FLUORIDE ACTION NETWORK PESTICIDE PROJECT

Return to FAN's Pesticide Homepage

Return to Abstracts Page


1999 Fluoride Abstracts. Part 1.

Abstracts for the following years:
Part 1 - mainly biochemistry and physiology (brain, hormonal, G-proteins, etc.)
Part 2 ("b") - all other

2007

2007-b

2004

2004-b

2001

2001-b

1998

1998-b

1995

1995-b

1992

1992-b

1989

1989-b

1986

1986-b

1983

1982

1976 -
1977
1970 -
1971

2006

2006-b

2003

2003-b

2000

2000-b

1997

1997-b

1994

1994-b

1991

1991-b

1988

1988-b

1985

1985-b

1981

1980

1974 -
1975
1968 -
1969

2005

2005-b

2005-b continued

2002

2002-b

1999

1999-b

1996

1996-b

1993

1993-b

1990

1990 -b

1987

1987-b

1984

1984-b

1979

1978

1972 -
1973
Up to
1967

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11938978&dopt=Abstract

Wei Sheng Yan Jiu 1999 Jul;28(4):210-2

[Effect of fluoride exposure on synaptic structure of brain areas related to learning-memory in mice]

[Article in Chinese]

Zhang Z, Xu X, Shen X, Xu X.

Department of Biology, Zhejiang Normal University, Jinhua 321004, China.

The learning-memory behavior was tested in mice on a Y-maze after drinking different concentration of sodium fluoride. The impairment on the structure of Gray 1 synaptic interface in the CA3 area of mice hippocampus were quantitatively analyzed by electron microscopy and computer image processing appliance. The main results are as follows: the learning ability of mice drinking high concentration of fluoride presented remarkable deterioration, the thickness of post-synaptic density (PSD) was decreased, and the width of synaptic cleft was remarkably increased.

PMID: 11938978 [PubMed - indexed for MEDLINE]

Note the following comment on the above abstract:

Fluoride 2002; 35(2):132

COMMENT

Bruce Spittle

These findings in mice of altered learning and hippocampal structural change after drinking water containing sodium fluoride complement previous rat and human studies. Fluoride administration may be followed by altered behaviour or learning

(see Mullenix PJ, Denbesten PK, Schunior A, Kernan WJ. Fluoride 1995;28:151-2;
Li XS, Zhi JL, Gao RO. Fluoride 1995;28:189-92;
Zhao LB, Liang GH, Zhang DN, Wu XR. Fluoride 1996;29:190-2;
Mullenix PJ. Fluoride 1998;31:S23;
Lu Y, Sun ZR, Wu LN, Wang X, Lu W, Liu SS. Fluoride 2000;
33:74-8). Similarly it may lead to brain changes (see Isaacson RA, Varner JA, Jensen KF. Fluoride 1998;31:96-9; Varner JA, Jensen KF, Horvath W, Isaacson RL. Fluoride 1998; 31:91-5;
Jensen K, Varner J, Isaacson R. Fluoride 1998;31:S23;
Chlubek D, Nowacki P, Mikolajek W, Lagocka R, Jakubowska K, Rzeuski R. Fluoride 1998;31;S24;
Shivarajashankara YM, Shivashankara AR, Bhat GP, Rao SM, Rao SH. Fluoride 2002;35:12-21).

In toto there is now a consistent body of scientific evidence that fluoride can alter learning and brain structure in ways that are both significant and deleterious.

 

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10377600&dopt=Abstract

Cesk Fysiol 1999 Feb;48(1):9-15

[Reassessment of the role of aluminum in the development of Alzheimer's disease]

[Article in Czech]

A Strunecka and J Patocka

Katedra fyziologie a vyvojove biologie Prirodovedecke fakulty Univerzity Karlovy, Praha.

The pathophysiology of Alzheimer's disease (AD) is related to the alterations in neurotransmission, beta-amyloid production, plaque formation and cytoskeletal abnormalities. The question of aluminium relevance to the etiology of AD cannot yet be adequately answered. Aluminium is currently regarded as the putative risk factor for the disease. Our paper shows that some of pathologic changes are not raised by aluminium alone, but by the aluminofluoride complexes. These complexes may act as the initial signal stimulating impairment of homeostasis, degeneration and death of the cells. By influencing energy metabolism these complexes can accelerate the aging and impair the functions of the nervous system. In respect to the etiology of AD, the long term action of aluminofluoride complexes may represent a serious and powerful risk factor for the development of AD.

Publication Types:

PMID: 10377600 [PubMed - indexed for MEDLINE]


Fluoride 1999; 32(4):230-242

Pharmacological and toxicological effects of aluminofluoride complexes

A Strunecka (a) and J Patocka (b)

(a) Department of Physiology and Developmental Physiology, Faculty of Sciences, Charles University, Vinicna 7, Prague, Czech. E-mail: astrun@cesnet.cz
(b) Department of Toxicologyy, Military Medical Academy, Hradec Kralove, Vzech Republic

Summary: Laboratory investigations have often used aluminofluoride complexes for stimulation of various guanine nucleotide binding proteins. These complexes form spontaneously in aqueous solutions containing fluoride and traces of aluminum and appear to act as phosphate analogs. In view of the ubiquity of phosphate in cell metabolism and together with the dramatic increase in the amount of reactive aluminum now found in ecosytems, aluminofluoride complexes represent a strong potental danger for living organisms including humans. Although the possibility of pathophysiological consequences of their long-term action are not yet fully recognized, the pharmacoloical and toxicological effects of aluminofluoride complexes on animal and human cells, tissues, and organs are identified and summarized in this review.


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10516619&dopt=Abstract

NMR Biomed 1999 Oct;12(6):373-80

Quantitative 19F NMR study of trifluorothymidine metabolism in rat brain.

Pouremad R, Bahk KD, Shen YJ, Knop RH, Wyrwicz AM.

Department of Neurobiology and Physiology and the Lurie Comprehensive Cancer Center, Northwestern University and Northwestern University Medical School, Evanston, IL 60201, USA.

Metabolism of trifluorothymidine (TFT) and its transport across the blood-brain barrier (BBB) has been measured quantitatively in rats by fluorine-19 nuclear magnetic resonance spectroscopy ((19)F NMR). It is demonstrated that TFT crosses the BBB in micromolar quantities and is metabolized in brain tissue primarily to its free base trifluoromethyluracil (TFMU) by the enzyme thymidine phosphorylase (TP). It is further proposed that the rate of TFMU production can be used as a measure of cerebral TP. The glycols of both TFMU, and to a lesser degree TFT, are generated via an oxidative route. In contrast, the major pathway for hepatic metabolism of this compound is through reduction of the nitrogen base moiety and generation of 5-6-dihydro species followed by ring degradation. Thus, in addition to TFMU as well as the dihydroxy (glycol)-, and the dihydro-species of both TFT and TFMU, alpha-trifluoromethyl-beta-ureidopropionic acid (F(3)MUPA) and alpha-trifluoromethyl-beta-alanine (F(3)MBA) were detected in liver extracts. The total metabolite levels in liver were 2-5 times higher than in the brain. Low levels of fluoride ion were detected in all the extracts from brain and liver, as well as blood and urine. This study characterizes TFT as a potential chemotherapeutic agent for use against brain tumors. Copyright 1999 John Wiley & Sons, Ltd.

