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2002 Fluoride Abstracts. Part 1.
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Physiol Res 2002 Dec;51(6):557-564
Fluoride plus aluminum: useful tools in laboratory investigations, but messengers of false information.
Strunecka A, Strunecky O, Patocka J.
Department of Physiology and Developmental Biology, Faculty of Sciences, Charles University, Vinicna 7, 128 43 Prague 2, Czech Republic. strun@natur.cuni.cz
Aluminofluoride complexes (AlF(x)) form spontaneously in aqueous solutions containing fluoride and traces of aluminum ions and appear to act as phosphate analogs. These complexes have become widely utilized in laboratory investigations of various guanine nucleotide-binding proteins. Reflecting on many laboratory studies, a new mechanism of fluoride and aluminum action on the cellular level is being suggested. The long-term synergistic effects of these ions in living environment and their hidden danger for human health are not yet fully recognized.
PMID: 12511178 [PubMed - as supplied by publisher]
Fluoride 2002; 35(4):244XXVth 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: strun@natur.cuni.cz
Intensive laboratory research on the mechanisms of signal transduction has produced experimental data that could change our understanding of the action of fluoride at the cellular level. After reflecting on these laboratory studies, 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 to effector molecules. The discovery of aluminofluoride complexes (AlFx) as a new class of phosphate analogues has been followed by demonstrations of their usefulness in laboratory investigations and their pharmacological efficacy. AlFx complexes interact with all known G-protein-activated effector enzymes. G-proteins take part in an enormous variety of biological signaling systems, helping control almost all important life processes. The family of cell-surface receptors 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 physiological process which is not potentially influenced by AlFx. The aluminofluoride complex 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.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12622200&dopt=AbstractIndian 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, IndiaSummary: A study was made of the effect of fluoride on oxidative stress in rats during their early stages in life. Wistar albino rats were exposed to 30 ppm and 100 ppm fluoride (from sodium fluoride) in drinking water during the last one week of intrauterine life and then up to ten weeks after birth. Oxidative stree 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=AbstractNeurotoxicol 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.pdfFluoride 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=12164550&dopt=Abstract
Neurotoxicology 2002 May;23(1):7-17Caramiphen and scopolamine prevent soman-induced brain damage and cognitive dysfunction.
Raveh L, Weissman BA, Cohen G, Alkalay D, Rabinovitz I, Sonego H, Brandeis R.
Department of Pharmacology, Israel Institute for Biological Research, Ness Ziona. lili@iibr.gov.il
Exposure to soman, a toxic organophosphate nerve agent, causes severe adverse effects and long term changes in the peripheral and central nervous systems. The goal of this study was to evaluate the ability of prophylactic treatments to block the deleterious effects associated with soman poisoning. scopolamine, a classical anticholinergic agent, or caramiphen, an anticonvulsant anticholinergic drug with anti-glutamatergic properties, in conjunction with pyridostigmine, a reversible cholinesterase inhibitor, were administered prior to sbman (1 LD50). Both caramiphen and scopolamine dramatically attenuated the process of cell death as assessed by the binding of [3H]RoS-4864 to peripheral benzodiazepine receptors (omega3 sites) on microglia and astrocytes. In addition, caramiphen but not scopolamine, blocked the soman-evoked down-regulation of [3H]AMPA binding to forebrain membrane preparations. Moreover, cognitive tests utilizing the Morris water maze, examining learning and memory processes as well as reversal learning, demonstrated that caramiphen abolished the effects of soman intoxication on learning as early as the first trial day, while scopolamine exerted its effect commencing at the second day of training. Whereas the former drug completely prevented memory deficits, the latter exhibited partial protection. Both agents equally blocked the impairment of reversal learning. In addition, there is a significant correlation between behavioral parameters and [3H]RoS-4864 binding to forebrain membrane preparations of rats, which participated in these tests (r(21) = 0.66, P < 0.001; r(21) = 0.66, P < 0.001, -0.62, P < 0.002). These results demonstrate the beneficial use of drugs exhibiting both anti-cholinergic and anti-glutamatergic properties for the protection against changes in cognitive parameters caused by nerve agent poisoning. Moreover, agents such as caramiphen may eliminate the need for multiple drug therapy in organophosphate intoxications.
PMID: 12164550 [PubMed - in process]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12411198&dopt=AbstractZhonghua 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]
Fluoride 2002; 35(3):143-147Editorial
Paradoxical dose-response effects of fluorideAW Burgstahler
Editor, Fluoride
Excerpt: ... What they show is that, under certain circumstances, the inhibitory or stimulatory impact of fluoride can actually be greater at a lower level of intake than at a higher level. An impressive illustration of this fact is seen in the administration of fluoride as aluminum fluoride to rats. In both a 45-week study (10) and a confirmatory 52-week study (11), the neuronal, cerebrovascular, and nephritic toxicity of AlF3 at 0.5 ppm Al3+ (= 1 ppm F) in the drinking water was significantly greater than with AlF3 at 5 or 50 ppm Al3+. Sodium fluoride at equivalent concentrations of 1, 10, and 100 ppm F produced analogous but qualitatively different changes in the brain and kidneys. Clearly, like evidence for unanticipated supra-linear (paradoxical) toxic effects of low-level ionizing radiation (12), these findings have important potential implications for human health, in this case with respect to the presence of certain critical levels of aluminum in combination with fluoride (13).
References:
10. Issacson R et al. (1997). Toxin-induced blood vessel inclusions caused by chronic administration of aluminum and sodium fluoride and their implications for dementia. Ann NY Acad Sci 825:152-66.
11. Varner JA et al. (1998). Chronic administration of aluminum-fluoride or sodium fluoride to rats in drinking water: alterations n neuronal and cerebrovascular integrity. Brain Res 784-284-98.
12. Gofman JW, O'Connor E (1985). Health effects of common exams. San Francisco: Sierra Club Books.
13. Lubkowska A et al. (2002). Interactions between fluorine and aluminum. Fluoride 35:73-7.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11754869&dopt=AbstractBiochem Pharmacol 2002 Jan 1;63(1):11-9
Protein levels of neurofilament subunits in the hen central nervous system following prevention and potentiation of diisopropyl phosphorofluoridate (DFP)-induced delayed neurotoxicity(1).
Xie K, Gupta RP, Abou-Donia MB.
Neurotoxicology Laboratory, School of Life Science, University of Science and Technology of China, 230027, Hefei, Anhui, P. R. China.
Diisopropyl phosphorofluoridate (DFP) is an organophosphorus ester, which produces delayed neurotoxicity (OPIDN) in hens in 7-14 days. OPIDN is characterized by mild ataxia in its initial stages and severe ataxia or paralysis in about 3 weeks. It is marked by distal swollen axons, and exhibits aggregations of neurofilaments (NFs), microtubules, proliferated smooth endoplasmic reticulum, and multivesicular bodies. These aggregations subsequently undergo disintegration, leaving empty varicosities. Previous studies in this laboratory have shown an increased level of medium-molecular weight NF (NF-M) and decreased levels of high- and low-molecular weight NF (NF-H, NF-L) proteins in the spinal cord of DFP-treated hens. The main objective of this investigation was to study the effect of DFP administration on NF subunit levels when OPIDN is prevented or potentiated by pretreatment or post-treatment with phenylmethylsulfonyl fluoride (PMSF), respectively. Hens pretreated or post-treated with PMSF were killed 1, 5, 10, and 20 days after the last treatment. The alteration in NF subunit protein levels observed in DFP-treated hen spinal cords was not observed in protected hens. Estimation of NFs in the potentiation experiments, however, showed a different pattern of alteration in NF subunit levels. The results showed that an alteration in NF subunit levels in DFP-treated hens might be related to the development of OPIDN, since these changes were suppressed in PMSF-protected hens. However, results from PMSF post-treated hen spinal cords suggested that potentiation of OPIDN by PMSF was mediated by a mechanism different from that followed by DFP alone to produce OPIDN.
PMID: 11754869 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11814414&dopt=AbstractBrain Res 2002 Feb 1;926(1-2):126-36
SSeCKS immunolabeling in rat primary sensory neurons.
Siegel SM, Grove BD, Carr PA.
Department of Anatomy and Cell Biology, University of North Dakota, 501 North Columbia Road, Grand Forks, ND 58202, USA.
SSeCKS (src suppressed C kinase substrate) is a protein kinase C substrate that may play a role in tumor suppression. Recently described in fibroblasts, testes and mesangial cells, SSeCKS may have a function in the control of cell signaling and cytoskeletal arrangement. To investigate the distribution of SSeCKS throughout the nervous system, representative sections of brain, spinal cord and dorsal root ganglia were processed using immunofluorescence. Labeling of central axonal collaterals of primary sensory neurons was observed in the dorsal horn at all spinal levels. SSeCKS-immunoreactivity was also observed in the cerebellum, medulla and sensory ganglia (including trigeminal ganglia). The pattern and distribution of anti-SSeCKS labeling in dorsal root ganglia and the dorsal horn of the spinal cord was similar to that observed for other markers of small primary sensory neurons. Therefore, the coexistence of SSeCKS with substance P, CGRP and acid phosphatase was examined in sections of sensory ganglia, spinal cord and medulla using double immunofluorescent labeling for SSeCKS and substance P/CGRP or sequential SSeCKS immunofluorescence and acid phosphatase/fluoride-resistant acid phosphatase enzyme histochemistry. A small portion of the SSeCKS-labeled cell bodies appeared to represent a subpopulation of substance P (4.8%) and CGRP (4.7%) containing neurons, while 45.0% contained fluoride-resistant acid phosphatase reactivity. These results indicate that SSeCKS has a restricted distribution within the nervous system and that expression of this protein may reflect the specific signaling requirements of a distinct population of nociceptive sensory neurons.
PMID: 11814414 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11850065&dopt=AbstractBrain 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=11884237&dopt=AbstractToxicol Appl Pharmacol 2002 Feb 15;179(1):57-63
Selective inhibitors of fatty acid amide hydrolase relative to neuropathy target esterase and acetylcholinesterase: toxicological implications.
Quistad GB, Sparks SE, Segall Y, Nomura DK, Casida JE.
Environmental Chemistry and Toxicology Laboratory, University of California, Berkeley, California 94720-3112, USA.
