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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
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section
for fluorine & organofluorine pesticides.
•
When time allows more information will be added.
2003.
Appl Toxicol. Nov-Dec;23(6):437-46.
Histopathological and biochemical changes in lung
tissues of rats following administration of fluoride
over several generations.
Aydin
G, Cicek E, Akdogan M, Gokalp O.
Suleyman Demirel University Faculty of Medicine, Department
of Pathology, Isparta, Turkey.
The possible effects of multigenerational administration of
sodium fluoride (NaF) via drinking water on lung tissue morphology
and biochemistry and body and lung weight were investigated
in second-generation adult male rats. For this purpose we
selected 45 Albino adult Wistar rats in nine cages, each of
which consisted of four females and one male. Twenty-eight
pregnant rats were selected for the experiment, divided into
four groups of seven rats given 1 (control group), 10, 50
and 100 mg l(-1) NaF in drinking water during the gestation
period. After gestation the rats had 165 pups in total. The
mothers received fluoridated water during the lactation period
and the offspring of the first generation had access to fluoridated
water during the suckling period (21 days) and after the weaning
period (30 days) until they became mature and at the start
of the second part of the experiment. During this time 23
pups died and 79 female and 63 male first-generation rats
survived. These first-generation rats were then used to obtain
the second-generation offspring in the same manner as before,
which were subjected to the same treatments. At the end of
6 months the rats were sacrificed and autopsied. Serum fluoride
levels and the activities of principal antioxidant enzymes
were determined in lung tissue samples taken from all groups.
In addition, the lung tissues were submitted for histopathological
examination. Histological findings showed alveolar congestion,
alveolar cell hyperplasia and necrosis, prominent alveolar
septal vessels, epithelial desquamation and macrophages in
the alveolar spaces in the experimental groups. Additionally,
there were inflammatory infiltrations in peribronchial, perivascular,
intraparenchymal and respiratory tract lumen; intraparenchymal
hyperaemic vessels; respiratory epithelial desquamation and
proliferation; intraparenchymal thick valled vessels; parenchymal
fibrosis; bronchiolitis; pneumonic and focal emphysematous
areas. Furthermore, the lung parenchyma was observed to have
a distorted appearance with loss of alveolar architecture.
These histopathological findings were more pronounced for
the rat groups of 50 and 100 mg l(-1) fluoride. No significant
histopathological changes were observed in the rats of the
control group. The increased activities of superoxide dismutase
(SOD) and reduced glutathione peroxidase (GSH-Px) and the
decreased activity of catalase (CAT) in the lung tissues with
10 mg l(-1) fluoride might indicate activation of the antioxidant
defence mechanism. The decrease in SOD, GSH-Px and CAT activities
with 50 and 100 mg l(-1) fluoride and the increase in thiobarbituric
acid-reactive substance levels might be related to oxidative
damage that occurred in the lung. This
multigenerational evaluation of the long-term effect of different
doses of fluoride intake through drinking water on lung damage
shows that the lung tissues were damaged, there was emphysema
and inflammation of lung parenchyma associated with loss of
alveolar architecture and the degree of lung damage seemed
to correlate with the increased dosage of fluoride.
A similar relationship was observed between the degree of
lung damage, body and lung weight and serum fluoride levels
according to the fluoride dose. Therefore, these
results contribute to a better understanding of chronic fluoride
toxicity in lung tissue of second-generation rats, especially
via drinking water, and the biochemical findings were in agreement
with histological observations.
In addition, increased fluoride concentration did not affect
reproduction or the number of pups dying but the body weight
and lung weight ratios were affected by the high dose of fluoride
in a dose-related pattern. Copyright (c) 2003 John Wiley &
Sons, Ltd.
PMID: 14635268 [PubMed - in process] |
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12723891&dopt=Abstract
2003.
Hum Exp Toxicol 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.
magne.refsnes@fhi.no
In the present study, possible mechanisms involved in fluoride-induced
apoptosis in a human epithelial lung cell line (A549) were examined.
Sodium fluoride (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 when 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 activity 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, whereas 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, PKA, tyrosine kinase and Ca2+-linked enzymes,
whereas PI-3 kinase seems to exert a counteracting effect.
PMID: 12723891 [PubMed - in process]
• Note: The
following is the article, without graphs, as it appeared in this
journal. We present this as PubMed did not provide an abstract.
Annals of the New York
Academy of Sciences 973:218-220 (2002)
Involvement
of Protein Kinase C in Fluoride-Induced Apoptosis
in Different Types of Lung Cells
M. REFSNES,
H. KERSTEN, P. E. SCHWARZE and M. LG
Division of Environmental
Medicine Norwegian Institute of Public Health, N-0403 Oslo, Norway
Address for correspondence: Dr. M. Refsnes, Division of Environmental
Medicine, Norwegian institute of Public Health, P.O. Box 4404 Nydalen,
N-0403 Oslo, Norway. Voice: +4722042533; fax: +4722042686. magne.refsnes@fhi.no
INTRODUCTION The
lung is a target for fluoride-induced toxicity. Fluoride is known
to induce apoptosis in different cell types. We previously
showed that sodium fluoride (NaF) induced apoptosis in a human epithelial
lung cell line (A549) and in epithelial type 2 cells isolated from
rat lung, the type 2 cells being most sensitive. Involvement of
different MAP kinases was also demonstrated. In the present study,
the ability of NaF to induce apoptosis in rat alveolar macrophages
and A549 cells was compared, and the role of protein kinase C (PKC)
in the apoptotic process was examined.