PMID: 10516619 [PubMed - indexed for MEDLINE]


Chinese Journal of Endemiology 1999

Effects of fluoride on activities of nitric oxide synthase in rat brain

Xu S, Shu B, Chen Z

For Correspondence: Institute of Environmental Medicine, Tongji Medical University, Wuhan 430030, China

Objective: To study the mechanism of neurotoxicity of fluoride.

Methods: The activities of nitric oxide synthase (NOS) from rat brain were determined by chemiluminescent method.

Results: The activities of NOS from rats exposed to sodium fluoride (NaF) were significantly higher than those of control rats. When NaF was added to NOS, an increase in activities of NOS was observed. This increase can be inhibited by NG-Nitiol-L-Arginine, an inhibitor of nitric oxide synthase.

Conclusions: Fluoride can enhance the activities of NOS in rat brain.


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12214122&dopt=Abstract

J Alzheimers Dis 1999 Nov;1(4,5):231-247

Cholinergic Muscarinic Receptor Signaling by the Phosphoinositide Signal Transduction System in Alzheimer's Disease.

Jope RS.

Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294-0017, USA.

Recent years have seen the advent of new methods capable of measuring the activity of receptor-coupled, G-protein-mediated, phosphoino-sitide second messenger production in membranes prepared from postmortem human brain. Considering the interest in treating Alzheimer's disease (AD) patients with cholinergic agonists, several investiga-tions have used this new methodology to analyze the functional state of cholinergic muscarinic receptors coupled to phosphoinositide signaling directly in AD brain. Several, but not all, reports indicate that cholinergic agonist-induced phosphoinositide signaling is severely impaired in AD, potentially due to impaired activation of the receptor-coupled G-protein. Additionally, deficits in AD also have been reported in the two second messenger pathways activated following phosphoinositide hydrolysis, inositol-1,4,5,-triphos-phate receptor binding and protein kinase C activation, indicating further that phosphoinositide signaling is impaired in AD. Sources of limitations in current methodologies and issues for further exploration are discussed. Speculation concerning potential links between cholinergic receptor-linked signaling and early events in the formation of amyloid plaques and neurofibrillary tangles is provided. Especially intriguing is the potential for the development of synergistic neurotoxicity where deficits of phosphoinositide signaling and increased production of Abeta interact to exacerbate alterations in each process that occur in AD, leading to a feed-forward cycle of progressive neuronal dysfunction.

PMID: 12214122 [PubMed - as supplied by publisher]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10455554&dopt=Abstract

Arch Physiol Biochem 1999 Feb;107(1):15-21

Fluoride enhances the effect of aluminium chloride on interconnections between aggregates of hippocampal neurons.

van der Voet GB, Schijns O, de Wolff FA.


Toxicology Laboratory Leiden University Medical Center Leiden, The Netherlands.

The role of fluoride in aluminium neurotoxicity was studied using an in vitro system of cultured hippocampal neurons from foetal rats. Sodium fluoride (50 microM) and aluminium chloride (12.5 microM) were administered alone or in a specific combination (50 + 12.5 microM) in a 14-day culture in a chemically defined medium before staining of neurofilaments. Neuronal aggregates interconnected by neuritic fibers were detected light microscopically in control cultures. The aggregates and the fibers stained positive for neurofilament proteins. In cultures treated with aluminium chloride the development of the interconnecting fibers was affected, resulting in a fusion pattern of the aggregates. This phenomenon was enhanced when sodium fluoride was given together with aluminum chloride. It was concluded that aluminium interferes with the metabolism of the neuronal cytoskeleton and that this interference is potentiated by fluoride.

PMID: 10455554 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10479070&dopt=Abstract

Int J Dev Neurosci 1999 Jul;17(4):357-67

Fluoride-induced depletion of polyphosphoinositides in rat brain cortical slices: a rationale for the inhibitory effects on phospholipase C.

Sarri E, Claro E.

Departament de Bioquimica i de Biologia Molecular, Facultat de Medicina, Universitat Autonoma de Barcelona, Spain.

Fluoride, which is used commonly as a pharmacological tool to activate phosphoinositide-phospholipase C coupled to the heterotrymeric Gq/11 proteins, inhibited the phosphorylation of phosphatidylinositol (PtdIns) to polyphosphoinositides (PtdIns4P and PtdIns4,5P2) in membranes from rat brain cortex. Fluoride enhanced basal production of 3H-inositol phosphates in membranes prepared from brain cortical slices that had been prelabeled with [3H]inositol, but inhibited the stimulation elicited by carbachol in the presence of GTPgammaS. However in both cases fluoride depleted [3H]PtdIns4P content by 95%. The inhibitory effects of fluoride on the release of 3H-inositol phosphates in slices were not apparent in a pulse [3H]inositol-labeling strategy, but became dramatic in a continuous labeling protocol, particularly at long incubation times. Prelabeling slices with [3H]inositol in the presence of fluoride precluded polyphosphoinositide labeling, and eliminated phospholipase C responsiveness to carbachol under normal or depolarizing conditions, and to the calcium ionophore ionomycin. The lack of response of 3H-polyphosphoinositide-depleted slices to phospholipase C stimuli was not due to fluoride poisoning, unaccessibility of the [3H]inositol label to phospholipase C or desensitization of Gq/11, as the effect of carbachol and GTPgammaS was restored, in the presence of ATP, in membranes prepared from slices that had been labeled in the presence of fluoride. In conclusion, our data show that fluoride, at a concentration similar to that used to stimulate directly Gq/11-coupled phospholipase C, effectively blocks the synthesis of phospholipase C substrates from PtdIns.

PMID: 10479070 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10340306&dopt=Abstract

Neuropharmacology 1999 May;38(5):691-8

Phenylmethylsulfonyl fluoride inhibitory effects on acetylcholinesterase of brain and muscle.

Skau KA, Shipley MT.

Division of Pharmaceutical Sciences, College of Pharmacy, University of Cincinnati, OH 45267-0004, USA. ken.skau@uc.edu

Differential inhibition of brain versus peripheral acetylcholinesterase (AChE) by phenylmethylsulfonyl fluoride (PMSF) suggested that PMSF might preferentially inhibit different AChE molecular forms. AChE inhibition was examined after systemic and in vitro PMSF treatment. Systemic administration resulted in no overt behavioral changes but produced a 71% reduction in brain AChE; hemidiaphragm, extensor digitorum longus and soleus muscles showed 65, 50 and 41% reductions. Muscle asymmetric AChE was reduced to the greatest extent (50-80%). The tetrameric form was inhibited in brain and hemidiaphragm (60-76%) but spared in other muscles (18-22%). Monomeric AChE was spared in all tissues. When PMSF was added to a muscle homogenate all forms were inhibited equally. Purified monomer and tetramer forms were inhibited equally in vitro. These results suggest that PMSF inhibition of AChE is a consequence of a selective inhibition of membrane-associated forms and that the apparent brain selectivity is related to the greater fraction of membrane-associated AChE in brain.

PMID: 10340306 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10422761&dopt=Abstract

Eur J Pharmacol 1999 Jun 18;374(2):207-11

  4-(2-Aminoethyl)benzenesulfonyl fluoride attenuates tumor-necrosis-factor-alpha-induced blood-brain barrier opening.

Megyeri P, Nemeth L, Pabst KM, Pabst MJ, Deli MA, Abraham CS.