Fatty acid amide hydrolase (FAAH) plays an important role in nerve function by regulating the action of endocannabinoids (e.g., anandamide) and hydrolyzing a sleep-inducing factor (oleamide). Several organophosphorus pesticides and related compounds are shown in this study to be more potent in vivo inhibitors of mouse brain FAAH than neuropathy target esterase (NTE), raising the question of the potential toxicological relevance of FAAH inhibition. These FAAH-selective compounds include tribufos and (R)-octylbenzodioxaphosphorin oxide with delayed neurotoxic effects in mice and hens plus several organophosphorus pesticides (e.g., fenthion) implicated as delayed neurotoxicants in humans. The search for a highly potent and selective inhibitor for FAAH relative to NTE for use as a toxicological probe culminated in the discovery that octylsulfonyl fluoride inhibits FAAH by 50% at 2 nM in vitro and 0.2 mg/kg in vivo and NTE is at least 100-fold less sensitive in each case. More generally, the studies revealed 12 selective in vitro inhibitors for FAAH (mostly octylsulfonyl and octylphosphonyl derivatives) and 9 for NTE (mostly benzodioxaphosphorin oxides and organophosphorus fluoridates). The overall in vivo findings with 16 compounds indicate the expected association of AChE inhibition with acute or cholinergic syndrome and >70% brain NTE inhibition with delayed neurotoxic action. Surprisingly, 75-99% brain FAAH inhibition does not lead to any overt neurotoxicity or change in behavior (other than potentiation of exogenous anandamide action). Thus, FAAH inhibition in mouse brain does not appear to be a primary target for organophosphorus pesticide-induced neurotoxic action (cholinergic or intermediate syndrome or delayed neurotoxicity).
PMID: 11884237 [PubMed - indexed for MEDLINE]
Fluoride 2002; 35(4):244-245XXVth ISFR Conference Abstract
Interactions between guanosine diphosphate (GDP) and aluminum fluoride (AlF3)
Machoy Z (1), Gutowska I (2), Straszko J (3), Machalinski B (2)
(1) Dept. of Biochemistry and Chemistry and
(2) Dept. of General Pathology, Pomeranian Academy of Medicine (PAM),
(3) Dept. of Physical Chemistry, Technical Univ., Szczecin, Poland.
For Correspondence: Machoy Z, Dept. of Biochemistry and Chemistry, PAM, Al. Powstancow Wlkp. 72, 70-111 Szczecin, Poland. Email: machalin@sci.pam.szczecin.plFluorine-aluminum compounds are now being studied with increasing interest. The neurotoxic properties of AlF3 are most important medically because of reports connecting AlF3 with the pathogenesis of Alzheimer's disease. One hypothesis is that the complex of aluminum and fluorine can influence the G-protein receptors and the resulting phosphorylation. Moreover, AlF3 activates several guanine nucleotides mimicking the actions of some neurotransmitters and hormones. Some physico-chemical properties of AlF3 and GDP, as well as their antagonist interactions in many biochemical pathways, have been analyzed. The aim of this study was to investigate of interaction between AlF3 and GDP by virtual molecular modeling using the HyperChem computer program. The semi-empiric method (PM3), with Polak-Ribeier's optimization algorithm, was used. The PM3 method is suitable for modeling of the molecules containing elements of the main groups of the periodic table. The results indicated that the main sites of the reaction in GDP are phosphate groups. The computer analyses obtained from PM3 molecular modeling confirmed that the GDP molecule is attacked initially by one of the F - ions from AlF3. It gets near the phosphate moiety of the phosphate group and pulls it back from GDP (the O-P bond makes itself longer). Next, the remaining part of the AlF 2+ attacks the oxygen atom connecting the phosphate groups in GDP and causes breaking of the P-O bond. The two-stage nature of the reaction was confirmed by calculations con-cerning the length of the bonds, total energy E, and the molecular heat of formation. AlF3 can attack GDP in the space of the first and second phosphate rest, although according to our calculations, the outer one has priority. The mechanism presented clarifies the interactions between the inorganic AlF3 complex and the biologically important GDP nucleotide.
Fluoride 2002; 35(4):258-259XXVth ISFR Conference Abstract
Fluoride levels in liver, kidney, and brain of mice after subacute oral treatment with fluoride
Tsunoda M (1), Nakano K (2), Liu Y (3), Itai K (4), Tsunoda H (5)
(1) Dept. of Public Health, Fukushima Medical Univ., Hikarigaoka 1, Fukushima, 960-1295, Japan; E-mail: mtsunoda@fmu.ac.jp;
(2) Fukushima Institute of Public Health, Fukushima;
(3) Dept. of Environmental Health, China Medical Univ., Shenyang, P. R. China;
(4) Dept. of Hygiene and Preventive Medicine, Iwate Medical Univ., Morioka, Japan;
(5) Honorary Professor of Iwate Medical Univ., Morioka.Contamination of groundwater by fluoride has been reported in China and India. It is of interest to determine the levels of fluoride in organs after exposure to fluoride via drinking water. It is also interesting to know whether neurological effects of fluoride can be induced or not by the oral exposure. The purpose of this study was to determine fluoride levels in organs of mice exposed to fluoride via drinking water. The neurological effects of fluoride was also studied by determining neurotransmitter levels.
Adult male BALB/c mice (six per group) were exposed to 0, 1, 5, 25, 125 ppm of sodium fluoride in drinking water for a month. Following the treatment period, mice were euthanized, and the liver, kidneys, and brain removed. Brain samples were dissected into six regions. Half the cerebrum was used for the determination of fluoride ion concentration. Fluoride in each organ was isolated by pyrohydrolysis, recovered into water solution, and determined using a flow-injection apparatus with a fluoride ion selective electrode as the detector. The concentrations of neurotransmitters and their metabolites in brain regions were determined by HPLC. The mean value of fluoride concentration in liver was 0.087 µg/g for control, 0.077 µg/g for 1 ppm, 0.085 µg/g for 5 ppm, 0.085 µg/g for 25 ppm and 0.228 µg/g for 125 ppm group. The 125 ppm group had a significantly higher mean value com-pared to other groups.
The mean value of fluoride concentration in kidney was 0.143 µg/g for control, 0.135 µg/g for 1ppm, 0.122 µg/g for 5 ppm, 0.150 µg/g for 25 ppm and 0.350 µg/g for 125 ppm group. The 125 ppm group also had a significantly higher mean value compared to other groups. There were no significant dif-ferences of fluoride concentration in cerebrum among the different groups. There were no significant differences in the levels of neurotransmitters or their metabolites in any brain regions among the groups.
The higher concentration of fluoride in kidney among the 125 ppm group may be related to renal damage. The absence of an elevation in fluoride in brain was consistent with there being no alteration in the levels of neurotransmitters and their metabolites in brain regions among the groups.
From TOXNETToxicologist 2002 Mar;66(1-S):268
Evaluation of the subchronic toxicity and one generation reproductive effects of a fluoroalkylethanol mixture.
Mylchreest E, Stadler JC, Makovec GT, Everds NE, Ladics GS.
DuPont Haskell Lab. for Health and Environmental Sciences, Newark, DE.
The objective of this study was to evaluate the subchronic and reproductive toxicity of a fluoroalkylethanol mixture which is employed as an intermediate in the production of other fluoroorganic compounds utilized as protectants and surfactants. Test material was administered by gavage at dosages of 0, 25, 100, or 250 mg/kg/day. No test substance-related mortality or neurotoxicity occurred in the study. Body weights and/or nutritional parameters were significantly reduced at 100 and 250 mg/kg/day but similar to control after recovery. Broken and absent teeth were observed at 250 mg/kg/day. Microscopic tooth lesions (ameloblast degeneration/disorganization) occurred at 100 and 250 mg/kg/day and persisted after recovery. Plasma and urine fluoride levels were elevated in a dose-dependent manner. Decreased red cell mass parameters occurred at 250 mg/kg/day and persisted after 36 days of recovery. The 100 and 250 mg/kg/day groups had increased (p less than 0.05) liver weights which persisted in the high dose after recovery and correlated with microscopic hepatocellular hypertrophy in males and females (250 mg/kg/day subchronic animals only). Hepatic beta-oxidation was increased in a dose-dependent manner and persisted after recovery at 250 mg/kg/day. Increased kidney weights occurred at 25 (females only), 100 and 250 mg/kg/day which persisted in the high dose after recovery and correlated with microscopic tubular hypertrophy (males only). Thyroid follicular hypertrophy was present at 100 and 250 mg/kg/day but was not present after recovery. The test material contains 2% residual iodides. Litter size at birth and pup weights during lactation were reduced at greater than or equal to 100 mg/kg/day. No other reproductive parameter was affected. There were no adverse effects observed for either subchronic or reproductive toxicity in animals dosed with 25 mg/kg/day. A wide margin of safety exists between potential human exposure levels and the doses which result in adverse effects. Medical Subject Headings (MeSH):
From TOXNETChung-Kuo Kung Kung Wei Sheng (China Public Health) 2002 Apr;18(4):427-9
[Study on antagonistic effects of selenite on fluoride-induced impairments of testis and epididymis in rats]
Yang KD, Liu SH, Ying CJ.
Department of Environmental Health, Tongji Medical College, HuaZhong University of Science and Technology, Wuhan, China.
Objective: To study the mechanisms of the antagonistic action of selenite on fluoride-induced male reproductive damages, and find out the optimal level of selenite in drinking water against fluoride toxicity.
Methods: Five groups of SD male rats were provided with deionized drinking water containing 0 and 150 mg/L NaF, and containing both 150 mg/L NaF and 0.5, 2.0 or 4.0 mg/L Na2SeO3 respectively for 8 weeks, observing the levels of fluoride in blood and urine as well as the impairments of testis and epididymis of rats induced by 150 mg/L NaF.
Results: Fluoride could cause the elevation of fluorine concentrations in blood and urine, the abnormalities of trace elements in serum and testis, as well as the significant increase of lipid peroxide (LPO) levels, and the obvious decreases of activities of glutathione peroxidase (GSH-Px) and ATPase in testis and epididymis of rats exposed to fluoride in drinking water. 2.0 mg/L Na2SeO3 in drinking water induced acceleration of fluoride excretion obviously in urine and possessed the certain adjustment of changes of trace elements in serum and testis, the most significant antagonistic effects of increases of LPO levels and decreases of GSH-Px and ATPase activities in testis and epididymis of rats exposed to fluoride, those of 0.5 and 4.0 mg/L Na2SeO3 were not powerful.
