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1995 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

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1984-b

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1978

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Up to
1967

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7760776&dopt=Abstract

Neurotoxicol Teratol. 1995 Nov-Dec;17(6):685-8.  

Neurotoxicity of sodium fluoride in rats.

Mullenix PJ, Denbesten PK, Schunior A, Kernan WJ.

Toxicology Department, Forsyth Research Institute, Boston, MA 02115, USA.

Fluoride (F) is known to affect mineralizing tissues, but effects upon the developing brain have not been previously considered. This study in Sprague-Dawley rats compares behavior, body weight, plasma and brain F levels after sodium fluoride (NaF) exposures during late gestation, at weaning or in adults. For prenatal exposures, dams received injections (SC) of 0.13 mg/kg NaF or saline on gestational days 14-18 or 17-19. Weanlings received drinking water containing 0, 75, 100, or 125 ppm F for 6 or 20 weeks, and 3 month-old adults received water containing 100 ppm F for 6 weeks. Behavior was tested in a computer pattern recognition system that classified acts in a novel environment and quantified act initiations, total times and time structures. Fluoride exposures caused sex- and dose-specific behavioral deficits with a common pattern. Males were most sensitive to prenatal day 17-19 exposure, whereas females were more sensitive to weanling and adult exposures. After fluoride ingestion, the severity of the effect on behavior increased directly with plasma F levels and F concentrations in specific brain regions. Such association is important considering that plasma levels in this rat model (0.059 to 0.640 ppm F) are similar to those reported in humans exposed to high levels of fluoride.


PMID: 7760776 [PubMed - indexed for MEDLINE]


NOTE: Martin Rodbell and Alfred G. Gilman shared the 1994 Nobel Prize for the discovery of "G-proteins and the role of these proteins in signal transduction in cells." Rodbell's Nobel lecture, cited below, is available at:

http://www.nobel.se/medicine/laureates/1994/rodbell-lecture.pdf

Biosci Rep 1995 Jun;15(3):117-33

No Abstract available

Nobel Lecture. Signal transduction: evolution of an idea.

Rodbell M.

Publication Types:

    • Review
    • Review, Tutorial

PMID: 7579038 [PubMed - indexed for MEDLINE]


Fluoride 1995; 28(4):189-192

Effect of fluoride exposure on intelligence in children

Li XS (a), Zhi JL (b), Gao RO (c)

(a) Guizhou Provincial Sanitary and Anti-epidemic Station, Guiyang City, 550001, China
(b) Anshun Prefecture Sanitary and Anti-Epidemic Station
(c) Zhijin County Sanitary and Anti-Epidemic Station

Summary: The intelligence was measured of 907 children aged 8-13 years living in areas which differed in the amount of fluoride present in the environment. The Intelligence Quotient (IG) of children living in areas with a medium or severe prevalence of fluorosis was lower than that of children living in areas with only slight fluorosis or no fluorosis. The development of intelligence appered to be adversely affected by fluoride in the areas with a medium or severe prevelence of fluorosis but to a minor extent only in areas with only a slight prevalence of fluorosis. A high fluoride intake was associated with a lower inteligence. No correlation was found between age and intelligence in the areas with a medium and severe prevalence of fluorosis. The effect of exposure to a high level of fluoride on intelligence may occur at an early stage of development of the embryo and infant when the differentiation of brain nerve cells is occurring and development is most rapid.

 

From TOXNET

Inhal Toxicol 1995;7(6):863-71

Critical periods of exposure and developmental outcome.

Daston GP, Manson JM

Miami Valley Laboratories, Procter & Gamble Co., Cincinnati, OH.