Department of Pediatrics, Albert Szent-Gyorgyi Medical University, Szeged, Hungary. megyerip@pedia.szote.u-szeged.hu

The effect of serine protease inhibitor 4-(2-aminoethyl)benzenesulfonyl fluoride (AEBSF) was investigated on the prevention of tumor-necrosis-factor-alpha (TNF-alpha)-induced blood-brain barrier opening. TNF-alpha (10,000 IU) was injected intracarotidly to newborn pigs pretreated with 0, 2.4, 4.8, 9.6 and 19.2 mg/kg AEBSF (n = 6 in each group). AEBSF dose-dependently inhibited the TNF-alpha-induced increase in the blood-brain barrier permeability for sodium fluorescein (MW = 376) in all of the five brain regions examined, while only 19.2 mg/kg AEBSF could significantly (P < 0.05) decrease the change in Evan's blue-albumin (MW = 67,000) transport in two regions. In conclusion, AEBSF attenuates vasogenic brain edema formation.

PMID: 10422761 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12016983&dopt=Abstract

Wei Sheng Yan Jiu 1999 Nov;28(6):337-8

[Effect of fluoride-arsenic exposure on the neurobehavioral development of rats offspring]

[Article in Chinese]

Zhang C, Ling B, Liu J, Wang G.

College of Public Health, Xinjiang Medical University, Urumqi 830054, China.

In order to explain the effects of fluoride-arsenic exposure on the neurobehavioral development of rats, a two generations-one nest reproductive test was used. Wistar rats were exposed to fluoride and arsenic for two generations. The results demonstrated that: with the increasing concentrations of fluoride and arsenic, the positive rates of early physiological development and nerve reflex were decreased obviously, and the abilities of learning and memory of the offspring were decreased, the swimming and enduring anoxia time gradually shortened. The pathological changes of brain under electron microscope were as follows: decreased number of nerve cells, irregular cell nucleus, organellae degeneration, and obvious decreased number of synapses. It was demonstrated that fluoride-arsenic displayed distinct damage on the nerve system of the offspring.

PMID: 12016983 [PubMed - in process]


Full report available free at http://jcs.biologists.org/cgi/reprint/112/22/3869.pdf

J Cell Sci 1999 Nov;112 ( Pt 22):3869-78

Trimeric G proteins modulate the dynamic interaction of PKAII with the Golgi complex.

Martin ME, Hidalgo J, Vega FM, Velasco A.

Department of Cell Biology, Faculty of Biology, University of Seville, Spain.

The Golgi complex represents a major subcellular location of protein kinase A (PKA) concentration in mammalian cells where it has been previously shown to be involved in vesicle-mediated protein transport processes. We have studied the factors that influence the interaction of PKA typeII subunits with the Golgi complex. In addition to the cytosol, both the catalytic (Calpha) and regulatory (RIIalpha) subunits of PKAII were detected at both sides of the Golgi stack, particularly in elements of the cis- and trans-Golgi networks. PKAII subunits, in contrast, were practically absent from the middle Golgi cisternae. Cell treatment with either brefeldin A, AlF(4-) or at low temperature induced PKAII dissociation from the Golgi complex and redistribution to the cytosol. This suggested the existence of a cycle of association/dissociation of PKAII holoenzyme to the Golgi. The interaction of purified RIIalpha with Golgi membranes was studied in vitro and found not to be affected by brefeldin A while it was sensitive to modulators of heterotrimeric G proteins such as AlF(4-), GTPgammaS, beta(gamma) subunits and mastoparan. RII(alphaa) binding was stimulated by recombinant, myristoylated Galpha(i3) subunit and inhibited by cAMP. Pretreatment of Golgi membranes with bacterial toxins known to catalyze ADP-ribosylation of selected Galpha subunits also modified RIIalpha binding. Taken together the data support a regulatory role for Golgi-associated Galpha proteins in PKAII recruitment from the cytosol.

PMID: 10547348 [PubMed - indexed for MEDLINE]


Fluoride 1999; 32(4):204-214

Effects of protein supplementatin and deficiency on fluoride-induced toxicity in reproductive organs of male mice

NJ Chinoy and Dipti Mehta

For correspondence: NJ Chinoy, Reproductive Endocrinology and Toxicology Uite, Department of Zoology, School of Sciences, Gujarat University, Ahmedabad, India

Summary: Feeding a protein-deficient diet to male mice treated for 30 days with NaF (5, 10, 20 mg/kg body weight) caused a significant decrease in protein levels in testeis, cauda epididymis, and vas deferens. The activity of testicular SDH and 3B- and 17B-HDS as well as ATPase in cauda epididymis and vas deferens also decreased as compared to controls fed a normal protein diet. The decrease was more significant in mice treated with 10 and 20 mg NaF/kg than with 5 mg/kg. By contrast, levels of cholesterol in testis and glycogen in the vas deferens were significantly enhanced as compared to controls. A protein-supplemented diet fed along with NaF in the same three doses did not cause any change in these parameters, which remained the same as the controls.

These results clearly indicate that protein supplementation is beneficial to overcome to toxic effects of fluoride on testicular steroidogenesis, protein, carbohydrate, and energy and oxidation metabolisms in the reporductive organs of male mice. Protein deficiency, on the other hand, aggravates fluoride toxicity. A protein-supplemented diet might therefore substantially mitigate certain fluoride-induced health hazards in humans living in endemic areas.


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10602388&dopt=Abstract

Hum Exp Toxicol 1999 Nov;18(11):645-52

Fluoride-induced interleukin-6 and interleukin-8 synthesis in human epithelial lung cells.

Refsnes M, Becher R, Lag M, Skuland T, Schwarze PE.

Department of Environmental Medicine, National Institute of Public Health, P.O. Box 4404 Torshov, N-0403 Oslo, Norway.

Exposure to fluorides has been associated with asthmatic symptoms among workers in the aluminium industry. In a recent experimental study hydrogen fluoride (HF) was found to induce a weak inflammatory response in humans. In the present study the potential of sodium fluoride (NaF) and HF to induce cytokine response was examined and how these responses are modulated by Al3+ in a human epithelial lung cell line (A549). Dose-response experiments showed a maximal release of IL-6 and IL-8 at a concentration of 5 mM NaF 24 h after addition. The responses to HF were of a similar magnitude as for NaF. Time-course experiments showed a NaF-induced IL-6 response at 5 h, whereas an IL-8 response was observed after 10 h. Cycloheximide treatment completely abolished the NaF-induced cytokine responses. A marked increase in the mRNA level for IL-6 was observed already 2 h after exposure to 5 mM NaF, and presumably is a prerequisite for the subsequent increase of IL-6. The fluoride-induced effects on IL-6 and IL-8 release were strongly reduced by pretreatment with deferoxamine (an Al3+-chelator), and enhanced by addition of Al3+. This indicates that an AlF4-- complex, a known activator of GTP-binding proteins, is involved in fluoride-induced IL-6 and IL-8 responses in A549 cells.