Conclusion: Na2SeO3 of 2.0 mg/L is the optimal level for the antagonistic effect on testis and epididymis impairments.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11875076&dopt=AbstractJ Biol Chem 2002 May 10;277(19):16768-74
Functional characterization of the G protein regulator RGS13.
Johnson EN, Druey KM.
Molecular Signal Transduction Section, Laboratory of Allergic Diseases, NIAID, National Institutes of Health, Rockville, Maryland 20852, USA.
The signaling cascades evoked by G protein-coupled receptors are a predominant mechanism of cellular communication. The regulators of G protein signaling (RGS) comprise a family of proteins that attenuate G protein-mediated signal transduction. Here we report the characterization of RGS13, the smallest member of the RGS family, which has been cloned from human lung. RGS13 has been found most abundantly in human tonsil, followed by thymus, lung, lymph node, and spleen. RGS13 is a GTPase-activating protein for Galpha(i) and Galpha(o) but not Galpha(s). RGS13 binds Galpha(q) in the presence of aluminum magnesium fluoride, suggesting that it bears GTPase-activating protein activity toward Galpha(q). RGS13 blocks MAPK activity induced by Galpha(i)- or Galpha(q)-coupled receptors. RGS13 also attenuates GTPase-deficient Galpha(q) (Galpha(q)QL) mediated cAMP response element activation but not transcription evoked by constitutively active Galpha(12) or Galpha(13). Surprisingly, RGS13 inhibits cAMP generation elicited by stimulation of the beta(2)-adrenergic receptor. These data suggest that RGS13 may regulate Galpha(i)-, Galpha(q)-, and Galpha(s)-coupled signaling cascades.
PMID: 11875076 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11867686&dopt=AbstractJ Leukoc Biol 2002 Mar;71(3):487-94
Beryllium fluoride-induced cell proliferation: a process requiring P21(ras)-dependent activated signal transduction and NF-kappaB-dependent gene regulation.
Misra UK, Gawdi G, Pizzo SV.
Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
We studied the effect of beryllium fluoride on murine peritoneal macrophages and determined its effects on signal transduction and genetic regulation. At low concentration (1-5 nM), BeF(2) caused an approximate twofold increase in [(3)H]thymidine uptake and cell number, but above 5 nM, it showed cytotoxic effects. BeF(2) increased cellular inositol (1,4,5)trisphosphate (IP(3)) and [Ca(2)(+)](i) about twofold. The rise in [Ca(2)(+)](i) occurred consequent to release from IP(3)-sensitive Ca(2)(+) stores and from influx, mainly via L-type channels. A significant increase in the levels of MEK1, ERK1, p38 MAPK, and JNK phosphorylation was observed in BeF(2)-exposed macrophages. The levels of NF-kappaB and CREB transcription factors and the proto-oncogenes c-fos and c-myc were also elevated significantly. Intracellular Ca(2)(+) chelation blocked the effect of BeF(2). We conclude that BeF(2) at low concentration exerts its mitogenic effects in peritoneal macrophages by elevating [Ca(2)(+)](i), which triggers the activation of p21(ras)-dependent MAPK signaling cascades.
PMID: 11867686 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12466482&dopt=AbstractJ Gen Virol 2002 Dec;83(Pt 12):3055-3066
Role of G protein and protein kinase signalling in influenza virus budding in 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, Virology 290, 329-341, 2001 ). In this report, we demonstrate that G protein signalling 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 budding. Furthermore, in filter-grown lysophosphatidylcholine-permeabilized virus-infected MDCK cells, membrane-impermeable GTP analogues, such as guanosine 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 of protein kinase A (H-89 and 8-bromoadenosine 3',5'-cyclic monophosphate) or of 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 protein in virus-infected cells. Also, in digitonin-permeabilized MDCK cells, the introduction of CK2 substrate peptides caused a down-regulation of virus budding. These results suggest that CK2 activity also regulates influenza virus budding.
PMID: 12466482 [PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids12497681&dopt=AbstractJ Reprod Med 2002 Nov;47(11):919-24
Influence of NaMFP [sodium monofluorophosphate] therapy on plasma leptin concentration in postmenopausal women.
Oral B, Ozbasar D.
Department of Obstetrics and Gynecology, Suleyman Demirel University School of Medicine, Isparta, Turkey. bahao@hotmail.com
OBJECTIVE: To investigate the effect of a low dose of fluoride on the plasma leptin concentration in postmenopausal women.
STUDY DESIGN: One hundred one healthy, postmenopausal women participated in this comparative study. To evaluate the influence of NaMFP treatment and body mass index (BMI) on leptin concentrations, patients were allocated to one of four groups: postmenopausal women
(1) on NaMFP with BMI < 25 (n = 29),
(2) on NaMFP with BMI > or = 25 (n = 26),
(3) not on NaMFP with BMI > or = 25 (n = 24) and
(4) not on NaMFP with BMI < 25 (n = 22).
Plasma leptin levels were measured before and 12 months after the initiation of NaMFP or, in groups 3 and 4, after the start of the study. Ninety-eight women completed the study.
RESULTS: There were significant differences in leptin concentrations at baseline and 12 months between NaMFP users with BMI > or = 25 and BMI < 25 and between women not taking NaMFP with BMI > or = 25 and BMI < 25 (group 2 versus 1 and 3 versus 4). After controlling for BMI, the use of NaMFP was not found to be related to the leptin value (group 1 versus 4 and group 2 versus 3). Although plasma leptin concentrations tended to be decreased slightly at 12 months in NaMFP users, this decrease was not statistically significant (P = .065).
CONCLUSION: Leptin concentrations are significantly higher in obese, postmenopausal women than in nonobese, postmenopausal women. Plasma leptin concentrations are slightly but nonsignificantly influenced by long-term, low-dose fluoride treatment. Further studies are needed to elucidate the role of NaMFP on plasma leptin concentrations.
PMID: 12497681 [PubMed - in process]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12220599&dopt=AbstractReprod Toxicol 2002 Jul;16(4):385
Testicular toxicity in sodium fluoride treated rats: association with oxidative stress.
Ghosh D, Das(Sarkar) S, Maiti R, Jana D, Das U.
Department of Human Physiology with Community Health, Reproductive Endocrinology and Family Welfare Research Unit, Vidyasagar University, 721 102, West Bengal, Midnapore, India
This study examined the effect of sodium fluoride, a water pollutant important through the world, including India, on testicular steroidogenic and gametogenic activities in relation to testicular oxidative stress in rats. Sodium fluoride treatment at 20mg/kg/day for 29 days by oral gavage resulted in significant diminution in the relative wet weight of the testis, prostate, and seminal vesicle without alteration in the body weight gain. Testicular Delta(5),3beta-hydroxysteroid dehydrogenase (HSD) and 17beta-HSD activities were decreased significantly along with significant diminution in plasma levels of testosterone in the fluoride-exposed group compared to the control. Epididymal sperm count was decreased significantly in the fluoride-treated group and qualitative examination of testicular sections revealed fewer mature luminal spermatozoa in comparison to the control. The seminiferous tubules were dilated in treated animals. Fluoride treatment was associated with oxidative stress as indicated by an increased level of conjugated dienes in the testis, epididymis, and epididymal sperm pellet with respect to control. Peroxidase and catalase activities in the sperm pellet were decreased significantly in comparison to the control. The results of this experiment indicate that fluoride at a dose encountered in drinking water in contaminated areas exerts an adverse effect on the male reproductive system and this effect is associated with indicators of oxidative stress.
PMID: 12220599 [PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12441371&dopt=AbstractToxicol Sci 2002 Dec;70(2):261-8
Nephrotoxicity of chlorofluoroacetic Acid in rats.
Lantum HB, Baggs RB, Krenitsky DM, Anders MW.
Department of Pharmacology and Physiology and Laboratory of Animal Medicine, University of Rochester Medical Center, 601 Elmwood Ave., Box 711, Rochester, New York 14642.
Dichloroacetic acid (DCA), chlorofluoroacetic acid (CFA), and difluoroacetic acid (DFA) are inhibitors of pyruvate dehydrogenase kinase. DCA is used for the clinical management of congenital lactic acidosis. Glutathione transferase zeta (GSTZ1-1) catalyzes the biotransformation of DCA and CFA, and DCA is a mechanism-based inactivator of GSTZ1-1. In rodents, DCA causes multiorgan toxicities and is hepatocarcinogenic. The toxic effects of CFA, which is an excellent substrate but a poor inactivator of GSTZ1-1, have not been investigated. The objective of this study was to investigate the nephrotoxicity of CFA. Rats given a single dose of 1.5 mmol/kg CFA became anuric and died within 24 h. Urinalysis and light microscopic analysis showed that rats given 0.6-1.2 mmol/kg CFA developed polyuria, glycosuria, and renal proximal tubular damage. Electron microscopic analysis indicated a role for apoptosis in CFA-induced cell death. The nephrotoxicity of CFA was associated with a dose-dependent increase in inorganic fluoride excretion. Treatment of rats with DCA for 5 days to inactivate GSTZ1-1 failed to prevent metabolism of CFA to fluoride and did not block CFA-induced renal damage. A role for GSTZ1-1-catalyzed release of fluoride from CFA is proposed but a role for other enzymes cannot be excluded. DFA, which is not metabolized to fluoride by GSTZ1-1, was given to rats as a control and was also nephrotoxic: rats given 1.2 mmol DFA/kg/day for 5 days had normal urine volumes but showed proximal and distal tubular damage; fluoride excretion was not elevated. The mechanism of DFA-induced nephrotoxicity is not known but appears to differ from that of CFA.
PMID: 12441371 [PubMed - in process]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12485864&dopt=AbstractAnn N Y Acad Sci 2002 Nov;973:218-20
No Abstract available
Involvement of protein kinase C in fluoride-induced apoptosis in different types of lung cells.
Refsnes M, Kersten H, Schwarze PE, Lag M.
Division of Environmental Medicine Norwegian Institute of Public Health, N-0403 Oslo, Norway. magne.refsnes@fhi.no
PMID: 12485864 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12411202&dopt=AbstractZhonghua Yu Fang Yi Xue Za Zhi 2002 Jul;36(4):235-8
Effects of selenium and fluoride on apoptosis and lipid peroxidation in human hepatocytes.
