatic
glucose-6-phosphatase activities;
4) Glusosuria in fluorosis is due to decreased renal Na/K-ATPase activity
(but fluoride administered directly did not damage the renal Na/glucose
cotransporter (SGLT);
5) Renal calcification in fluorosis is due to stimulation of parathyroid
function; and
6) The decrease in renal Na/K-ATPase and SGLT activities with aging and
hypertension is due to a decrease in phosphorylation activity by protein
kinase C
(PKC) etc. (decrease in PKC productivity with aging and hypertension).

PMID: 12187767 [PubMed - in process]



Inhal Toxicol 2002 Feb;14(2):119-32

Human exposure to hydrogen fluoride induces acute neutrophilic, eicosanoid,
and antioxidant changes in nasal lavage fluid.

Lund K, Refsnes M, Ramis I, Dunster C, Boe J, Schwarze PE, Skovlund E, Kelly
FJ, Kongerud J.

Department of Respiratory Medicine, The National Hospital, University of
Oslo, N-0027 Oslo, Norway.

The development of asthmalike symptoms among aluminum potroom workers has
been associated with exposure to fluorides. In the present study, the
nasal response in humans was examined subsequent to short-term hydrogen
fluoride (HF) exposure. Ten healthy subjects were exposed to HF (3.3-3.9
mg/m(3)) for
1 h. Nasal lavage (NAL) was performed before, immediately after, and 1.5 h
after the end of exposure. Control lavages were performed on the same
at the same time points but without HF exposure. At the end of HF exposure,
of 10 individuals reported upper airway symptoms. A significant increase was
observed in the number of neutrophils and total cells, while there was a
decrease in cell viability. The changes in neutrophil numbers correlated
significantly with the reported airway symptoms. HF also induced a
significant increase in
tumor necrosis factor-alpha and the total protein content of NAL fluid.
the eicosanoids, prostaglandin E(2), leukotriene B(4), and peptide
leukotrienes were elevated after exposure. Of the antioxidants measured, the
concentration of uric acid increased after exposure. In conclusion, exposure
to HF
induced immediate nasal inflammatory and antioxidant responses in healthy
volunteers. These findings may contribute to a further understanding of the
way HF
exerts damage to the airways and show that HF could represent an

PMID: 12122575 [PubMed - indexed for MEDLINE]


Wei Sheng Yan Jiu 2002 Apr;31(2):78-80
[Study on lipid peroxidation of electrolyzing-aluminum workers]

[Article in Chinese]

Guo Z, Zhu Q, Hu C, Yang Y.

School of Public Health, Anhui Medical University, Hefei 230032, China.

In order to study the changes in lipid peroxidation level and anti-oxidase
activity in electrolyzing-aluminum workers exposed to both aluminum and
and to find out the sensitive biological monitoring indicators, 65
electrolyzing-aluminum workers are recruited as exposed group and 52 healthy
workers as
control group. Serum and urine aluminum and fluoride concentration, serum
glutathione peroxidase(GSH-Px) activity, serum malonyl dialdehyde (MDA)
concentration, whole blood superoxide dismutase(SOD) activity, serum cuprum
and zinc
concentration, and X-ray of skeleton are detected and taken. The results
that aluminum and fluoride concentration in serum and urine increase, GSH-Px
activity reduces, MDA concentration increases and SOD activity increases,
concentration increases and zinc concentration reduces significantly (P <
0.001) in exposed group compared with those of control group. Both serum
and fluoride concentration are correlated inversely with GSH-Px activity,
correlated with MDA concentration and SOD activity. It is suggested that
serum aluminum and fluoride concentration can clearly reflect the loading
of body aluminum and fluoride. Occupational exposure to both aluminum and
fluoride lead to rising of lipid peroxidation and abnormal metabolism of
and zinc before changes in skeleton occurred. Serum MDA concentration and
GSH-Px activity might be the potential early-stage indicators of biological
surveillance for electrolyzing-aluminum workers' health. The increase of SOD
may be a kind of body compensations.