PMID: 10602388 [PubMed - indexed for MEDLINE]


Fluoride 1999; 32(4):215-229

Reversible toxicity of fluoride and aluminum in liver and gastrocnemius muscle of female mice

NJ Chinoy and TN Patel

For correspondence: NJ Chinoy, Reproductive Endocrinology and Toxicology Uite, Department of Zoology, School of Sciences, Gujarat University, Ahmedabad, India

Summary: Effects of administration of sodium fluoride and aluminum chloride at doses of 10 mg and 200 mg/kg body weight, respectively, were studied for 30 days on the liver and muscle of female mice (Mus musculus). The possible therapeutic effects of Vitamin C (AA, 15 mg/animal/day), Ca (25 mg/animal/day) or vitamin E (2 mg/animal day) administered alone or in combination on NaF+AlCl3-treated animals during the withdrawal period were also investigated. A decrease in the protein levels of liver and gasrocnemius muscle by F and Al might be due to alteration in metabolism. A significant accumulation of glycogen levels in liver and muscle could be correlated with reduced activity of phosphorylase. Hence carbohydrate metabolism was altered in these organs. The deline in the activity of SDH in the gastrocnemius muscle and liver suggests reduction in their oxidative metabolism which could be related to structural alterations in the mitochondria. A decrease in activity of cholinesterase in liver and muscle may result from toxic effects of NaF, AlCl3, and NaF+AlCl3, which might have led to alteration in the utilization of acetylcholine thus affecting the transmission of nerve impulses in these tissues. Elevated levels of SGPT and SCOT may indicate hepatic damage and changes in its funciton by the treatment. Upon withdrawal of combined treatment, a significant recovery occurred in most of the parameters of liver, muscle and serum. However, none of the values were comparable to control. On the other hand, cholinesterase activity in liver and muscle as well as phosphorylase in liver recovered partially. The toxic effects of NaF+AlCl3 on all the parameters were reversed significantly by the administration of AA, Ca, or vitamin E alone, probably due to the antioxidant action of AA and vitamin E and the role of calcium in metabolism. By the combined treatment with these antidotes, complete recovery occurred and values were comparable to control in all the parameters studied which might be the result of their additive or synergistic effect.


Fluoride 1999; 32(4):243-247

Adverse effects of combined arsenic and fluoride on liver and kidney in rats

Liu K (a), Wang GQ, Ma LY, Jang P, Xiao BY, Zhang C

(a) For correspondence: Department of Environmental Hygiene, Xinjiang Medical University, Urumqi, Xinjiang, China 830054

Summary: In a subacute animal study, the effects of arsenic and fluoride on liver and kidney in rats were investigated. The results indicated that arsenic, fluoride and their combination affected the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and the contents of malondialdehyde (MDA) and sulphhydryl groups (-SH). Antagonistic effects were found between arsenic and fluoride as well as on Zn, Fe, Ca, and Mg in liver and Ca, Mg, Sr, and Al in kidney. Arsenic significantly increased the liver and kidney content of Fe. For Mn there seemed to be synergism between arsenic and fluoride. The effects of arsenic and fluoride on liver and kidney have two aspects: one is direct action; the other is indirect - disturbances of free radical balance and abnormal metabolism of some inorganic elements.


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10639761&dopt=Abstract

Indian J Chest Dis Allied Sci 1999 Jan-Mar;41(1):27-34

Experimental pulmonary fluorosis.

Purohit SD, Gupta RC, Mathur AK, Gupta N, Jeswani ID, Choudhary VK, Purohit SK.

Department of Tuberculosis, J.L.N. Medical College, Ajmer.

An experimental study was undertaken to observe effects of fluoride ingestion on lung tissue. The study was conducted on 15 albino rabbits of either sex and experimental fluorosis was induced by daily oral administration of sodium fluoride (NaF) solution. Rabbits were divided into three groups according to the quantity of fluoride ingestion: Group A: rabbits fed with 10 mg/kg/day NaF, Group B: 20 mg/kg/day NaF; and Group C: controls. After six months, the rabbits were sacrificed and their lung tissue was submitted for histopathological examination and fluoride content estimation. On gross examination, pale areas on the surface and dark brown congested areas on cut-section of lungs were seen in rabbits of groups A and B. Histopathological changes of alveolar haemorrhage, congestion, edema fluid, necrosis of alveolar epithelium, distortion of alveolar architecture and desquamation of epithelium of respiratory tract with damage to tracheal cartilage were observed in these groups. These changes were more marked in group B rabbits. Fluoride content of lung tissue homogenate was significantly higher in groups A and B (mean 1.206 ppm and 1.978 ppm respectively) as compared to control (0.1585 ppm). It was concluded that prolonged fluoride ingestion damages pulmonary tissues of rabbits. To the best of our knowledge, effect of chronic fluoride ingestion on lungs has not been reported in the literature, therefore, we had undertaken this study to analyse the effect of chronic fluoride ingestion on lungs.

PMID: 10639761 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10570952&dopt=Abstract

FEBS Lett 1999 Sep 24;458(3):419-23

Aluminum fluoride inhibits phospholipase D activation by a GTP-binding protein-independent mechanism.

Li L, Fleming N.

Department of Oral Biology, University of Manitoba, Winnipeg, Canada.

Aluminum fluoride (AlF4-) inhibited guanine nucleotide-activated phospholipase D (PLD) in rat submandibular gland cell-free lysates in a concentration-dependent response. This effect was consistent in permeabilized cells with endogenous phospholipid PLD substrates. Inhibition was not caused by either fluoride or aluminum alone and was reversed by aluminum chelation. Inhibition of PLD by aluminum fluoride was not mediated by cAMP, phosphatases 1, 2A or 2B, or phosphatidate phosphohydrolase. AlF4- had a similar inhibitory effect on rArf-stimulated PLD, but did not block the translocation of Arf from cytosol to membranes, indicating a post-GTP-binding-protein site of action. Oleate-sensitive PLD, which is not guanine nucleotide-dependent, was also inhibited by AlF4-, supporting a G protein-independent mechanism of action. A submandibular Golgi-enriched membrane preparation had high PLD activity which was also potently inhibited by AlF4-, leading to speculation that the known fluoride inhibition of Golgi vesicle transport may be PLD-mediated. It is proposed that aluminum fluoride inhibits different forms of PLD by a mechanism that is independent of GTP-binding proteins and that acts via a membrane-associated target which may be the enzyme itself.

PMID: 10570952 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10200575&dopt=Abstract

Cell Death Differ 1999 Mar;6(3):245-55

De novo expression of the class-A macrophage scavenger receptor conferring resistance to apoptosis in differentiated human THP-1 monocytic cells.

Liao HS, Matsumoto A, Itakura H, Pittman T, Kodama T, Geng YJ.

Cardiovascular and Pulmonary Research Institute, Allegheny University of the Health Sciences, Pittsburgh, Pennsylvania 15212, USA.

The class-A macrophage scavenger receptor (MSR) is a trimeric multifunctional protein expressed selectively in differentiated monomyeloid phagocytes which mediates uptake of chemically modified lipoproteins and bacterial products. This study investigated whether MSR plays a role in the regulation of apoptosis, a model of genetically programmed cell death. De novo expression of MSR occurred in human THP-1 monocytic cells differentiated with phorbol esters, which activated a nuclear transcription factor binding to the Ap1/ets-like domain of the MSR promoter. The phorbol ester-stimulated THP-1 cells also expressed increased levels of the pro-apoptotic gene products, caspase-3 and Fas ligand, but the cells exhibited no change in apoptosis. Global activation of GTP-binding proteins with fluoride anions triggered apoptosis of THP-1 cells in a time- and concentration-dependent manner, demonstrated by nuclear shrinkage and fragmentation and internucleosomal DNA fragmentation. However, the MSR-expressing THP-1 macrophage-like cells showed a significant reduction in apoptosis compared to undifferentiated control THP-1 cells, which produce MSR at undetectable levels. Fluoride stimulation also triggered apoptosis of human Jurkat T cells. Stimulation with phorbol ester made no difference in apoptosis between treated and untreated Jurkat cells. Finally, Chinese hamster ovary (CHO) cells overexpressing the class-A MSR type I by cDNA transfection showed markedly increased resistance to G-protein-coupled apoptosis. Thus, de novo expression of MSR associated with monocyte maturation into macrophages appears to confer the resistance of macrophages to apoptotic stimulation by G-protein activation.