Wang A, Xia T, Ran P, Bai Y, Yang K, Chen X.
Department of Environmental Health, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430030, China.
OBJECTIVE: To study the influence of selenium and fluoride on apoptosis and lipid peroxidation in human hepatocytes in vitro.
METHODS: The apoptosis, cell cycle, GSH content and lipid peroxides (LPO) level in human hepatocytes, LPO level and LDH, AST and ALT activity in cell culture supernatants were investigated after hepatacytes were incubated with selenium and/or fluoride for around 12 hours periods in vitro.
RESULTS: The percentage of hepatocyte apoptosis bodies (15.557 +/- 2.056)%, the number of cells in S phase (4.823 +/- 0.454)% and LPO level in liver tissue and supernatant [(2.884 +/- 0.589) and (3.547 +/- 0.561) nmol/L MDA/mg.prot, respectively], AST and LDH activity in supernatants (91.1 +/- 36.4 and 140.4 +/- 7.6 U/L, respectively) in the fluoride treated group was higher than the control group [(10.313 +/- 1.023)%, (3.253 +/- 0.743)%, (1.473 +/- 0.401) nmol/L MDA/mg.prot, (1.694 +/- 0.443) nmol/L MDA/mg.prot, (54.5 +/- 3.2) U/L and (126.4 +/- 2.6) U/L, respectively], The GSH content in live tissue [(4.225 +/- 0.781) micro g/mg.prot] is lower than control group [(7.595 +/- 1.042) micro g/mg.prot]. Selenium treatment reduced these kinds of toxicity of fluoride through raising GSH content, reducing LPO level, LDH and AST activity and percentage of apoptosis bodies.
CONCLUSIONS: Selenium can antagonist apoptosis and lipid peroxidation of hepatocytes induced by fluoride.
PMID: 12411202 [PubMed - in process]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12271658&dopt=AbstractChem Commun (Camb) 2002 Sep 7;(17):1886-7
Vinyl fluoride as an isoelectronic replacement for an enolate anion: inhibition of type II dehydroquinases.
Frederickson M, Coggins JR, Abell C.
University Chemical Laboratory, Lensfield Road, Cambridge, UK CB2 1EW.
A vinyl fluoride analogue of the intermediate in the reaction catalysed by type II dehydroquinase enzymes has been synthesized over seven steps from (-)-quinic acid and shown to be a potent enzyme inhibitor.
PMID: 12271658 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12411197&dopt=AbstractZhonghua Yu Fang Yi Xue Za Zhi 2002 Jul;36(4):219-21
[Effects of selenium and zinc on rat renal apoptosis and change of cell cycle induced by fluoride]
[Article in Chinese]
Yu R, Xia T, Wang A, Chen X.
Department of Environmental Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
OBJECTIVE: This study was conducted to study the effects of sodium fluoride (NaF) on rat renal apoptosis and proliferation, the antagonistic effect of selenium-zinc preparation (Se-Zn) to NaF.
METHODS: Wistar rats were provided with distilled water containing NaF (50 mg/L) and administered by gavage with different dosed of Se-Zn for six months. Kidney cell apoptosis and the cell cycle of proliferation were detected by TUNEL (TdT-mediated dUTP Nick End Labelling) and flow cytometry.
RESULTS: NaF caused rat renal apoptosis, reduce the cell number of G(2)/M period in cell cycle and decrease the relative content of DNA significantly. Se-Zn inhibited the effects of NaF on apoptosis and increased the cell number of G(2)/M period in cell cycle, but failed to increase relative content of DNA.
CONCLUSION: It was suggested that NaF could induce apoptosis and change the cell cycle in rat renal cells and Se-Zn could antagonize apoptosis and the changes of cell cycle induced by NaF.PMID: 12411197 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11786381&dopt=AbstractJ Endocrinol 2002 Jan;172(1):137-43
- Differential effects of genistein on apoptosis induced by fluoride and pertussis toxin in human and rat pancreatic islets and RINm5F cells.
Elliott J, Scarpello JH, Morgan NG.
Cellular Pharmacology Group, School of Life Sciences, Keele University, Keele, Staffordshire ST5 5BG, UK.
Clonal pancreatic beta-cell lines have been used widely for the study of the factors involved in the regulation of apoptosis but it has not been firmly established that the response of normal islets mirrors that found in transformed beta-cells. In the present work, the role of pertussis toxin (Ptx)-sensitive G-proteins in the control of beta-cell apoptosis was studied in isolated rat and human islets of Langerhans and compared with the clonal beta-cell line, RINm5F. Annexin-V and deoxycarboxyfluoroscein diacetate staining was used to identify viable, apoptotic and necrotic cells directly, under fluorescence illumination. Treatment of human and rat islet cells with the G-protein activator fluoride (NaF; 5 mM) caused a marked increase in apoptosis that was further potentiated in islets pretreated with Ptx. The tyrosine kinase inhibitor genistein (100 microM) also increased islet cell apoptosis and the combination of 100 microM genistein and 5 mM NaF did not lead to any diminution of the apoptotic response. This latter effect was quite different from that seen in RINm5F cells where the combination of 100 microM genistein and 5 mM NaF resulted in much less apoptosis than was observed with either agent alone. In islets treated with a lower concentration of genistein (25 microM; that did not, itself, increase cell death), the drug attenuated NaF-induced apoptosis and also blocked the enhancement mediated by Ptx. These results revealed that human (and rat) islets are equipped with a Ptx-sensitive pathway that may be regulated by tyrosine phosphorylation and is anti-apoptotic. However, they also define conditions under which marked differences in response between RINm5F cells and normal islets were observed and they suggest that care should be taken when extrapolating data obtained with clonal cell lines to the situation in normal islet cells.
PMID: 11786381 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12206820&dopt=AbstractToxicol In Vitro 2002 Oct;16(5):531
Inhibition of vacuolation toxin activity of Helicobacter pylori by iodine, nitrite and potentiation by sodium chloride, sterigmatocystin and fluoride.
Ma F, Zhao W, Kudo M, Aoki K, Misumi J.
Department of Public Health and Hygiene, Oita Medical University, 1-1 Idaigaoka, Hasama-machi, 879-5593, Oita, Japan
The toxin VacA produced by Helicobacter pylori is an important determinant of virulence. VacA causes vacuolation of cultured cells such as HeLa cells. Iodine, nitrite, sodium chloride, thiocyanate and fungus toxin sterigmatocystin are universally present in nature and could possibly be related to carcinogenesis of the stomach. The present study was designed to examine the effects of the above-mentioned compound on VacA-induced vacuolation of HeLa cells, which was quantitated using the neutral red uptake assay. VacA-induced vacuolation was inhibited by BafA1 and NPPB. Formation of large vacuoles was inhibited in the presence of iodine, nitrite, but enhanced by sodium chloride, thiocyanate, fluoride and sterigmatocystin. Our results indicate that VacA toxin may interact with other gastric cancer risk factors present naturally in the environment, and suggest that those compounds may modulate the development of gastric cancer induced by H. pylori.
PMID: 12206820 [PubMed - in process]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12022883&dopt=AbstractBiochemistry 2002 May 28;41(21):6789-97
Mitochondrial aconitase modification, functional inhibition, and evidence for a supramolecular complex of the TCA cycle by the renal toxicant S-(1,1,2,2-tetrafluoroethyl)-L-cysteine.
James EA, Gygi SP, Adams ML, Pierce RH, Fausto N, Aebersold RH, Nelson SD, Bruschi SA.
Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA.
Metabolism of the common industrial gas tetrafluoroethylene in mammals results in the formation of S-(1,1,2,2)-tetrafluoroethyl-L-cysteine (TFEC), which can be bioactivated by a mitochondrial C-S lyase commonly referred to as beta-lyase. The resultant "reactive intermediate", difluorothioacetyl fluoride (DFTAF), is a potent thioalkylating and protein-modifying species. Previously, we have identified mitochondrial HSP70, HSP60, aspartate aminotransferase, and the E2 and E3 subunits of the alpha-ketoglutarate dehydrogenase (alphaKGDH) complex as specific proteins structurally modified during this process. Moreover, functional alterations to the alphaKGDH complex were also detected and implicated in the progression of injury. We report here the identification, by tandem mass spectrometry, and functional characterization of the final remaining major protein species modified by DFTAF, previously designated as P99(unk), as mitochondrial aconitase. Aconitase activity was maximally inhibited by 56.5% in renal homogenates after a 6 h exposure to TFEC. In comparison to alphaKGDH, aconitase inhibition (up to 79%) in a cell culture model for TFEC-mediated cytotoxicity was greater and preceded alphaKGDH inhibition, indicating that aconitase modification may constitute an early event in TFEC-mediated mitochondrial damage and cell death. These findings largely define the initial lesion of TFEC-mediated cell death and also have implications for the modeling of mitochondrial enzymatic architecture and the localization and identity of renal mitochondrial cysteine S-conjugate beta-lyase.
PMID: 12022883 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12145871&dopt=AbstractLik Sprava 2002 Apr-Jun;(3-4):104-6
[Features of the effects of zinc and fluorine on functional status of rat liver]
[Article in Russian]
Inoiatov FSh.
Intoxication of rats of both sexes three months in duration leads to development of cytolysis and hepatocellular insufficiency, with females displaying a higher degree of it. At the same time, fluorine promotes development of hypolipoperoxidation in males. In females, unlike males, intensification of LPO tended to grow higher and was to be seen with both agents. SOD activation has been revealed in exposure of females to zinc and of males to both fluorine and zinc. Also revealed in the animals was activation of catalase, especially so in males. Activation of membranodestructive processes in the liver of test animals brings about a decline in the pharmacometabolizing function of the organ.
PMID: 12145871 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12189624&dopt=AbstractVopr Med Khim 2002 Mar-Apr;48(2):174-9
[Toxic effects of various water pollutants on structural and functional parameters of hepatocytes]
[Article in Russian]
Karimov KhIa, Inoiatova FKh, Inoiatov FSh.
Tashkent State Second Medical Institute, Uzbekistan.