Abstract: The most unique aspect of the field of developmental toxicology, which sets it apart from all other areas of toxicologic investigation, is the rapidly changing susceptibility of the conceptus to insult. In this presentation, an overview of the changing susceptibility of the conceptus will be given, with a discussion of the difficulties this presents for risk assessment. Prenatal development of all mammalian species can be divided up into the preimplantation, embryonic, and fetal periods, with each period possessing its own characteristic susceptibility and unique response to prenatal insult. Most developmental toxicity studies have focused on the embryonic period, with malformations as the outcome of major concern. As understanding of mammalian development has increased, it is now clear that susceptibility to functional impairments, as well as to physiologic alterations, also exist during the embryonic and fetal period, which have major consequences for the offspring. The pattern of outcome can vary dramatically depending on the time of exposure; differences in exposure intervals as short as one day can result in a shifting of the pattern of malformation and even determine whether malformations, embryonic death, or functional impairment occurs. Consequently, in considering risk assessment for developmental toxicity, the time of exposure has to be taken into consideration, as well as the level of exposure.

Substance (CAS Registry Number):
Ethylene oxide (75-21-8) Cadmium (7440-43-9)
Ethylnitrosourea (759-73-9) Colchicine (64-86-8)
Ethyl methanesulfonate (62-50-0) Mercuric chloride (7487-94-7)
Triethylenemelamine (51-18-3) Sodium fluoride (7681-49-4)
Ethylenethiourea (96-45-7) -

 

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8983996&dopt=Abstract

Exp Brain Res 1995;106(3):505-8

Attenuation of high-voltage-activated Ca2+ current run-down in rat hippocampal CA1 pyramidal cells by NaF.

Breakwell NA, Behnisch T, Publicover SJ, Reymann KG.

Department of Physiology, Trinity College Dublin, Ireland.

Calcium currents in CA1 neurons from rat hippocampus were studied with the whole-cell, patch-clamp technique. Under control conditions high-voltage-activated (HVA) calcium currents activated from membrane potentials of -80 mV and -40 mV underwent "run-down". The rate of run-down of the current activated from -40 mV was significantly attenuated by inclusion of the G-protein activator NaF (1 mM) in the pipette and also irreversibly attenuated by brief batch application of NaF (10 mM). This effect was significantly reduced by inclusion of high (10 mM) ethyleneglycoltetraacetate (EGTA) concentrations in the pipette, suggesting an involvement of calcium-dependent processes. It is suggested that activation of guanine nucleotide-binding proteins by NaF leads to a long-lasting attenuation of HVA calcium current run-down in hippocampal CA1 cells.

PMID: 8983996 [PubMed - indexed for MEDLINE]


Fluoride 1995; 28(2):75-86

Amelioration of fluoride toxicity in some accessory reproductive glands and spermatozoa of rat

Chinoy NF, Narayana MV, Dalal V, Rawat M, Patel D

Reproductive Endocrinology and Toxicology Unit, School of Sciences, Gujarat University, Ahmedabad 380 009, India

Summary: Sodium fluoride (NaF) at a dose of 10 mg/kg body weight was administered orally to male rats (Rettus norvegicus) daily for 30 and 50 days to evaluate the effect of the physiology of some sex accessory glands and sperm functions. The effects of withdrawal upon cessation of NaF ingestion, and of administering ascorbic acid (AA) and/or calcium (Ca++) along with NaF, were also investigated. The results revealed that the NaF treatment caused a significant elevation in serum fluoride levels with a simultaneous rise in Ca++ levels. This could be attributed to the formation of a calcium fluoride complex leading to calcium accumulation. The treatment resulted in structural and metabolic alterations in sperm, leading to low sperm motility, a low sperm mitochondrial activity index (SMAI), reduced viability (live:dead ratio), and changes in sperm membrane phospholipids (particularly phosphatidylinositol, phosphatidylserine and phosphatidylethanolamine, which would affect hormone receptor interaction and their functions). A significant reduction in electrolyte levels of sperm also occurred which would also affect their viability. The protein levels in cauda epididymal sperm suspension, vas deferens, seminal vesicle and prostate were significantly decreased after NaF administration, which may be due to altered protein metabolism by interference of fluoride ions. The changes in epididymal protein profile, with absence of some proteins and induction of some new ones, were probably a result o the "stress proteins" in NaF-treated rats affecting the structural and functional integrity of sperm. Glycogen accumulation in vas deferens and a decrease in fructose in seminal vesicles and vas deferens indicated disturbances in carbohydrate metabolism in these organs. However, withdrawl of treatment resulted in partial recovery. A significant recovery from NaF-induced toxic effects occurred following administation of ascorbic acid and/or calcium, while combined treatment (AA + Ca++) for 70 days manifested a synergistic effect. The transient fluoride-induced effects were reversible.