PMID: 10200575 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10560735&dopt=Abstract

Bioorg Med Chem Lett 1999 Nov 1;9(21):3113-8

Alpha-trifluoromethylated acyloins induce apoptosis in human oral tumor cell lines.

Kawase M, Sakagami H, Kusama K, Motohashi N, Saito S.

Faculty of Pharmaceutical Sciences, Josai University, Sakado, Saitama, Japan.

Cytotoxic activity of newly synthesized trifluoromethyl ketones and related compounds was studied using two human oral tumor cell lines (HSG and HSC-2). Among them, alpha-trifluoromethylacyloins (1 and 2) were found to induce apoptotic cell death, as judged by the terminal deoxynucleotidyl transferase (TdT) dUTP nick end-labeling (TUNEL) method which detects DNA nick or fragments. Furthermore, the cytoplasm of 1 or 2 treated HSG cells was stained by M30 monoclonal antibody, which detects the product resulting from the cleavage of cytokeratin 18 by activated caspase.

PMID: 10560735 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10560744&dopt=Abstract
 
Bioorg Med Chem Lett 1999 Nov 1;9(21):3159-64
 
Synthesis and apoptogenic activity of fluorinated ceramide and dihydroceramide analogues.
 
De Jonghe S, Van Overmeire I, Gunst J, De Bruyn A, Hendrix C, Van Calenbergh S, Busson R, De Keukeleire D, Philippe J, Herdewijn P.
 
University of Gent, Faculty of Pharmaceutical Sciences, Laboratory for Medicinal Chemistry, Belgium.
 
Short-chain 3-fluoro-(dihydro)ceramide analogues are synthesized from L-serine using diethylaminosulfur trifluoride (DAST) as fluorinating agent. The apoptogenic activity of these compounds was measured in three different cell lines and compared with their hydroxylated counterparts.
 
PMID: 10560744 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10491850&dopt=Abstract

SAR QSAR Environ Res 1999;10(2-3):207-13

Effects of chemical reactivity of the toxicity of phosphorus fluoridates.

White WE.

Edgewood Chemical and Biological Center, Aberdeen Proving Ground, MD 21010, USA.

Semiempirical quantum calculations were performed on a series of organophosphorus fluoridates to determine the relative reactivity for hydrolysis. This value was determined by subtracting the energy of the metastable intermediate from the energy of the stable molecule. Plotting this relative reactivity for each compound vs. its toxicity resulted in a parabolic curve with nerve agents and other similarly toxic compounds in the center. The more reactive phosphinates and less reactive phosphates were at the edges of the graph in the region of lower toxicity. The results indicate that for compounds meeting minimal structural requirements, chemical reactivity is the principal determinant of cholinesterase inhibition.

PMID: 10491850 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10447562&dopt=Abstract

Arch Toxicol 1999 Aug;73(6):346-51

Usefulness of the assessment of urinary enzyme leakage in monitoring acute fluoride nephrotoxicity.

Usuda K, Kono K, Dote T, Nishiura H, Tagawa T.

World Health Organization Organization Mondiale De La Sante Batiment L-216 CH-1211 Geneve 27, Suisse.

A single oral dose of sodium fluoride (NaF) in aqueous solution was given to male Wistar rats. Twenty-four-hour urine samples were collected and examined to evaluate fluoride-induced acute renal damage. The following parameters were measured in 24-h urine: urine volume and urinary excretion of fluoride, N-acetyl-beta-d-glucosaminidase (NAG), alpha-glutathione-S-transferase (alpha-GST), and creatinine (CR). Fluoride exposure produced specific, dose-dependent changes of these parameters. Significant increases of fluoride and fluoride-induced polyuria were observed. NAG as specific marker of proximal convoluted tubule (PCT) function showed a significant increase when the lowest dose of fluoride was administered. At this minimal dose, alpha-GST, a specific marker for the S3 segment, did not show a significant increase but presented the strongest relationship (r = 0. 83) to fluoride dose. No significant changes were measured for CR excretion, which showed a low correlation coefficient (r = 0.36) to administered fluoride. The specific differences in the increase pattern of these parameters show that the PCT is more susceptible to damage by low-dose fluoride than the S3 segment or the glomerulus. We concluded that both NAG and alpha-GST are useful for the diagnosis of fluoride-induced acute nephrotoxicity. Proper evaluation of these urinary indices may be of help to establish the site and extent of kidney injury in acute fluoride toxicity.

PMID: 10447562 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11939006&dopt=Abstract

Wei Sheng Yan Jiu 1999 Mar 30;28(2):74-6

[The toxicity of combination of selenium, fluoride and arsenic on rat embryos]

[Article in Chinese]

Li Y, Sun M, Wu D, Chen X.

National Center for Material and Infant Health, Beijing Medical University, Beijing 100083, China.

Whole embryo rotated culture technique was used to investigate the toxicity of combination of selenium, fluoride and arsenic on rat embryos at day 9.5 of gestation. The result of factorial analysis (3 x 3 x 3) showed that the main effect of combination of selenium, fluoride and arsenic on the developmental toxicity was synergistic. The mixtures with different level of these three chemicals in combination could result in different developmental toxicity. The low level combinations mainly caused teratogenic effect, and the high level combinations(selenium 2.0 micrograms + fluoride 10 micrograms + arsenic 1.0 microgram/ml culture media) caused lethal effect. The results suggested that the disorders of yolk-sac placenta in structure and function were one of teratogenic mechanisms for the combination of selenium, fluoride and arsenic.

PMID: 11939006 [PubMed - in process]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10786137&dopt=Abstract

Dent Mater J 1999 Sep;18(3):271-7

Cytotoxicity of a trial resin composite liner containing TiK2F6 on rat dental pulp cells.

Itota T, Torii Y, Sogawa N, Sogawa C, Inoue K.

Department of Operative Dentistry, Okayama University Dental School, Japan.

The aim of this study was to assess the toxicological responses of a resin composite containing TiK2F6 and NaF in rat dental pulp cells. Trial resin composite liners were made, containing 3 wt% fluorides (TiK2F6 or NaF). These specimens were immersed in 5 ml of cell culture medium supplemented at 37 degrees C for 24 hours. The eluates were used for the experiments. We judged the cytotoxicity of the samples by the cell viability. The original elute solution was serially diluted and then the medium was exchanged for the dilute medium. The cell viability at 1, 2 or 5 days after commencement of re-culturing was calculated. The viability of cells in the eluate from the resin composite liners containing TiK2F6 and NaF decreased with time. The cytotoxicity of TiK2F6 was weaker than that of NaF at all times.

PMID: 10786137 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10447558&dopt=Abstract

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

Inflammatory responses of rat alveolar macrophages following exposure to fluoride.

Hirano S, Ando M, Kanno S.