A prolonged intragastral intoxication of male and female rats by low doses of fluorine, zinc, chromium, arsenite, and combination of these compounds lead to developing cytolysis and hepatic-cellular insufficiency. These changes are more pronounced in female rats especially if chromium, arsenite and a combination of toxicants were used. They lead to developing hyper lipid peroxidation in male rats the most expressed by intoxication with arsenite and combined effect. Unlike to male rats LPO intensity in female rats was more pronounced and fixed by effect of all preparations. SOD activation was revealed to be in male rats by effect of chromium and especially zinc, in female rats by effect of fluorine and zinc. A distinctive inhibition of SOD activity determined to be by using arsenite and combination of toxicants. Activation of catalase especially in male rats was also revealed. Activation of membrane-destructive processes in the liver of experimental animals results in reducing pharmaco-metabolizing function of this organ.
PMID: 12189624 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12187767&dopt=AbstractYakugaku 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, Shizuoka 422-8526, Japan. ysuketa@theia.ocn.ne.jp
The authors' research focuses on polyuria, natriuresis, glucosuria, glycemia, and renal calcification in occupational lead poisoning and endemic fluorosis. 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 the 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]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12122575&dopt=AbstractInhal 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 immediate 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 subjects at the same time points but without HF exposure. At the end of HF exposure, 7 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. Among 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 human 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 occupational hazard.
PMID: 12122575 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12109808&dopt=Abstract
Biomed Pharmacother 2002 Jun;56(4):169-72Effects of sodium fluoride on total serum protein levels and transaminase activity in rats.
Qujeq D, Laghaie B, Gholipour A, Solimani N, Hassenzadeh S.
Department of Biochemistry and Biophysics, Babol University of Medical Sciences, Iran. dqujeq@hotmail.com
Transaminase activity and serum total protein level were investigated in adult rats after oral treating with sodium fluoride at three doses, 10, 20 and 30 mg/kg daily for 90 days. After 90 days, the average total serum protein level of the rats in the treatment group decreased significantly compared with that in the control [1.9 +/- 0.1 (mean +/- S.D., n = 140) vs. 3.1 +/- 0.2] mg/dl, P< 0.05. Serum transaminase activity in the treatment group increased compared with that in the control [5.3 +/- 0.4 (mean +/- S.D., n = 140) vs. 3.2 +/- 0.3] micromol/min per ml, P < 0.05.
PMID: 12109808 [PubMed - in process]
Full report availavle at: http://www.fluoride-journal.com/02-35-1/351-38.pdfFluoride 2002; 35(1):38-50
Toxic effects of fluoride on rabbit kidney
A Shashi (a), JP Singh, SP Thapar (b)
(a) Department of Zoology, Punjabi University, Patiala - 147 002, Punjab, India. E-mail: aggarwalshashi@rediffmail.com;
(b) Department of Anatomy, Dayanand Medicial College and Hospital, Ludhiana, India.Summary: The purpose of this study was to assess renal damage in experimental fluorosis. Young albino rabbits were injected with 5, 10, 20, and 50 mg NaF/kg body weight/day for fifteen weeks and then sacrificed. No significant clinical signs of toxicity were found in animals exposed to the lowest dose. At the higher doses, however, the cytoachitecture of the kidneys exhibited increasing amounts of cloudy swellings, degeneration of tubular epithelia, tissue necrosis, extensive vacuolization in renal tubules, hypertrophy and atro-phy of glomeruli, exudation, interstitial oedema, and interstitial nephritis. These changes in the kidneys result in impaired renal function in chronic fluoride intoxication.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11996908&dopt=AbstractBone 2002 May;30(5):705-11
Bone cell mitogenic action of fluoroaluminate and aluminum fluoride but not that of sodium fluoride involves upregulation of the insulin-like growth factor system.
Lau KH, Goodwin C, Arias M, Mohan S, Baylink DJ.
Musculoskeletal Disease Center (151), Jerry L. Pettis Memorial VA Medical Center, 11201 Benton Street, Loma Linda, CA 92357, USA. laub@lom.med.va.gov
The fluoroaluminate (AlF(4)(-)) ion and sodium fluoride (NaF) have previously been shown to be bone cell mitogens. This study sought to determine whether the bone cell mitogenic action of AlF(4)(-) and/or NaF would involve the insulin-like growth factor (IGF) regulatory system. We evaluated the effect of mitogenic doses of AlF(4)(-) and NaF on the mRNA levels and the protein level (in conditioned media [CM]) of several components of the IGF system (i.e., IGF-2, IGF binding protein [IGFBP]-4, and IGFBP-5) in human TE85 osteosarcoma cells. Aluminum fluoride (AlF(3)) was included for comparison. NaF, AlF(3), and AlF(4)(-), each at 50-100 micromol/L, increased [3H]thymidine incorporation in TE85 cells. Mitogenic concentrations of AlF(3) and AlF(4)(-): (1) increased the mRNA (up to twofold after 24 h treatment) and protein (in CM) levels (up to 2.5-fold after 48 h treatment) of IGF-2; (2) increased the mRNA level (twofold) and the protein level in CM (up to threefold) of stimulatory IGFBP-5; and (3) either reduced slightly or had no effect on the mRNA and protein (in CM) levels of the inhibitory IGFBP-4. Conversely, mitogenic concentrations of NaF had no significant effects on the protein (in CM) or mRNA level of IGF-2, IGFBP-4, or IGFBP-5. The addition of an inhibitory concentration of IGFBP-4 completely abolished the bone cell mitogenic activity of AlF(3) and AlF(4)(-) but not that of NaF. The findings of this study provide strong evidence that the bone cell mitogenic activity of AlF(4)(-) and AlF(3), but not that of NaF, is mediated by the upregulation of the IGF regulatory system.
PMID: 11996908 [PubMed - in process]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12359072&dopt=AbstractJ Biochem (Tokyo) 2002 Oct;132(4):573-9
Formation and Characterization of Kinesin.ADP. Fluorometal Complexes.
Shibuya H, Kondo K, Kimura N, Maruta S.
Department of Bioengineering, Faculty of Engineering, Soka University, Hachioji, Tokyo 192-8577, Japan. shinsaku@t.soka.ac.jp
Recent crystallographic studies of motor proteins showed that the structure of the motor domains of myosin and kinesin are highly conserved. Thus, these motor proteins, which are important for motility, may share a common mechanism for generating energy from ATP hydrolysis. We have previously demonstrated that, in the presence of ADP, myosin forms stable ternary complexes with new phosphate analogues of aluminum fluoride (AlF(4)(-)) and beryllium fluoride (BeF(n)), and these stable complexes mimic the transient state along the ATPase kinetic pathway [Maruta et al. (1993) J. Biol. Chem. 268, 7093-7100]. In this study, we examined the formation of kinesin.ADP.fluorometals ternary complexes and analyzed their characteristics using the fluorescent ATP analogue NBD-ATP (2'(3')-O-[6-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)hexanoyl]-ADP). Our results suggest that these ternary complexes may mimic transient state intermediates in the kinesin ATPase cycle. Thus, the kinesin.ADP.AlF(4)(-) complex resembles the kinesin.ADP state, and the kinesin.ADP.BeF(n) complex mimics the kinesin.ADP.P(i) state.
PMID: 12359072 [PubMed - in process]
[FAN Note:]
-- Kinesin: Protein associated with neuronal microtubules; involved in anterograde ATP-dependent transport of organelles and vesicles. http://www.fleshandbones.com/physiology/davies/glossary.cfm?letter=D
-- the track-following molecular motors kinesin, myosin and dynein are responsible not only for the transport and targetting of cellular components, but also for tensioning, sliding and rearranging cellular arrays of microtubules and actin filaments, and even for governing their rates of assembly and disassembly. http://mc11.mcri.ac.uk/ebiochem.html
-- The microtubule cytoskeleton plays an essential role in many cellular processes including growth, division, differentiation, intracellular transport, and secretion... Microtubules play an essential role in eukaryotic cells, notably as the rails along which vesicles are transported around the cell. They also act as guides for the movement of chromosomes during cell division. Microtubules are continuously being formed and dismantled, at varying speed depending on cell activity. http://www.cnrs.fr/Cnrspresse/n388/html/en388a05.htm
-- Eukaryotic cells (from the Greek meaning truly nuclear) comprise all of the life kingdoms except monera. They can be easily distinguished through a membrane-bound nucleus. Eukaryotic cells also contain many internal membrane-bound structures called organelles. These organelles such as the mitochondrion or chloroplast serve to perform metabolic functions and energy conversion. Other organelles like intracellular filaments provide structural support and cellular motility. The function of individual organelles is described in detail in the Cell Anatomy Section. Another important member of the eukaryote family is the plant cell. They function essentially in the same manner as other eukaryotic cells, but there are three unique structures which set them apart. Plastids, cell walls, and vacuoles are present only in plant cells. http://library.thinkquest.org/C004535/eukaryotic_cells.html
-- The structural similarity between the kinesin and myosin cores suggests that these motors diverged from a common ancestor and may use a similar strategy for converting chemical energy into mechanical work. http://mc11.mcri.ac.uk/khome/KinesinCrystalStruc.html
-- Definition of a myosin: A protein that: (1) binds to F-actin; (2) has actin-activated ATPase activity; (3) converts the energy of ATP hydrolysis into directed movement. http://idp.med.ufl.edu/Core/Outln5/S5L4_L.pdf
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11927263&dopt=Abstract
Chem Biol 2002 Mar;9(3):375-81MgF(3)(-) as a transition state analog of phosphoryl transfer.
Graham DL, Lowe PN, Grime GW, Marsh M, Rittinger K, Smerdon SJ, Gamblin SJ, Eccleston JF.
Computational & Structural Sciences, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts, United Kingdom.
The formation of complexes between small G proteins and certain of their effectors can be facilitated by aluminum fluorides. Solution studies suggest that magnesium may be able to replace aluminum in such complexes. We have determined the crystal structure of RhoA.GDP bound to RhoGAP in the presence of Mg(2+) and F(-) but without Al(3+). The metallofluoride adopts a trigonal planar arrangement instead of the square planar structure of AlF(4)(-). We have confirmed that these crystals contain magnesium and not aluminum by proton-induced X-ray emission spectroscopy. The structure adopted by GDP.MgF(-) possesses the stereochemistry and approximate charge expected for the transition state. We suggest that MgF3(-) may be the reagent of choice for studying phosphoryl transfer reactions.