The results, corroborated by earlier data from our laboratory, show that fluoride has a definite effect on male reproduction and fertility. Ascorbic acid and calcium are proposed as therapeutic agents in endemic populations for ameiloration of effects of fluoride.


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7734335&dopt=Abstract

Int J Exp Pathol 1995 Feb;76(1):1-11

Effects of chronic fluoride toxicity on the morphology of ductus epididymis and the maturation of spermatozoa of rabbit.

Kumar A, Susheela AK.

Department of Anatomy, All India Institute of Medical Sciences, New Delhi.

This study used light and scanning electron microscopy to observe the effect of chronic fluoride toxicity on the structure of the ductus epididymis, testis and spermatozoa in rabbit. The rabbits were treated with 10 mg NaF/kg body weight/day for 20 and 23 months. Serum fluoride was estimated by the fluoride ion-specific electrode method. Fluoride levels in the sera of both 20 and 23-month treated rabbits were significantly increased (P < 0.001). Loss of stereocilia, significant decrease (P < 0.001) in the height of the pseudostratified columnar epithelium and significant increase (P < 0.001) in the diameter of both the caput and cauda ductus epididymis were observed only in the 23-month fluoride treated rabbits. The decreases in the epithelial cell height (P < 0.01) and the tubular diameter (P < 0.001) of the testis were significant only in 23-month treated animals. Spermatozoa in the lumen of the testis of both treated groups of animals and in the caput and cauda ductus epididymis of 20-month treated animals appeared normal, but spermatozoa in the caput and cauda ductus epididymis of 23-month treated animals were fragmented. In the 23-month fluoride treated rabbits, the weights of the caput and cauda epididymis were significantly reduced (P < 0.025) and there was also a reduction in the number of secretory granules in these organs. The structural changes observed in the caput and cauda ductus epididymis might adversely affect the maturation of spermatozoa.

PMID: 7734335 [PubMed - indexed for MEDLINE]


Fluoride 1995; 28(3):128-130

The influence of fluoride on the content of testosterone and cholesterol in rat

Zhao ZL, Wu NP, Gao WH

Department of Preventive Medicine, Ningxia Medical College, 750004 China

Summary: Fifty four Wistar male rats were randomly divided into three groups, drinking water containing 0.6 mg/L (control group). 100 mg/L, and 200 mg/L sodium fluoride, respectively. Rats were killed at the second, fourth and sixth weeks after experiment initiation, respectively. The levels of serum testosterone, testis cholesterol, and hepatic tissue cholesterol were determined. Results showed that the serum testosterone level had decreased with time in rats drinking water containing 100 and 200 mg/L fluoride. While testis cholesterol level did not change, it was significantly decreased in the liver at the fourth and sixth week when compared with the control group. Results suggest that fluoride may have some harmful effects on the reproductive system in male rats.


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7482578&dopt=Abstract

Toxicol Lett 1995 Oct;80(1-3):115-21

Selective promotion by phenylmethanesulfonyl fluoride of peripheral and spinal cord neuropathies initiated by diisopropyl phosphorofluoridate in the hen.

Peraica M, Moretto A, Lotti M.

Universita degli Studi di Padova, Istituto di Medicina del Lavoro, Italy.

This paper reports studies in hens showing that diisopropyl phosphorofluoridate (DFP) neuropathy is promoted by PMSF when initiated either in central (spinal cord) or peripheral nervous system. Moreover, the critical site for promotion is in peripheral nerve axons rather than in their cell bodies. Selective promotion in peripheral nerves was achieved by giving PMSF into sciatic artery monolaterally (7 mg/kg) to birds where neuropathy was initiated by DFP, either systematically (0.3 mg/kg s.c.) or intra-arterially (0.04 mg/kg in the same artery). Birds developed monolateral neuropathy in the leg where PMSF was delivered. Promotion of spinal cord neuropathy was achieved by giving PMSF (120 mg/kg s.c.) to birds where neuropathy was initiated selectively in spinal cord. This was obtained by protecting peripheral axons with intra-arterial bilateral injections of PMSF (0.55 x 2 mg/kg) followed by DFP (0.3, 0.4 or 0.7 mg/kg s.c.). The resulting syndrome was characterized by spastic ataxia.