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

Inhalation exposure to fluoride compounds has been associated with respiratory failure. We have addressed effects of fluoride on alveolar macrophages and lung responses to intratracheally (i.t.) instilled fluoride in rats. I.t. instillation of fluoride at doses of 200 and 400 microg F/rat caused significant polymorphonuclear leukocyte (PMN) infiltration in the rat lung at 20 h post-administration, while 100 microg fluoride did not recruit a significant number of PMNs in the alveolar space. Total RNA was extracted from the lung lavage cells obtained from 5 h post i.t. instillation and mRNA levels of chemokines and proinflammatory cytokines were semi-quantitatively evaluated by reverse transcriptase-polymerase chain reaction (RT-PCR). I.t. instillation of fluoride significantly enhanced mRNA expression of cytokines such as interleukin-1beta (IL-1beta), tumor necrosis factor-alpha, cytokine-induced neutrophil chemoattractant, and macrophage inflammatory proteins-1alpha and -2. Fluoride-induced augmentation in IL-1beta mRNA expression was also examined by Northern hybridization following in vitro exposure of alveolar macrophages to fluoride. However, the enhancement of IL-1beta mRNA expression following in vitro exposure to fluoride was observed only at 500 microM, a dose higher than the 50% lethal concentration (LC(50)). Non-specific adhesion of alveolar macrophages to the plastic dish was significantly increased following in vitro exposure to fluoride. The fluoride-induced non-specific adhesion was significantly reduced by anti-CD18, suggesting that beta(2) integrin played a role in the increase of adherence. Those results suggest that fluoride activates alveolar macrophages, enhances the production of chemokines and proinflammatory cytokines, and causes PMN infiltration in the lung.

PMID: 10447558 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9856731&dopt=Abstract
Anesthesiology 1998 Dec;89(6):1543-52

Halothane attenuates calcium sensitization in airway smooth muscle by inhibiting G-proteins.

Kai T, Jones KA, Warner DO.

Department of Anesthesiology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA.

BACKGROUND: Halothane directly relaxes airway smooth muscle partly by decreasing the Ca2+ sensitivity. In smooth muscle, receptor stimulation is thought to increase Ca2+ sensitivity via a cascade of heterotrimeric and small monomeric guanine nucleotide-binding proteins (G-proteins). Whether this model is applicable in the airway and where halothane acts in this pathway were investigated.
METHODS: A beta-escin-permeabilized canine tracheal smooth muscle preparation was used. Exoenzyme C3 of Clostridium botulinum, which inactivates Rho monomeric G-proteins, was used to evaluate the involvement of this protein in the Ca2+ sensitization pathway. The effects of halothane on different stimulants acting at different levels of signal transduction were compared: acetylcholine on the muscarinic receptor, aluminum fluoride (AIF4-) on heterotrimeric G-proteins, and guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS) on all G-proteins.
RESULTS: Exoenzyme C3 equally attenuated acetylcholine- and AIF4--induced Ca2+ sensitization, suggesting that these pathways are both mediated by Rho. Halothane applied before stimulation equally attenuated acetylcholine- and AIF4--induced Ca2+ sensitization. However, when added after Ca2+ sensitization was established, the effect of halothane was greater during Ca2+ sensitization induced by acetylcholine compared with AIF4-, which, along with the previous result, suggests that halothane may interfere with dissociation of heterotrimeric G-proteins. Halothane applied during GTPgammaS-induced Ca2+ sensitization had no significant effect on force, suggesting that halothane has no effect downstream from monomeric G-proteins.
CONCLUSION: Halothane inhibits increases in Ca2+ sensitivity of canine tracheal smooth muscle primarily by interfering with the activation of heterotrimeric G-proteins, probably by inhibiting their dissociation.

PMID: 9856731 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10626206&dopt=Abstract

IARC Sci Publ 1999;(150):29-43

Formation and repair of DNA adducts in vinyl chloride- and vinyl fluoride-induced carcinogenesis.

Swenberg JA, Bogdanffy MS, Ham A, Holt S, Kim A, Morinello EJ, Ranasinghe A, Scheller N, Upton PB.

Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill 27599, USA.

Vinyl chloride is a known human and animal carcinogen that induces angiosarcomas of the liver. We review here studies on the formation and repair of DNA adducts associated with vinyl chloride and vinyl fluoride in exposed and control rodents and unexposed humans. These vinyl halides induce etheno (epsilon) adducts that are identical to those formed after lipid peroxidation. Of these adducts, N2,3-ethenoguanine (epsilon G) is present in greatest amounts in tissues of exposed animals. After exposure to vinyl chloride for four weeks, epsilon G levels attain steady-state concentrations, such that the amount of newly formed adducts equals the number of adducts that are lost each day. We report the first dosimetry of epsilon G in rats exposed to 0, 10, 100 or 1100 ppm vinyl chloride for five days or four weeks. The number of adducts increased in a supralinear manner. Exposure to 10 ppm vinyl chloride for five days caused a two- to threefold increase in epsilon G over that of the controls, while four weeks' exposure resulted in a fivefold increase. This was confirmed with [13C2]vinyl chloride and by measuring exogenous and endogenous adducts in the same animals. Exposure to 100 ppm vinyl chloride for four weeks caused a 25-fold increase in epsilon G levels over that found in control rats, while exposure to 1100 ppm resulted in a 42-fold increase. The amount of endogenous epsilon G was similar in liver DNA from rats and humans. A comparable response to exposure was seen in rats and mice exposed to 0, 25, 250 or 2500 ppm vinyl fluoride for 12 months. There was a very high correlation between epsilon G levels in rat and mouse liver at 12 months and the incidence of haemangiosarcoma at two years. We were able to demonstrate that the target cell population for angiosarcoma, the nonparenchymal cells, contained more epsilon G than hepatocytes, even though nonparenchymal cells are exposed by diffusion of vinyl halide metabolites formed in hepatocytes. The expression of N-methylpurine-DNA glycosylase mRNA was induced in rat liver after exposure to either 25 or 2500 ppm vinyl fluoride. When this induction was investigated in hepatocytes and nonparenchymal cells, it was found that the latter had only 20% of the N-methylpurine-DNA glycosylase mRNA of hepatocytes, and that only the hepatocytes had induction of this expression after exposure to vinyl fluoride. Thus, the target cells for vinyl halide carcinogenesis have much lower expression of this DNA repair enzyme, which has been associated with etheno adduct repair.

Publication Types:

PMID: 10626206 [PubMed - indexed for MEDLINE]


NOTE: AG Gilman, co-author of this report, shared the 1994 Nobel Prize for the discovery of "G-proteins and the role of these proteins in signal transduction in cells."

Full report available free at http://www.jbc.org/cgi/content/full/274/48/34483

J Biol Chem 1999 Nov 26;274(48):34483-92

Selective regulation of Galpha(q/11) by an RGS domain in the G protein-coupled receptor kinase, GRK2.

Carman CV, Parent JL, Day PW, Pronin AN, Sternweis PM, Wedegaertner PB, Gilman AG, Benovic JL, Kozasa T.

Department of Biochemistry, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.