PMID: 11927263 [PubMed - indexed for MEDLINE]
- http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14694637&dopt=Abstract
Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi. 2002 Jun;20(3):192-4.
[Study on the correlation of the biochemical indexes in flouride workers]
[Article in Chinese]
Huang Z, Li K, Hou G, Shen Z, Wang C, Jiang K, Luo X.
Henan Institute of Occupational Disease, Zhengzhou 450052, China.
OBJECTIVE: To explore the correlation among some biochemical indexes in the fluoride workers.
METHODS: The activities of superoxide dismutase(SOD), glutathione peroxidase (GSH-Px), catalase (CAT), alkaline phosphatase (AKP) and the level of calcitonin (CT), parathyroid hormone (PTH), IgG, IgA, IgM, Cu2+, Zn2+, Ca2+, Mg2+ and Se2+, F- in serum and in urine were measured in fifty male fluoride workers and fifty controls.
RESULTS: The levels of F-, CT, PTH, AKP and GSH-Px in serum and F- in urine in exposed group were significantly different from that in control group. Correlation analysis indicated that F- in urine and CAT(r = 0.3133, P < 0.05), CT and PTH(r = 0.5173, P < 0.01), Se2+ and CAT(r = 0.4354, P < 0.05) were positively correlated. There were significantly negative correlation between F- in serum and GSH-Px (r = -0.5202, P < 0.01) and positive correlation among Cu2+, Zn2+, Ca2+ and Mg2+ in serum.
CONCLUSION:
(1) Excess of fluoride may affect secretion of calcium adjusting hormone (CT, PTH);
(2) Changes of AKP and GSH-Px may be regarded as health monitoring indexes;
(3) The correlation of biochemical indexes plays an important role in studying the mechanism and the early prevention and treatment of industrial fluorosis.
PMID: 14694637 [PubMed - in process]
- http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11960978&dopt=Abstract
J Biol Chem 2002 Jun 21;277(25):22547-52
Evidence for a transition state analog, MgADP-aluminum fluoride-acetate, in acetate kinase from Methanosarcina thermophila.
Miles RD, Gorrell A, Ferry JG.
Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802-4500, USA.
Aluminum fluoride has become an important tool for investigating the mechanism of phosphoryl transfer, an essential reaction that controls a host of vital cell functions. Planar AlF(3) or AlF(4)(-) molecules are proposed to mimic the phosphoryl group in the catalytic transition state. Acetate kinase catalyzes phosphoryl transfer of the ATP gamma-phosphate to acetate. Here we describe the inhibition of acetate kinase from Methanosarcina thermophila by preincubation with MgCl(2), ADP, AlCl(3), NaF, and acetate. Preincubation with butyrate in place of acetate did not significantly inhibit the enzyme. Several NTPs can substitute for ATP in the reaction, and the corresponding NDPs, in conjunction with MgCl(2), AlCl(3), NaF, and acetate, inhibit acetate kinase activity. Fluorescence quenching experiments indicated an increase in binding affinity of acetate kinase for MgADP in the presence of AlCl(3), NaF, and acetate. These and other characteristics of the inhibition indicate that the transition state analog, MgADP-aluminum fluoride-acetate, forms an abortive complex in the active site. The protection from inhibition by a non-hydrolyzable ATP analog or acetylphosphate, in conjunction with the strict dependence of inhibition on the presence of both ADP and acetate, supports a direct in-line mechanism for acetate kinase.
PMID: 11960978 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12419692&dopt=AbstractFood Chem Toxicol 2002 Dec;40(12):1781-8
Sodium fluoride-induced hypoproteinemia and hypoglycemia in parental and F(1)-generation rats and amelioration by vitamins.
Verma RJ, Guna Sherlin DM.
Department of Zoology, University School of Sciences, Gujarat University, Ahmedabad 380 009, India
Oral administration of sodium fluoride (NaF; 40 mg/kg body weight) daily from day 6 of gestation to day 21 of lactation caused, compared with the distilled water control (group 2), significant reductions in body weight and feed consumption as well as concentration of glucose and protein in the serum of P- and F(1)-generation rats; however, sodium and potassium concentrations in the serum were significantly higher than those of the vehicle control (group 2). Administration of either vitamins C (50 mg/kg body weight/day), D (2 ng/0.2 ml olive oil/animal/day) or a combination of vitamins C+D+E along with NaF caused significant amelioration in body weight and feed consumption, as well as glucose, protein, sodium and potassium concentrations in the serum of P- and F(1)-generation rats compared with the NaF-only treated group. Withdrawal of NaF treatment during lactation caused significant amelioration in feed consumption (days 15-21 only), sodium, potassium, glucose and protein concentrations in the serum of both P- and F(1)-generation rats. Co- treatment with vitamin E (2 mg/0.2 ml olive oil/animal/day) caused significant amelioration in body weight (days 15 and 20 of gestation only), sodium, potassium, glucose (only in P-generation females) and protein (only in P-generation female) concentrations in the serum of rats than in NaF-treated rats alone. It is concluded that co-treatment with vitamins C, D and C+D+E were found more effective in ameliorating NaF-induced effects than vitamin E and withdrawal of NaF treatment during lactation.
PMID: 12419692 [PubMed - in process]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12206591&dopt=AbstractEur J Oral Sci 2002 Aug;110(4):296-301
Amine fluoride gel affects the viability and the generation of superoxide anions in human polymorphonuclear leukocytes: an in vitro study.
Knoll-Kohler E, Stiebel J.
Institute of Pharmacology, Benjamin Franklin Medical Center, Freie Universitat Berlin, Germany. kno@zedat.fu-berlin.de
Amine hydrofluorides are widely used to prevent caries. As an acidulated gel, they were also studied for their applicability to reduce pathogenic bacteria in periodontal pockets. We assessed the toxicity of this pharmaceutical amine hydrofluoride preparation on human polymorphonuclear leukocytes in vitro by measuring Trypan blue exclusion and the generation of superoxide anions (O2) by the chemotactic peptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) after a 3-min contact with gel. Depending on the experimental conditions, gel dilutions up to 1.3 x 10(4) resulted in an increase in Trypan blue-colored cells and liberation of beta-glucuronidase. Dilutions between 3 x 10(4) and 1 x 10(5) augmented the fMLP-mediated O2- generation, which could be prevented by Ca2+ chelation with BAPTA-AM (1,2'-bis (o-aminophenoxyethane-N.N.N'.N'-tetraacetic acid tetra (acetoxymethyl) ester) and ethyleneglycoltetraacetic acid (EGTA) or inhibition of protein kinase C (PKC) with staurosporine and bisindolylmaleimide I. respectively. Compared with data published on the minimal inhibitory concentration for periodontal pathogenic bacteria, the cytotoxicity of amine hydrofluorides on eukaryotic cells is much greater and thus of consequence for their clinical use.
PMID: 12206591 [PubMed - in process]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12905771&dopt=AbstractZhongguo Yi Xue Ke Xue Yuan Xue Bao. 2002 Oct;24(5):491-4.
[Expression of Fas, FasL, and NF-kappa B in the process of osteoclast-like cell apoptosis effected by sodium fluoride]
[Article in Chinese]
Sun YM, Yang FJ, Li YM, Lu B, Zhu M, Qiu MC.
Department of Radiobiology, Institute of Radiation Medicine, CAMS, PUMC, Tianjin 300192, China.
OBJECTIVE: To detect the changes in the expression of apoptosis signals: Fas, FasL and NF-kappa B in the process of osteoclast-like cell (OLC) apoptosis effected by sodium fluoride.
METHODS: After co-culture of osteoclast-like cells with 0, 5, 10 and 15 mg/L sodium fluoride, Fas, FasL and NF-kappa B antibody expressions were detected by immune-histochemistry.
RESULTS: The expression of Fas and FasL increased with the concentration of the sodium fluoride, however the expression of NF-kappa B decreased with the concentration of sodium fluoride.
CONCLUSION: In the process of OLC apoptosis induced by sodium fluoride, the expression of Fas and FasL increased, and that of NF-kappa B decreased with the concentration of sodium fluoride respectively, and the changes of the expression present a dose-dependent pattern.PMID: 12905771 [PubMed - in process]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11867637&dopt=Abstract
- J Biol Chem 2002 May 10;277(19):16599-605
Fluoride exposure attenuates expression of Streptococcus pyogenes virulence factors.
Thongboonkerd V, Luengpailin J, Cao J, Pierce WM, Cai J, Klein JB, Doyle RJ.
Core Proteomics Laboratory, Kidney Disease Program, Department of Medicine, University of Louisville, Louisville, Kentucky 40202, USA.
Fluoridation causes an obvious reduction of dental caries by interference with cariogenic streptococci. However, the effect of fluoride on group A streptococci that causes rheumatic fever and acute poststreptococcal glomerulonephritis is not known. We have used proteomic analysis to create a reference proteome map for Streptococcus pyogenes and to determine fluoride-induced protein changes in the streptococci. Cellular and extracellular proteins were resolved by two-dimensional polyacrylamide gel electrophoresis and identified by matrix-assisted laser desorption ionization mass spectrometry. 183 protein spots were visualized, and 74 spots representing 60 unique proteins were identified. A 16-h exposure to sodium fluoride caused decreased expression of proteins required to respond to cellular stress, including anti-oxidants, glycolytic enzymes, transcriptional and translational regulators, and protein folding. Fluoride caused decreased cellular expression of two well-characterized S. pyogenes virulence factors. Fluoride decreased expression of glyceraldehyde-3-phosphate dehydrogenase, which acts to bind fibronectin and promote bacterial adherence. We also performed proteomic analysis of protein released by S. pyogenes into the culture supernatant and observed decreased expression of M proteins following fluoride exposure. These data provide evidence that fluoride causes decreased expression by S. pyogenes proteins used to respond to stress, virulence factors, and implicated in non-suppurative complications of S. pyogenes, including glomerulonephritis and rheumatic fever.
PMID: 11867637 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11843158&dopt=AbstractChemistry 2002 Jan 18;8(2):457-66
Theoretical prediction of the hydrogen-bond basicity pK(HB).
Lamarche O, Platts JA.
Department of Chemistry, Cardiff University, UK.