PMID: 7482578 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8962792&dopt=Abstract

Biol Trace Elem Res 1995 Dec;50(3):209-19

Effects of aluminum chloride on the kinetics of rat cortex synaptosomal ATP diphosphohydrolase (EC 3.6.1.5).

Schetinger MR, Wyse AT, Da Silva LB, Barcellos CK, Dias RD, Sarkis JJ.

Centro de Ciencias Naturais e Exatas, Universidade Federal de Santa Maria, Brasil.

Aluminum chloride (AlCl3), a neurotoxic compound, inhibited ATP diphosphohydrolase activity of synaptosomes obtained from cerebral cortex of adult rats. The metal ion significantly inhibited ATPase and ADPase activities of the enzyme at all concentrations tested in vitro (0.01, 0.05, 0.5, 5, and 10 mM) in the presence of 1.5 mM calcium. When tested in the absence of Ca2+, and with increasing amounts of Al3+, enzyme activity remained below basal levels, suggesting that the trivalent cation Al3+ is not a substitute for the divalent cation Ca2+ in ATP-Ca2+ and ADP-Ca2+ complexes. The Al3+ inhibition was competitive with respect to Ca2+. The enzyme inhibition was reversed by the addition of deferoxamine (DFO). NaF significantly inhibited ATP diphosphohydrolase activity, and this inhibition was reversed by the addition of Ca2+ to the medium. Such inhibition was not potentiated by AlF4, which is an inhibitor of cation-transport ATPases.

PMID: 8962792 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7488163&dopt=Abstract

Biochem Biophys Res Commun 1995 Nov 13;216(2):669-75

Effect of protein kinase and phosphatase inhibitors on expression of hypoxia-inducible factor 1.

Wang GL, Jiang BH, Semenza GL.

Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-3914, USA.

Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric bHLH-PAS protein essential for erythropoietin gene transcription in hypoxic cells. Here we show that both 2-aminopurine and sodium fluoride, inhibitors of serine/threonine kinases and phosphatases, respectively, interfered with the hypoxic induction of HIF-1 DNA-binding activity and expression of HIF-1 alpha and HIF-1 beta(ARNT) subunits. Genistein, an inhibitor of tyrosine kinases, completely blocked the synthesis of both HIF-1 subunits as well as HIF-1 DNA-binding activity. Sodium orthovanadate, an inhibitor of tyrosine phosphatases increased the basal level of HIF-1 proteins and HIF-1 activity. These data suggest that protein phosphorylation events play an important role in the hypoxia signal-transduction pathway that leads to synthesis of HIF-1 alpha and HIF-1 beta proteins and the induction of HIF-1 DNA-binding activity.

PMID: 7488163 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8747751&dopt=Abstract

No abstract available

Neurotoxicol Teratol 1995 Nov-Dec;17(6):685-8

Comment on: Neurotoxicol Teratol. 1995 Mar-Apr;17(2):169-77.

Neurotoxicity of sodium fluoride in rats.

Ross JF, Daston GP.

Publication Types:

PMID: 8747751 [PubMed - indexed for MEDLINE]


Fluoride 1995; 28(3):125-127

Micronucleus and sister chromatid exchange frequency in endemic fluorosis

DQ Wu and Y Wu

Inner Mongolia Sanitary and Anti-epeidemic Station, Hohhot 010020, China

Summary: Inhabitants of the Hohhot Region in Inner Mongolia who drink high-fluoride (4-15 mg/L) water were compared for their micronucleus (MN) rate and sister chromatid exchange (SCE) frequency in their peripheral blood lymphocytes. In persons with fluorosis as well as those considered "healthy", the MN rate and SCE frequency were significantly higher (t test) than in a neighbouring control group drinking low-fluoride water.