METHODS A549 cells, presumably
originating from human type 2 cells, were cultured as previously
described. Primary rat alveolar macrophages were isolated by bronchoalveolar
lavage. The macrophages were cultured in RPMI 1640 medium, with
antibiotics and 5% fetal bovine serum for 1 hour at a density of
1.5 x 106 cells per milliliter, and the attached macrophages were
used for further studies. Both cell types were exposed to NaF and
assessed for PKC activity and apoptosis. In some experiments the
cells were pretreated with TPA (100 nM) for 20 hours to down-regulate
PKC or with the PKC inhibitor GF109203X (20 M) for 1 hour and further
incubated with NaF. The PKC activity was measured by a commercial
assay (Amersham). Apoptosis was measured by flow cytometry.
RESULTS AND DISCUSSION
NaF induced more marked apoptosis in macrophages than in A549 cells
and at much lower concentrations. This may reflect the difference
between cells from different species, but more conceivably reflects
the use of primary lung cells versus an established tumor cell line.
Furthermore, NaF induced a slight, but significant
increase in PKC activity in both cell types. PKC down-regulation
induced by TPA pretreatment prevented these increases, but more
importantly it strongly reduced basal PKC
activity. PKC down-regulation almost completely prevented
NaF-induced apoptosis in both cell types, suggesting that PKC may
allow NaF-induced apoptosis. GF109203X inhibited PKC activity to
the same extent as did TPA pretreatment . Surprisingly, GF109203X
increased the apoptosis of A549 cells and was without effect on
macrophages . The reason for the lack of an inhibitory effect is
unclear, but it may indicate that the effect of GF109203X is too
transient to suppress apoptosis or that GF109203X cannot inhibit
a specific PKC isoform crucial for the apoptotic response. In conclusion,
NaF induced apoptosis in both rat alveolar
macrophages and A549 cells via mechanisms that involved PKC.
References:
1.HIRANO, S. & M. ANDO. 1996. Apoptotic
cell death following exposure to fluoride in rat alveolar macrophages.
Arch. Toxicol. 70: 249-251.
2.LOWETH, A., G.T. WILLIAMS, J.H. SCARPELLO & N.G. MORGAN. 1996.
Heterotrimeric G-proteins are implicated in the regulation of apoptosis
in pancreatic b-cells. Exp. Cell. Res. 229: 69-76.
3.THRANE, E.V., M. REFSNES, G.H. THORESEN, et al. 2001. Fluoride-induced
apoptosis in epithelial lung cells involves activation of MAP kinases
p38 and possibly JNK. Toxicol. Sci. 61: 83-91.-
Free Full Text.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11567778&dopt=Abstract
Toxicology 2001
Oct 15;167(2):145-58
Mechanisms in fluoride-induced interleukin-8
synthesis in human lung epithelial
cells.
Refsnes
M, Thrane EV, Lag M, Hege Thoresen G, Schwarze PE.
Department of Environmental Medicine, National Institute of Public
Health, PO Box 4404, Nydalen, N-0403, Oslo, Norway. magne.refnes@folkhelsa.no
Sodium fluoride (NaF)
has previously been reported to induce a strong IL-8 response in
human epithelial lung cells (A549) via mechanisms that seem to involve
the activation of G proteins. In the present study the signal pathways
downstream of the G proteins have been examined.
NaF induced a weak, but sustained increase in PKC activity.
In contrast, the PKC activator TPA induced a relatively strong,
but transient effect and augmented the NaF-induced
PKC activity. TPA induced a marked IL-8 response compared to NaF.
PDB, another PKC activator, was less effective, but augmented the
IL-8 response to NaF. Pretreatment
with TPA for 20 h, or the PKC inhibitor GF109203X for 1 h, abolished
the basal and NaF-induced PKC activities
and partially prevented the NaF-induced
IL-8 response. Inhibition of the MAP kinase p38 by SB202190 partially
reduced the IL-8 response to NaF, whereas
a reduction in ERK activity by PD98059 led to an increased response.
The NaF-induced IL-8 response was weakly
augmented by the PKA stimulator forskolin and the G(i) inhibitor
pertussis toxin. The PKA inhibitor H89 seemed to reduce the NaF-induced
IL-8 response, but the measured effect was not statistically significant.
BAPTA-AM, KN93 and W7, that inhibit Ca(2+)-linked effects, did not
affect the IL-8 response. Furthermore, the tyrosine kinase inhibitor
genestein, the PI-3 kinase inhibitor wortmannin and phosphatase
inhibition were without effects. In conclusion, the data suggest
that NaF-induced increase of IL-8 in
A549 cells involved PKC- and p38-linked pathways, whereas an ERK-dependent
pathway counteracted the response. Tyrosine kinases, Ca(2+)-linked
pathways, PI-3 kinase, PKA and phosphatase inhibition seem to play
no or minor roles in the fluoride-induced
IL-8 response.
PMID: 11567778 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8825685&dopt=Abstract
Arch Toxicol 1996;70(3-4):249-51
Apoptotic
cell death following exposure to fluoride
in rat alveolar macrophages.
Hirano
S, Ando M.
Regional Environment Division, National Institute for Environmental
Studies, Ibaraki, Japan.
Since inhaled fluoride is implicated in the
acute respiratory failure, cytotoxic effects of fluoride
on alveolar macrophages, primary target cells of inhaled toxicants,
were investigated. The LC50 of sodium fluoride
was estimated to be 0.41 mM, while 1 mM sodium chloride, bromide
and iodide had virtually no effects on the viability of alveolar
macrophages. Photomicroscopic observation
revealed that nuclei of the fluoride-exposed alveolar macrophages
were fragmented. The ladder formation was observed when DNA
isolated from fluoride-exposed alveolar
macrophages was electrophoresed in agarose gel.
These results suggest that cytotoxicity of fluoride is associated
with apoptosis in rat alveolar macrophages.
PMID: 8825685 [PubMed - indexed for MEDLINE]
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