Ab initio and DFT calculations on around 65 hydrogen bond or Lewis bases and their complexes with hydrogen fluoride have been performed, and a range of calculated properties from both free bases and complexes correlated with pK(HB), an experimental scale of hydrogen-bond basicity. For the entire range of bases, we found that the hydrogen-bond binding Gibbs free energy computed at the B3LYP/6-31+G(d,p) level of theory linearly correlated with pK(HB). Further improvements in the correlation and prediction of pK(HB) were possible with a non-linear fit by considering the hydrogen bonding Gibbs free energy of another possible stereoisomeric 1:1 complex and/or that of a linear 2:1 complex, which included a second hydrogen fluoride.
PMID: 11843158 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11836100&dopt=AbstractBioorg Med Chem 2002 Apr;10(4):929-34
Novel steroidal vinyl fluorides as inhibitors of steroid C17(20) lyase.
Burkhart JP, Weintraub PM, Gates CA, Resvick RJ, Vaz RJ, Friedrich D, Angelastro MR, Bey P, Peet NP.
Aventis Pharmaceuticals, Route 202-206, Bridgewater, NJ 08807-0800, USA.
20-fluoro-17(20)-pregnenolone derivatives were designed as enol mimics of pregnenolone. All of the targeted, novel fluoroolefins were potent inhibitors of C17(20) lyase.
PMID: 11836100 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11830596&dopt=AbstractJ Biol Chem 2002 Apr 19;277(16):13615-9
Remarkable stability of solubilized and delipidated sarcoplasmic reticulum Ca2+-ATPase with tightly bound fluoride and magnesium against detergent-induced denaturation.
Yamasaki K, Daiho T, Suzuki H.
Department of Biochemistry, Asahikawa Medical College, Asahikawa 078-8510, Japan.
Conditions were developed in the absence of Ca(2+) for purification, delipidation, and long term stabilization of octaethylene glycol monododecyl ether (C(12)E(8))-solubilized sarcoplasmic reticulum Ca(2+)-ATPase with tightly bound Mg(2+) and F(-), an analog for the phosphoenzyme intermediate without bound Ca(2+). The Ca(2+)-ATPase activity to monitor denaturation was assessed after treatment with 20 mm Ca(2+) to release tightly bound Mg(2+)/F(-). The purification and delipidation was successfully achieved with Reactive Red-agarose affinity chromatography. The solubilized Mg(2+)/F(-)-bound Ca(2+)-ATPase was very rapidly denatured at pH 8, but was perfectly stabilized at pH 6 against denaturation for over 20 days at 4 degrees C even without exogenously added phospholipid and at a high C(12)E(8)/enzyme weight ratio (10:1). The activity was not restored unless the enzyme was treated with 20 mm Ca(2+), showing that tightly bound Mg(2+)/F(-) was not released during the long term incubation. The perfect stability was attained with or without 0.1 mm dithiothreitol, but inactivation occurred with a half-life of 10 days in the presence of 1 mm dithiothreitol, possibly due to reduction of a specific disulfide bond(s). The remarkable stability is likely conferred by intimate gathering of cytoplasmic domains of Ca(2+)-ATPase molecule induced by tight binding of Mg(2+)/F(-). The present study thus reveals an essential property of the Mg(2+)/F(-)/Ca(2+)-ATPase complex, which will likely provide clues to understanding structure of the Ca(2+)-released form of phosphoenzyme intermediate at an atomic level.
PMID: 11830596 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11929560&dopt=AbstractOral Microbiol Immunol 2002 Apr;17(2):119-24
Fluoride and organic weak acids as respiration inhibitors for oral streptococci in acidified environments.
Phan TN, Nguyen PT, Abranches J, Marquis RE.
Department of Microbiology & Immunology and Center for Oral Biology, University of Rochester Medical Center, Rochester, NY 14642-8672, USA.
Oxygen metabolism (respiration) of Streptococcus mutans GS-5 involving NADH oxidases, mainly of the H(2)O-producing type, was found to be acid sensitive, as was NADH oxidase activity of cell extracts. Respiration of intact cells in acidified media was also highly sensitive to fluoride, with a 50% inhibitory concentration of about 0.02 mM at pH 4. In contrast, NADH oxidases in cell extracts were fluoride insensitive. Fluoride inhibition of respiration of intact cells was related to weak-acid effects leading to enhanced proton permeability of cells, cytoplasmic acidification and resultant acid inhibition of NADH oxidases and glycolysis. Organic weak acids, such as indomethacin and benzoate, were also effective inhibitors. H(2)O(2) production by intact cells of Streptococcus sanguis NCTC 10904, a peroxide producer, was similarly inhibited by fluoride or organic weak acids in acidified media. Thus, weak acids act as respiratory inhibitors for oral streptococci indirectly by acidifying the cytoplasm rather than acting as direct inhibitors of NADH oxidases.
PMID: 11929560 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11893417&dopt=AbstractToxicology 2002 Apr 2;172(3):181-90
Organophosphorus pesticides markedly inhibit the activities of natural killer, cytotoxic T lymphocyte and lymphokine-activated killer: a proposed inhibiting mechanism via granzyme inhibition.
Li Q, Nagahara N, Takahashi H, Takeda K, Okumura K, Minami M.
Department of Hygiene and Public Health, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan. qing-li@nms.ac.jp
We have previously found that diisopropyl methylphosphonate, an organophosphorus by-product generated during sarin synthesis in the Tokyo sarin disaster, significantly inhibited natural killer (NK) and cytotoxic T lymphocyte (CTL) activities. In the present study, to investigate whether organophosphorus pesticides (OPs) also affect NK and CTL activities, we firstly examined the effect of five OPs on human NK activity, and then the effect of Dimethyl 2,2-dichlorovinyl phosphate (DDVP), an OP on murine splenic NK, CTL and lymphokine-activated killer (LAK), and human LAK activities in vitro. To explore the underlying mechanism of decreased NK activity, we also investigated the effect of 4-(2-aminoethyl) benzenesulfonyl fluoride-HCl (p-ABSF), an inhibitor of serine proteases on NK, LAK and CTL activities, and the effect of DDVP on the activity of granzymes (serine proteases). We found that OPs significantly decreased human NK activity in a dose-dependent manner, but the degree of decrease in NK activity differed among the OPs investigated, and that DDVP significantly decreased NK, LAK and CTL activities in a dose-dependent manner, but the degree of decrease in these activities differed. p-ABSF showed a similar inhibitory pattern to DDVP, and had an additive inhibitory effect with DDVP on NK, LAK and CTL activities. We also found that DDVP significantly inhibited granzyme activity in a dose-dependent manner. These findings indicate that OPs significantly decrease NK, LAK and CTL activities in vitro via granzyme inhibition.
PMID: 11893417 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11893414&dopt=AbstractFood Chem Toxicol 2002 Apr;40(4):551-4
Hypocalcaemia in parental and F1 generation rats treated with sodium fluoride.
Verma RJ, Sherlin DM.
Department of Zoology, University School of Sciences, Gujarat University, 380 009, Ahmedabad, India. zooldeptgu@satyam.net.in
The potential of sodium fluoride (NaF) to affect serum cations was assessed in the parent (P) and F1 generation rats. The sperm-positive pregnant experimental female rats received 40 mg NaF/kg body weight from day 6 of gestation either up to 21 days of lactation or only up to gestation followed by withdrawal of the treatment during lactation. On day 21 of lactation, blood samples were collected from P and F1 generation rats, allowed to clot and centrifuged at 1000 g for 10 min to obtain serum for analysis of various cations. Statistically significant increases in the concentrations of sodium and potassium in the serum of P and F1 generation rats were observed in the NaF-treated group; however, calcium and phosphorus concentrations were significantly lower than their vehicle control. Withdrawal of NaF treatment during lactation caused significant recovery in sodium, potassium and phosphorus concentrations in P and F1 generation rats as compared with NaF-treated animals. Although statistically significant recovery was not observed, the calcium concentration in P and F1 generation rats was comparatively higher on withdrawal of NaF treatment than in the NaF-treated group. It is concluded that the exposure of 40 mg NaF/kg body weight in pregnant female rats caused significant alterations in cationic concentration which recovered significantly (except calcium) on withdrawal of the treatment.
PMID: 11893414 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11820897&dopt=AbstractOrg Lett 2002 Feb 7;4(3):431-4
Surprises in the energetics of host-guest anion binding to calix[4]pyrrole.
Schmidtchen FP.
Institut fur Organische Chemie und Biochemie, Technische Universitat Munchen, D-85747 Garching, Germany. schmidtchen@ch.tum.de
Contrary to common expectation, calorimetric measurements do not corroborate the preference of calix[4]pyrrole for fluoride over chloride in acetonitrile solution.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12375165&dopt=AbstractParasitol Res 2002 Nov;88(11):991-7
Characterization of an ecto-phosphatase activity in the human parasite Trichomonas vaginalis.
De Jesus JB, Podlyska TM, Hampshire A, Lopes CS, Vannier-Santos MA, Meyer-Fernandes JR.
Instituto de Microbiologia, Universidade Federal do Rio de Janeiro,Cidade Universitaria, Ilha do Fundao, 21941-590, Rio de Janeiro, R.J., Brazil.
We have characterized phosphatase activity present on the external surface of Trichomonas vaginalis, using intact living parasites. This enzyme hydrolyzes the substrate p-nitrophenylphosphate ( p-NPP) at a rate of 134.3+/-14.8 nmol Pi/h per 10(7) cells. This phosphatase activity decreased by increasing the pH from 6.8 to 8.4, a pH range in which cell viability was maintained for at least 1 h. Experiments using classical inhibitors of acid phosphatases, such as ammonium molybdate and sodium fluoride, as well as inhibitors of phosphotyrosine phosphatase, such as sodium orthovanadate, [monoperoxo(picolinato)oxovanadate(V)] (mpV-PIC) and [potassiumbisperoxo(1,10-phenanthroline)oxovanadate(V)] (bpV-PHEN), showed a decrease in this phosphatase activity, with different patterns of inhibition. Cytochemical analysis showed the localization of this enzyme on the parasite surface (cell body and flagellum) and in intracellular vacuoles. Phosphatase reaction products were also observed in exocytosed membrane-bound material.
PMID: 12375165 [PubMed - in process]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12022883&dopt=Abstract
Biochemistry 2002 May 28;41(21):6789-97
Mitochondrial aconitase modification, functional inhibition, and evidence for a supramolecular complex of the TCA cycle by the renal toxicant S-(1,1,2,2-tetrafluoroethyl)-L-cysteine.