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7885378&dopt=Abstract

Mutat Res 1995 Apr;334(2):243-6

Sister-chromatid exchanges in lymphocytes of workers at a phosphate fertilizer factory.

Meng Z, Meng H, Cao X.

Department of Environmental Science, Shanxi University, Taiyuan, People's Republic of China.

The frequencies of sister-chromatid exchange (SCE) in peripheral blood lymphocytes of 40 workers at a phosphate fertilizer factory in North China were studied. HF and SiF4 are main air pollutants in the factory, there is also some dust containing fluoride, phosphate fog, NH3 and SO2. It was shown that the chemicals caused an increase in SCE, and also induced cell mitotic delays. The mean SCEs/cell of the workers and the non-exposed controls were 7.47 +/- 0.31 and 4.94 +/- 0.14 (p < 0.01) respectively. SCEs/cell in 75% of 40 workers were higher than 6 while 40 controls all had values lower than 6. SCE frequencies of the workers increased with length of the chemical exposure period up to 10 years. Smoking enhanced the SCE frequencies induced by the chemicals.

PMID: 7885378 [PubMed - indexed for MEDLINE]


Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis 1995; 327(1-2):17-22

Sister-chromatid exchanges after exposure to metal-containing emissions

K Sivikova and J Dianovsky

Reprints: K Sivikova, University of Veterinary Medicine, Department of Veterinary Genetics, Kosice 04181, Slovakia

The effect of in vivo feeding of metal-containing emissions from an aluminum refining plant upon the induction of sister-chromatid exchanges (SCEs) and mitotic delay was investigated in cultured sheep lymphocytes. The experimental animals were given a daily dose of industrial emissions (mostly aluminum and fluoride) of either 0.75 g or 1.5 g/animal, for 1 year. The experiments were aimed at induction of chronic fluorosis under clinical conditions. A significant increase in mean serum fluoride, aluminum, arsenic and cadmium levels between both experimental groups and control was observed from 5 and 7 months on, respectively. The occurrence of SCEs in the experimental groups was higher (reaching statistical significance at a does of 1.5 g/animal) than that seen in the controls. The emission was found to reduce the proliferation index. A significant heterogeneity of the first, second and third metaphases as compared to the controls was also observed.


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7753108&dopt=Abstract

Mutat Res 1995 May;343(1):67-74

Chromosome aberrations in cultured rat bone marrow cells treated with inorganic fluorides.

Khalil AM.

Department of Biological Sciences, Yarmouk University, Irbid, Jordan.

The genotoxic effects of inorganic fluorides were investigated by treating cultured rat bone marrow cells with varying concentrations (0.1-100 microM) of potassium fluoride (KF) and sodium fluoride (NaF) for different durations (12, 24 and 36 h) and measuring the incidence of cells with aberrations and number of breaks per cell. Both forms of fluoride were found to be weak mutagens relative to the positive control N-methyl-N-nitro-N-nitrosoguanidine (MNNG). A specificity of fluoride ion in inducing chromosome aberrations (CA) was indicated by the observation that both NaF and KF behaved almost equivalently in this study and at significantly higher variations from the results with potassium chloride (KCl) and sodium chloride (NaCl).

PMID: 7753108 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7589911&dopt=Abstract

Fundam Appl Toxicol 1995 Jul;26(2):223-38

Inhalation oncogenicity bioassay in rats and mice with vinyl fluoride.

Bogdanffy MS, Makovec GT, Frame SR.

Haskell Laboratory for Toxicology and Industrial Medicine, Newark, Delaware 19714, USA.