G protein-coupled receptor kinases (GRKs) are well characterized regulators of G protein-coupled receptors, whereas regulators of G protein signaling (RGS) proteins directly control the activity of G protein alpha subunits. Interestingly, a recent report (Siderovski, D. P., Hessel, A., Chung, S., Mak, T. W., and Tyers, M. (1996) Curr. Biol. 6, 211-212) identified a region within the N terminus of GRKs that contained homology to RGS domains. Given that RGS domains demonstrate AlF(4)(-)-dependent binding to G protein alpha subunits, we tested the ability of G proteins from a crude bovine brain extract to bind to GRK affinity columns in the absence or presence of AlF(4)(-). This revealed the specific ability of bovine brain Galpha(q/11) to bind to both GRK2 and GRK3 in an AlF(4)(-)-dependent manner. In contrast, Galpha(s), Galpha(i), and Galpha(12/13) did not bind to GRK2 or GRK3 despite their presence in the extract. Additional studies revealed that bovine brain Galpha(q/11) could also bind to an N-terminal construct of GRK2, while no binding of Galpha(q/11), Galpha(s), Galpha(i), or Galpha(12/13) to comparable constructs of GRK5 or GRK6 was observed. Experiments using purified Galpha(q) revealed significant binding of both Galpha(q) GDP/AlF(4)(-) and Galpha(q)(GTPgammaS), but not Galpha(q)(GDP), to GRK2. Activation-dependent binding was also observed in both COS-1 and HEK293 cells as GRK2 significantly co-immunoprecipitated constitutively active Galpha(q)(R183C) but not wild type Galpha(q). In vitro analysis revealed that GRK2 possesses weak GAP activity toward Galpha(q) that is dependent on the presence of a G protein-coupled receptor. However, GRK2 effectively inhibited Galpha(q)-mediated activation of phospholipase C-beta both in vitro and in cells, possibly through sequestration of activated Galpha(q). These data suggest that a subfamily of the GRKs may be bifunctional regulators of G protein-coupled receptor signaling operating directly on both receptors and G proteins.

PMID: 10567430 [PubMed - indexed for MEDLINE]


Full report available free at http://www.pnas.org/cgi/content/full/96/26/14789

Proc Natl Acad Sci U S A 1999 Dec 21;96(26):14789-94

Comment in:

Beryllofluoride mimics phosphorylation of NtrC and other bacterial response regulators.

Yan D, Cho HS, Hastings CA, Igo MM, Lee SY, Pelton JG, Stewart V, Wemmer DE, Kustu S.

Department of Plant Biology, University of California, Berkeley, CA 94720, USA. dyan@nature.berkeley.edu


Two-component systems, sensor kinase-response regulator pairs, dominate bacterial signal transduction. Regulation is exerted by phosphorylation of an Asp in receiver domains of response regulators. Lability of the acyl phosphate linkage has limited structure determination for the active, phosphorylated forms of receiver domains. As assessed by both functional and structural criteria, beryllofluoride yields an excellent analogue of aspartyl phosphate in response regulator NtrC, a bacterial enhancer-binding protein. Beryllofluoride also appears to activate the chemotaxis, sporulation, osmosensing, and nitrate/nitrite response regulators CheY, Spo0F, OmpR, and NarL, respectively. NMR spectroscopic studies indicate that beryllofluoride will facilitate both biochemical and structural characterization of the active forms of receiver domains.

PMID: 10611291 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10569467&dopt=Abstract

Scand J Work Environ Health 1999 Oct;25(5):457

Association between exposure to potassium aluminum tetrafluoride and bronchial hyperreactivity and asthma.

Hjortsberg U.

Publication Types:

PMID: 10569467 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10561485&dopt=Abstract

FEBS Lett 1999 Nov 12;461(1-2):1-5

Aluminum fluoride inhibition of cabbage phospholipase D by a phosphate-mimicking mechanism.

Li L, Fleming N.

Department of Oral Biology, University of Manitoba, 780 Bannatyne Avenue, Winnipeg, Man., Canada.

Aluminum fluoride (AlF(4)(-)) inhibited phospholipase D (PLD) purified from cabbage in both PIP(2)-dependent and PIP(2)-independent assays, consistent with its previously observed effect on mammalian PLD. The possibility that AlF(4)(-) may exert this effect through its known phosphate-mimicking property was examined. Inorganic phosphate, as well as two phosphate analogs, beryllium fluoride and orthovanadate, also inhibited cabbage PLD. Enzyme kinetic studies confirmed that PLD followed Hill kinetics, characteristic for allosteric enzymes, with an apparent Hill coefficient (n(app)) of 3.8, indicating positive cooperativity among multiple substrate-binding sites and suggesting possible functional oligomerization of the enzyme. AlF(4)(-) modification of PLD kinetics was consistent with a competitive mode of enzyme inhibition. It is therefore proposed that AlF(4)(-), and other phosphate analogs, inhibits plant PLD by competing with a substrate phosphate group for a substrate-binding site, thereby preventing the formation of an enzyme-phosphatidyl intermediate. This may be a conserved feature of PLD superfamily enzymes.

PMID: 10561485 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10555980&dopt=Abstract

Biochemistry 1999 Nov 9;38(45):14981-7

Magnesium fluoride-dependent binding of small G proteins to their GTPase-activating proteins.

Graham DL, Eccleston JF, Chung CW, Lowe PN.

Division of Physical Biochemistry, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, United Kingdom.

GTPase-activating proteins (GAPs) enhance the intrinsic GTPase activity of small G proteins, such as Ras and Rho, by contributing a catalytic arginine to the active site. An intramolecular arginine plays a similar role in heterotrimeric G proteins. Aluminum fluoride activates the GDP form of heterotrimeric G proteins, and enhances binding of the GDP form of small G proteins to their GAPs. The resultant complexes have been interpreted as analogues of the transition state of the hydrolytic reaction. Here, equilibrium binding has been measured using scintillation proximity assays to provide quantitative information on the fluoride-mediated interaction of Ras and Rho proteins with their respective GAPs, neurofibromin (NF1) and RhoGAP. High-affinity fluoride-mediated complex formation between Rho.GDP and RhoGAP occurred in the absence of aluminum; however, under these conditions, magnesium was required. Additionally, the novel observation was made of magnesium-dependent, fluoride-mediated binding of Ras.GDP to NF1 in the absence of aluminum. Aluminum was required for complex formation when the concentration of magnesium was low. Thus, either aluminum fluoride or magnesium fluoride can mediate the high-affinity binding of Rho. GDP or Ras.GDP to GAPs. It has been reported that magnesium fluoride can activate heterotrimeric G proteins. Thus, magnesium-dependent fluoride effects might be a general phenomenon with G proteins. Moreover, these data suggest that some protein.nucleotide complexes previously reported to contain aluminum fluoride may in fact contain magnesium fluoride.

PMID: 10555980 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10505658&dopt=Abstract

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

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

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

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

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

Publication Types:
Clinical Trial

PMID: 10505658 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9892783&dopt=Abstract

Caries Res 1999;33(2):148-55

Fluoride augments the mitogenic and antigenic response of human blood lymphocytes in vitro.

Loftenius A, Andersson B, Butler J, Ekstrand J.

Division of Dental Toxicology, Department of Basic Oral Sciences, Karolinska Institute, Huddinge, Sweden. Annika.Loftenius@ofa.ki.se

It has been shown that fluoride, the agent responsible for reduction of dental caries worldwide and a recognized proliferative agent, is an adjuvant when given intragastrically to rats. Furthermore, plasma fluoride levels increase in humans after various fluoride treatments. The studies presented here show that fluoride also has the ability to affect the cells of the human immune system. This was tested by measuring the effect of sodium fluoride (NaF) on cytokine production by human whole blood cells stimulated in vitro. These studies revealed that NaF augments the human lymphocyte response from human blood to a mitogen (phytohemagglutinin, PHA) or a specific antigen (morbilli antigen from infected cells, MorbAg). The cytokine interferon-gamma (IFN-gamma), released from activated T and/or NK cells, was significantly (p<0.01) increased when whole blood cells were simultaneously incubated with 0.62 mmol/l NaF and PHA compared to PHA alone. This tendency was also true for NaF and MorbAg. The lymphocyte activation marker interleukin-2 receptor (measured in soluble form) increased after simultaneous stimulation of the cells with PHA and 0.62 mmol/l NaF compared to stimulation with PHA only. However, 0.62 mmol/l NaF did not enhance interleukin-6 release, in blood mainly produced by monocytes. The ability to influence the IFN-gamma release during an immune response could be one of the primary means by which the fluoride ion influences the immune system.