PMID: 12561533 [PubMed - in process]



Hum Exp Toxicol 2003 Mar;22(3):111-23

Fluoride-induced apoptosis in human epithelial lung cells (A549 cells): role
of different G protein-linked signal systems.

Refsnes M, Schwarze PE, Holme JA, Lag M.

Division of Environmental Medicine, Norwegian Institute of Public Health,
Geitmyrsvn. 75, PO Box 4404 Nydalen, N-0403 Oslo, Norway.

In the present study, possible mechanisms involved in fluoride-induced
apoptosis in a human epithelial lung cell line (A549) were examined. Sodium
(NaF) induced apoptosis in the A549 cells, with a maximum at 5-7.5 mM after
20 hours of exposure. The number of cells with plasma membrane damage
(PI-positive cells) increased moderately up to 5 mM, but markedly at 7.5 mM.
Deferoxamine (an Al3+ chelator) almost completely prevented these
NaF-induced responses,
which may suggest a role for G protein activation. The apoptotic effect was
partially reduced by the PKA inhibitor H89. NaF induced a weak but sustained
increase in PKC activity, whereas the PKC activator TPA induced a transient
effect. TPA, which enhanced the NaF-induced PKC activity, was not apoptotic
added alone, but facilitated the NaF-induced apoptosis and the increase in
PI-positive cells. PKC downregulation induced by TPA pretreatment almost
completely prevented the NaF-induced apoptosis and the increase in
PI-positive cells.
Pretreatment with the PKC inhibitor GF109203X, which abolished the PKC
after 3 hours, enhanced the NaF-induced apoptosis. KN93 (a CaM kinase II
inhibitor) and W7 (a calmodulin inhibitor) seem to reduce the apoptotic
effect of
NaF, whereas BAPTA-AM (a Ca2+ chelator) was without effect. The tyrosine
kinase inhibitor genistein also markedly reduced the NaF-induced apoptosis,
the PI-3 kinase inhibitor wortmannin augmented the response. In conclusion,
the present results suggest that NaF induces an apoptotic effect and an
increase in PI-positive A549 cells via similar mechanisms, involving PKC,
tyrosine kinase and Ca2+-linked enzymes, whereas PI-3 kinase seems to exert
counteracting effect.

PMID: 12723891 [PubMed - in process]



Crit Rev Oral Biol Med 2003;14(2):100-14

The biochemistry and physiology of metallic fluoride: action, mechanism, and

Li L.

Faculty of Dentistry, University of Manitoba, 780 Bannatyne Avenue, Winnipeg
R3E 0W2, MB, Canada; uml-@cc.umanitoba.ca

Fluoride is a well-known G protein activator. Activation of heterotrimeric
GTP-binding proteins by fluoride requires trace amounts of Al3+ or Be2+
AlFx mimics a gamma-phosphate at its transition state in a Galpha protein
and is
therefore able to inhibit its GTPase activity. AlFx also forms complexes
small GTP-binding proteins in the presence of their GTPase-activating
proteins (GAP). As phosphate analogs, AlFx or BeFx affect the activity of a
of phosphoryl transfer enzymes. Most of these enzymes are fundamentally
important in cell signal transduction or energy metabolism. Al3+ and F- tend
to form
stable complexes in aqueous solution. The exact structure and concentration
AlFx depend on the pH and the amount of F- and Al3+ in the solution. Humans
are exposed to both F and Al. It is possible that Al-F complexes may be
in vivo, or formed in vitro prior to their intake by humans. Al-F complexes
may play physiological or pathological roles in bone biology, fluorosis,
neurotoxicity, and oral diseases such as dental caries and periodontal
disease. The
aim of this review is to discuss the basic chemical, biochemical, and
toxicological properties of metallic fluoride, to explore its potential
and clinical implications.

PMID: 12764073 [PubMed - in process]



Wei Sheng Yan Jiu 2001 May;30(3):144-6

[Effects of selenium on the damage of learning-memory ability of mice
by fluoride]

[Article in Chinese]

Zhang Z, Shen X, Xu X.