The purpose of this study was to assess the oncogenic potential of vinyl fluoride in rats and mice when administered by inhalation. Male and female rats and mice were exposed to 0, 25, 250, or 2500 ppm vinyl fluoride 6 hr per day, 5 days per week, for 2 years (rats) or 18 months (mice). Slight body weight gain decrements were noted in groups of vinyl fluoride-exposed rats and mice. No significant clinical signs of toxicity were noted other than an increase in the incidence of palpable masses in the region of the mammary gland in female mice exposed to vinyl fluoride. Survival was decreased in male rats and mice of the 250 and 2500 ppm groups and female rats and mice of all vinyl fluoride-exposed groups compared to controls. Urinary fluoride excretion, an indicator of vinyl fluoride metabolism, increased with concentration and time although the dose relationship appeared to plateau at concentrations > or = 250 ppm. Gross observations made at necropsy of rats supported histological observations of hepatic hemangiosarcoma, hepatocellular adenoma and carcinoma, hepatic foci of clear cell and basophilic alteration, hepatic sinusoidal dilatation, metastatic lung tumors, and Zymbal's gland tumors. Hepatic hemangiosarcoma was the sentinel lesion in rats. Gross observations made at necropsy of mice supported histological observations of bronchioloalveolar adenoma and hyperplasia, hepatic hemangiosarcoma and hepatocellular hyperplasia with angiectasis and peliosis, and mammary gland adenocarcinoma and hyperplasia. Bronchioloalveolar adenoma appeared to be the sentinel lesion in mice. The spectrum of vinyl fluoride-induced tumors is similar to that induced by other monohaloethylenes in rats and mice. Under the conditions of this study, vinyl fluoride was carcinogenic in male and female rats and mice at concentrations greater than or equal to 25 ppm.

PMID: 7589911 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7709355&dopt=Abstract

Ter Arkh 1995;67(1):41-2

[The interrelationship of the thyroid and immune statuses of workers with long-term fluorine exposure]

[Article in Russian]

Balabolkin MI, Mikhailets ND, Lobovskaia RN, Chernousova NV.

Thyroid and immune statuses were studied in workers continuously exposed to fluorine. The examinees with euthyroid condition had immune disorders with an allergic tendency (increased number of B-lymphocytes, immunoglobulins A). In workers with subclinical hypothyrosis (tri-iodothyronine reduced in 51%), the immune alterations were more evident, T-lymphocytes count rose, but their functional activity declined, indicating impaired cooperation of immunocytes as a result of imperfect control under low concentrations of tri-iodothyronine.

PMID: 7709355 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8568925&dopt=Abstract

J Neurosci Res 1995 Oct 1;42(2):242-51

Transmitter release by non-receptor activation of the alpha-subunit of guanine nucleotide regulatory protein in rat striatal slices.

Zelles T, Chernaeva L, Baranyi M, Deri Z, Adam-Vizi V, Vizi ES.

Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.

The effects of 5 mM NaF + 10 microM AlCl3, a direct activator of guanine nucleotide-binding proteins (G proteins), on the release of [3H]dopamine ([3H]DA), [3H]gamma-aminobutyric acid ([3H]GABA), and [3H]acethylcholine ([3H]ACh) were investigated in slices of rat striatum. When the tissue was exposed to NaF + AlCl3 the release of [3H]DA, [3H]GABA, and [3H]ACh was enhanced significantly. In a calcium-free solution the release of [3H]GABA and [3H]DA was increased by NaF+AlCl3 much more than in the presence of [Ca2+]o. In slice preparations taken from reserpinized animals, in which the vesicular storage of [3H]DA was therefore prevented, NaF + AlCl3 had no effect on [3H]DA release. HPLC analysis of the radioactivity of the perfusate showed that, in the presence of NaF + AlCl3, the content of dihydroxyphenylacetic acid (DOPAC) in perfusate samples increased significantly, while in pargyline-treated animals only the DA content was increased. Inhibition of DA carriers by nomifensine or low temperature prevented the effect of NaF + AlCl3. N-ethylmaleimide (NEM) preincubation did not modify the effect of NaF + AlCl3 on [3H]DA release Neomycin (0.1 mM), a phospholipase C (PLC) inhibitor, significantly decreased the effect of NaF + AlCl3 on [3H]DA and [3H]GABA release. The internal concentration of Ca2+ in synaptosomes was enhanced by NaF + AlCl3 in normal solution. However, [Ca2+]i was not influenced by NaF + AlCl3 in Ca(2+)-free medium. It is concluded that a non-receptor-mediated activation, by NaF + AlCl3, of the alpha-subunit of a G protein, results in a [Ca2+]o-independent release of DA and GABA, but not that of ACh.