James EA, Gygi SP, Adams ML, Pierce RH, Fausto N, Aebersold RH, Nelson SD, Bruschi SA.
Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA.
Metabolism of the common industrial gas tetrafluoroethylene in mammals results in the formation of S-(1,1,2,2)-tetrafluoroethyl-L-cysteine (TFEC), which can be bioactivated by a mitochondrial C-S lyase commonly referred to as beta-lyase. The resultant "reactive intermediate", difluorothioacetyl fluoride (DFTAF), is a potent thioalkylating and protein-modifying species. Previously, we have identified mitochondrial HSP70, HSP60, aspartate aminotransferase, and the E2 and E3 subunits of the alpha-ketoglutarate dehydrogenase (alphaKGDH) complex as specific proteins structurally modified during this process. Moreover, functional alterations to the alphaKGDH complex were also detected and implicated in the progression of injury. We report here the identification, by tandem mass spectrometry, and functional characterization of the final remaining major protein species modified by DFTAF, previously designated as P99(unk), as mitochondrial aconitase. Aconitase activity was maximally inhibited by 56.5% in renal homogenates after a 6 h exposure to TFEC. In comparison to alphaKGDH, aconitase inhibition (up to 79%) in a cell culture model for TFEC-mediated cytotoxicity was greater and preceded alphaKGDH inhibition, indicating that aconitase modification may constitute an early event in TFEC-mediated mitochondrial damage and cell death. These findings largely define the initial lesion of TFEC-mediated cell death and also have implications for the modeling of mitochondrial enzymatic architecture and the localization and identity of renal mitochondrial cysteine S-conjugate beta-lyase.
PMID: 12022883 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12095014&dopt=AbstractEur J Anaesthesiol 2002 May;19(5):341-9
Fluoride ion toxicity in rabbit kidney thick ascending limb cells.
Cittanova ML, Estepa L, Bourbouze R, Blanc O, Verpont MC, Wahbe E, Coriat P, Daudon M, Ronco PM.
Departement d'Anesthesie-Reanimation, Hjpital Pitie-Salpetriere, Paris, France. marie-laure.cittanova@psl.ap-hop-paris.fr
BACKGROUND AND OBJECTIVE: Some halogenated agents, especially methoxyflurane, because of a higher level of fluoride production, induce a renal concentrating defect that could be related to an ascending limb impairment. We investigated the mechanisms of fluoride toxicity on an immortalized cell line.
METHODS: Cells were cultured for 2, 6 or 24 h in the presence of fluoride. Toxicity evaluation was based on: cell numbers, protein content, leucine-incorporation, lactate dehydrogenase (LDH) and N-acetyl-beta-glucosaminidase (NAG) releases, Na-K-ATPase and Na-K-2Cl activities, electron microscope studies. Infrared analysis and fluoride microdetermination allowed crystal components.
RESULTS: At 5 mmol after 24 h, fluoride decreased cell numbers (-14%, *P < 0.05), protein content (-16%*), leucine incorporation (-54%*), Na-K-2Cl activity (-84%*), increased LDH (+145%*) and NAG release (+190%*). Na-K-ATPase was more sensitive and impaired from 1 mmol for 24h and after 2 h at 5 mmol. Crystal formation in mitochondria occurred after 6 h at 5 mmol. Infra-red analysis and fluoride microdetermination established that crystals contained sodium, phosphate and fluoride.
CONCLUSIONS: The results suggest that the Na-K-ATPase pump is a major target for fluoride toxicity in Henle's loop.
PMID: 12095014 [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 fluoride 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 showed that aluminum and fluoride concentration in serum and urine increase, GSH-Px activity reduces, MDA concentration increases and SOD activity increases, cuprum concentration increases and zinc concentration reduces significantly (P < 0.001) in exposed group compared with those of control group. Both serum aluminum and fluoride concentration are correlated inversely with GSH-Px activity, and correlated with MDA concentration and SOD activity. It is suggested that serum aluminum and fluoride concentration can clearly reflect the loading capacity of body aluminum and fluoride. Occupational exposure to both aluminum and fluoride lead to rising of lipid peroxidation and abnormal metabolism of cuprum 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 activity may be a kind of body compensations.
PMID: 12561533 [PubMed - in process]
Bull Environ Contam Toxicol 2002 Apr;68(4):612-6
- As cited and abstracted in Fluoride 2002; 35(3):209
Lipid peroxidation and antioxidant defense systems in liver of rats in chronic fluoride toxicity.
Shivashankara AR, Shivarajashankara YM, Bhat PG, Rao SH.
Department of Biochemistry, MR Medical College, Gulbarga, Karnataka, India.Lipid peroxidation and response to antioxidant defense systems were examined in the liver of rat litters exposed to 30 and 100 ppm fluoride through drinking water during early stage of life till puberty. Increased lip peroxidation was seen as reflected by increased malondialdehyde levels. Total and reduced glutathione levels decreased and glutathione peroxidase activity increased. The ratio of reduced glutathione to total glutathione was decreased. Glutathione S-transferase was more elevated in the 30 than in the 100 ppm fluoride group. Ascorbic acid levels were decreased.
Full editorial at http://www.fluoride-journal.com/02-35-2/352-073.pdfFluoride 2002; 35(2):73-77
Editorial Review
Interactions between fluorine and aluminum
Anna Lubkowska (a), Beata Zyluk (b), Dariusz Chlubek (a, c)
(c) For Correspondence: Asst Prof Dariusz Chlubek MD PhD, Dept. of Biochemistry and Chemistry, Pomeranian Academy of Medicine (PAM), al. Powstancow Wlkp. 72, 70-111 Szczecin, Poland. E-mail: biochem@pam.szczecin.pl
(a) Dept. of Biochemistry and Chemistry,
(b) Dept. of Neurology, PAM, Szczecin, Poland.
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 µM) 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. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&list_uids=8825685&dopt=Abstract]
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. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&list_uids=8940250&dopt=Abstract]
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 at http://toxsci.oupjournals.org/cgi/content/full/61/1/83?ijkey=afjKDnA8vjjNU]
Full report available at http://www.fluoride-journal.com/02-35-4/354-231.pdfFluoride 2002; 35(4):231-238
Morphological effects of sodium fluoride on hematopoietic organs in mice
Anna Machalinska (a), Barbara Wiszniewska (b), Jolanta Tarasiuk (c), Boguslaw Machalinski (a)
(a) For Correspondence: Boguslaw Machalinski, MD, PhD. a Department of General Pathol-ogy, Pomeranian Academy of Medicine (PAM), Al. Powstancow Wlkp. 72, 70-111 Szczecin, Poland. E-mail: machalin@sci.pam.szczecin.pl;
(b) Department of Histology and Embryology, PAM, Al. Powstancow Wlkp. 72, 70-111 Szczecin, Poland;
(c) Department of Biochemistry, University of Szczecin, 3a Felczaka st, 71-412 Szczecin, Poland.SUMMARY: In connection with earlier studies, we examined early-response morphological effects of sodium fluoride (NaF) on hematopoietic organs in adult mice. Mature Balb C mice were given three injections of NaF in their tail veins on alternate days at total doses of 0, 10, and 50 mg NaF/kg bw. In the mice receiving NaF, morphological abnormalities were seen in the spleen as increased lymphocyte nodules, decreased white pulp, and increased red pulp infiltrated by lymphocytes. The changes were greater at the higher dose and, in other exposed mice, were still evident after three weeks. In contrast to the spleen, the liver, kidneys, and bone marrow showed little alteration.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12484561&dopt=AbstractExp Toxicol Pathol 2002 Nov;54(3):231-7
Inhibition of human renal acid phosphatases by nephrotoxic micromolar concentrations of fluoride.
Partanen S.
Department of Pathology, Helsinki University Central Hospital, Jorvi Hospital, Espoo, Finland. seppo.partanen@hus.fi
Fluoride is considered to be a nephrotoxic substance, due to the association of 50-180 microM serum concentrations of fluoride with dose-related, subclinical to overt clinical renal impairment. At these concentrations the cellular targets of fluoride in renal tissue remain unknown. Fluoride at micromolar concentrations inhibits some enzymes including phosphatases. Here the effects of fluoride on a recently characterized acid phosphatase complex present only in a few human tissues were studied. This enzyme complex consists of alkaline fixation-resistant beta-glycerophosphatase and tartrate-resistant a-naphthyl phosphatase, and these are different from activities of known types of acid phosphatase and specific phosphatases. In kidney, strong activities for this complex are detected only in the endothelium of the afferent arterioles and in glomeruli. It appeared that alkaline fixation-resistant and lysosomal acid phosphatase activities were significantly inhibited in afferent arterioles and glomeruli by 75 microM fluoride. Tartrate-resistant activity was significantly inhibited by greater concentrations (250 microM). Inhibition of acid phosphatases in the afferent arterioles and glomeruli may be one renal target of fluoride nephrotoxicity. Although the physiological substrates of this acid phosphatase complex are unknown, its specific and restricted location may indicate a role in regulation of renal circulation.
PMID: 12484561 [PubMed - in process]
Fluoride 2002; 35(3):153-160In vitro influence of sodium fluoride on ram semen quality and enzyme activities
Zakrzewska H (a), Udala J (b), Blaszczyk B (b)
(a) For correspondence: Dr. H. Zakrzewska, Dept. of Biochemistry, Agricultural University, 17 Slowackiego Street, 71-434 Szczecin, Poland
Summary: The percentage of spermatozoa in ram semen with intact acrosomes and the level of spermatozoa motility decreased significantly after dilution and after 5 hr incubation at 38¼C. Both indices decreased significantly in the presence of NaF at concentrations ranging from 20 ugmol/L to 0.1 mol/L. The activities of androgen-dependent enzymes - acid phosphatase (ACP), lactate dehydrogenase (LDH), and gamma-glutamyl transferase (y-GT-10S) - decreased significantly when the ejaculate was treated with NaF at concentrations of 20, 100, 200 ugmol/L (0.38; 1.9; 3.8 ppm F), but they returned to the initial value of the control at 0.1 mol/L (1900 ppm F). The activity of asparate transaminase (AspAT) displayed a large increase with the increasing lower F- concentration. These changes undoubtedly affect the physiological functions of the sperm.
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