PMID: 9892783 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10493878&dopt=Abstract

J Mol Biol 1999 Sep 17;292(2):321-32

Nucleotide-binding characteristics of human guanylate-binding protein 1 (hGBP1) and identification of the third GTP-binding motif.

Praefcke GJ, Geyer M, Schwemmle M, Robert Kalbitzer H, Herrmann C.

Abteilung Strukturelle Biologie, Max-Planck-Institut fur Molekulare Physiologie, Dortmund, 44202, Germany.

hGBP1 is a GTPase with antiviral activity encoded by an interferon- activated human gene. Specific binding of hGBP1 to guanine nucleotides has been established although only two classical GTP-binding motifs were found in its primary sequence. The unique position of hGBP1 amongst known GTPases is further demonstrated by the hydrolysis of GTP to GDP and GMP. Although subsequent cleavage of orthophosphates rather than pyrophosphate was demonstrated, GDP coming from bulk solution cannot serve as a substrate. The relation of guanine nucleotide binding and hydrolysis to the antiviral function of hGBP1 is unknown. Here we show similar binding affinities for all three guanine nucleotides and the ability of both products, GDP and GMP, to compete with GTP binding. Fluorimetry and isothermal titration calorimetry were applied to prove that only one nucleotide binding site is present in hGBP1. Furthermore, we identified the third canonical GTP-binding motif and verified its role in nucleotide recognition by mutational analysis. The high guanine nucleotide dissociation rates measured by stopped-flow kinetics are responsible for the weak affinities to hGBP1 when compared to other GTPases like Ras or Galpha. By means of fluorescence and NMR spectroscopy it is demonstrated that aluminium fluoride forms a complex with hGBP1 only in the GDP state, presumably mimicking the transition state of GTP hydrolysis. Tentatively, the involvement of a GAP domain in hGBP1 in GTP hydrolysis is suggested. These results will serve as a basis for the determination of the differential biological functions of the three nucleotide states and for the elucidation of the unique mechanism of nucleotide hydrolysis catalysed by hGBP1. Copyright 1999 Academic Press.

PMID: 10493878 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9917518&dopt=Abstract

Int J Mol Med 1999 Feb;3(2):115-26

Heterotrimeric G proteins as fluoride targets in bone (review).

Susa M.

Research Bone Metabolism, Novartis Pharma AG, CH-4002 Basel, Switzerland.

Fluoride is an acknowledged bone anabolic agent. Nevertheless, a narrow therapeutic window and the adverse effects at higher therapeutic doses prevent broad clinical application of fluoride for treatment of diseases of bone loss, such as osteoporosis. The cellular and molecular mechanisms of fluoride action are poorly understood. Recent advances in the elucidation of signal transduction pathways induced by fluoride in osteoblastic cells are reviewed. Fluoride and traces of aluminum form a complex, fluoroaluminate, which stimulates cellular heterotrimeric G proteins. Such complex can form in food, drinking water and in the organism after administration of sodium fluoride. Fluoroaluminate crosses the cell membrane and directly binds to the membrane-associated inactive G alpha protein subunits. Within the G alpha subunit, fluoroaluminate occupies the position next to GDP. The resulting G alpha-GDP-AlF4- complex assumes an active state conformation, which resembles that of G alpha-GTP complex. Under physiological conditions, G alpha-GTP complex is formed upon activation of seven transmembrane receptors that couple to heterotrimeric G proteins. Both fluoroaluminate-activated and receptor-activated G alpha subunits are capable of transmitting intracellular signals that lead to cellular responses. In bone-forming cells osteoblasts, fluoroaluminate stimulates pertussis toxin-sensitive G alpha i proteins. G alpha I activation leads to the reduction in cAMP (cyclic adenosine monophosphate) levels and to the activation of mitogen activated protein kinases, Erks (extracellular signal-regulated kinases) and p70 S6 kinase. These kinases are involved in the regulation of gene transcription and protein syntheses. Fluoroaluminate also stimulates pertussis toxin-insensitive proteins. Pertussis toxin-insensitive G proteins, most likely from G alpha 12 class, cause the activation of several cytoplasmic protein tyrosine kinases [Src, Pyk2 (proline-rich tyrosine kinase 2), and Fak (focal adhesion kinase)]. Activation of Erks can lead to osteoblast proliferation and differentiation, while activation of Src, Pyk2 and Fak can modulate the adhesion properties of osteoblasts. Osteoblast adhesion may, in turn, influence differentiation, migration, and apoptosis of these cells. The susceptibility of osteoblasts to fluoroaluminate can be achieved by their specific cellular context and by the rigidity of the surrounding bone tissue. In particular, higher levels of G alpha I proteins and of certain focal adhesion proteins are expressed by osteoblastic rather than by fibroblastic cells. The rigidity of adhesion substratum of osteoblasts may signal on its own and potentiate the signaling by fluoroaluminate. The information on mechanisms of intracellular signaling by fluoroaluminate can be utilized to identify a fluoroaluminate mimic, a drug that exhibits anabolic action on bone with a broader therapeutic range and less adverse effects than fluoride.

Publication Types:

PMID: 9917518 [PubMed - indexed for MEDLINE]


Report available free at http://www.jneurosci.org/cgi/content/full/19/3/890

J Neurosci 1999 Feb 1;19(3):890-9

G-proteins are involved in 5-HT receptor-mediated modulation of N- and P/Q- but not T-type Ca2+ channels.

Sun QQ, Dale N.

School of Biomedical Sciences, University of St. Andrews, Scotland KY16 9TS, United Kingdom.

5-HT produces voltage-independent inhibition of the N-, P/Q-, and T-type Ca2+ currents in sensory neurons of Xenopus larvae by acting on 5-HT1A and 5-HT1D receptors. We have explored the underlying mechanisms further and found that the inhibition of high voltage-activated (HVA) currents by 5-HT is mediated by a pertussis toxin-sensitive G-protein that activates a diffusible second messenger. Although modulation of T-type currents is membrane-delimited, it was not affected by GDP-beta-S (2 mM), GTP-gamma-S (200 microM), 5'-guanylyl-imidodiphosphate tetralithium (200 microM), aluminum fluoride (AlF4-, 100 microM), or pertussis toxin, suggesting that a GTP-insensitive pathway was involved. To investigate the modulation of the T currents further, we synthesized peptides that were derived from conserved cytoplasmic regions of the rat 5-HT1A and 5-HT1D receptors. Although two peptides derived from the third cytoplasmic loop inhibited the HVA currents by activating G-proteins and occluded the modulation of HVA currents by 5-HT, two peptides from the second cytoplasmic loop and the C tail had no effect. None of the four receptor-derived peptides had any effect on the T-type currents. We conclude that 5-HT modulates T-type channels by a membrane-delimited pathway that does not involve G-proteins and is mediated by a functional domain of the receptor that is distinct from that which couples to G-proteins.

PMID: 9920652 [PubMed - indexed for MEDLINE]


 

Back to the top

Return to FAN's Pesticide Homepage