College of Life and Environmental Science, Zhejiang Normal University,
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
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
(PSD) was decreased. The width of the synaptic cleft was remarkably
It was found that combined administration of fluoride and proper
of selenium could decrease the toxic effect of fluoride. There were
synergetic toxicities if the concentration of selenium was too high. The
suggested that selenium might antagonize the neurotoxicity of fluoride on
and morphology.

PMID: 12525083 [PubMed - in process]



Caries Res 2001 Mar-Apr;35(2):125-8

Fluoride deposition in the aged human pineal gland.

Luke J.

School of Biological Sciences, University of Surrey, Guildford, UK.

The purpose was to discover whether fluoride (F) accumulates in the aged
human pineal gland. The aims were to determine (a) F-concentrations of the
gland (wet), corresponding muscle (wet) and bone (ash); (b)
calcium-concentration of the pineal. Pineal, muscle and bone were dissected
from 11 aged
cadavers and assayed for F using the HMDS-facilitated diffusion,
electrode method. Pineal calcium was determined using atomic absorption
spectroscopy. Pineal and muscle contained 297+/-257 and 0.5+/-0.4 mg F/kg
wet weight,
respectively; bone contained 2,037+/-1,095 mg F/kg ash weight. The pineal
contained 16,000+/-11,070 mg Ca/kg wet weight. There was a positive
between pineal F and pineal Ca (r = 0.73, p<0.02) but no correlation between
F and bone F. By old age, the pineal gland has readily accumulated F and its
F/Ca ratio is higher than bone.

PMID: 11275672 [PubMed - indexed for MEDLINE]



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
(b) Nuclear Medicine Service, CHU Habib Bourguiba-Sfax.
(c) For correspondence: Dr N Zeghal, Animal Physiology Laboratory,
of Biology, FacultŽ des Sciences de Sfax-Route de la Soukra-Km 3.5, 3038
BP802, Tunisia. Email: Nejiba-@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
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
respectively. Consistent histological changes were present in the cerebellum
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
on Cancer.

Takahashi K, Akiniwa K, Narita K.

Department of Physical Medicine, Faculty of Medicine, University of Tokyo,

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
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
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
results of rat experiments. Brain tumors and T-cell system Hodgkin's
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
This may indicate a complexity of mechanisms of action of fluoride in the
especially in view of the coexising positive and negative correlations with
the fluoridation index. The likelihood of fluoride acting as a genetic cause
cancer requires consideration.

PMID: 11512573 [PubMed - indexed for MEDLINE]



Fluoride 2000; 33(2): 74-78

Effect of high fluoride water on intelligence of children

Y Lu (a), ZR Sun (a), LN Wu (a), X Wang, (a), W Lu (a), SS Liu (b)

(a) Dr Yan Lu, Department of Environmental Health, Tianjin Medical
University, Tianjin, China. Emai: yan-@hotmail.com.
(b) Tianjin Xiqing District Anti-Epidemic Station, Tianjin, China.

SUMMARY: The Intelligence Quotient (IQ) was measured in 118 children, aged
10-12 years, who were life-long residents in two villages of similar
size and social, educational and economic background but differing in the
level of fluoride in drinking water. The children in the high-fluoride area
(drinking water fluoride 3.15 ± 0.61 mg/L [ppm]) (mean ± S.D.) had higher
fluoride levels (4.99 ± 2.57 mg/L) than the children in the low-fluoride
(drinking water fluoride 0.37 ± 0.04 mg/L) (urinary fluoride 1.43 ± 0.64
The IQ of the 60 children in the high-fluoride area was significantly lower,
mean 92.27 ± 20.45, than that of the 58 children in the low-fluoride area,
103.05 ± 13.86. More children in the high-fluoride area, 21.6%, were in the
retardation (<70) or borderline (70-79) categories of IQ than children in
low fluoride area, 3.4%. An inverse relationship was also present between IQ
and the urinary fluoride level. Exposure of children to high levels of
may therefore carry the risk of impaired development of intelligence.

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