PMID: 8568925 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8750705&dopt=Abstract

Eur J Pharmacol 1995 Dec 29;294(2-3):451-7

Sodium fluoride attenuates the negative inotropic effects of muscarinic M2 and adenosine receptor agonists.

Neumann J, Kaspareit G, Kirchhefer U, Scholz H.

Abteilung Allgemeine Pharmakologie, Universitats-Krankenhaus Eppendorf, Hamburg, Germany.

Sodium fluoride increased the force of contraction in isolated guinea-pig papillary muscles concentration dependently, starting at 3 mmol/1. Sodium fluoride inhibited phosphorylase phosphatase activity in homogenates from guinea pig hearts, starting at 1 mmol/1. The positive inotropic effect of 3 mmol/1 sodium fluoride was not accompanied by an increase in cAMP content in guinea-pig papillary muscles. In papillary muscles, carbachol or (-)-N(6)-phenylisopropyladenosine reduced the positive inotropic effect of isoprenaline (10 nmol/1) or the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (60 mu mol/1). These negative inotropic effects of carbachol and (-)-N(6)-phenylisopropyladenosine were attenuated by additional sodium fluoride (3 mmol/l). It is concluded that sodium fluoride can impair the signal transduction of muscarinic M2 (carbachol) and adenosine receptor (-)-N(6)-phenylisopropyladenosine) agonists. This effect of sodium fluoride could support the hypothesis that the cardiac effects of muscarinic M2 and adenosine receptor agonists involve, at least in part, the activation of phosphatases.

PMID: 8750705 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7621860&dopt=Abstract

Eur J Immunol 1995 Jul;25(7):1828-35

Phosphatidylinositol 4,5-bisphosphate hydrolysis accompanies T cell receptor-induced apoptosis of murine thymocytes within the thymus.

Conroy LA, Jenkinson EJ, Owen JJ, Michell RH.

Centre for Clinical Research in Immunology and Signalling, Medical School, University of Birmingham, GB.

Regulation of the development of thymocytes into mature T cells within the thymus is now known to involve antigen-induced deletion, by apoptosis, of potentially autoreactive thymocytes, and it can be mimicked either by stimulating the T cell receptor (TcR) complex by monoclonal antibody (mAb) or by ionophore-induced elevation of cytosolic [Ca2+]. To identify signaling pathways employed by the TcR complex of immature thymocytes, we examined the effects of anti-CD3 and anti-TcR beta constant (c) region mAb, staphylococcal enterotoxin B (SEB) and pharmacological agents on the generation of inositol phosphates through hydrolysis of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] both in cultured fetal mouse thymic lobes and in the CD4+CD8+ immature thymocyte cell line, TM10G. Stimulation of the TcR complex with anti-CD3 mAb provoked an accumulation of inositol phosphates diagnostic of the occurrence of receptor-stimulated phosphoinositidase C (PLC) activation. Anti-TcRC beta mAb and SEB provoked smaller but similar responses. The PLC activation evoked by anti-CD3 mAb was suppressed by inhibitors of receptor tyrosine kinases and was unmodified by protein kinase C activation or elevation of cytosolic [Ca2+]. It thus appears that apoptosis triggered by TcR stimulation is associated with PLC activation by a receptor-regulated tyrosine kinase. Treatment of thymic lobes or TM10G cells with fluoroaluminate provoked apoptosis of a wider range of thymocyte subtypes and such stimulation also provoked an accumulation of inositol phosphates. The responses to fluoroaluminate were not prevented by inhibitors of tyrosine kinases, suggesting that unidentified GTP-binding proteins which couple to PLC activation may also be capable of initiating apoptosis by a route independent of the TcR. These results, when considered alongside previous studies of mature T cells, indicate that stimulation of immature thymocytes or of mature T cells through their TcR complex activates the PLC-catalyzed PtdIns(4,5)P2 hydrolysis signaling pathway, and thus that this signaling pathway may be implicated both in provoking apoptosis in immature T cells and in initiating proliferation in mature T cells.

PMID: 7621860 [PubMed - indexed for MEDLINE]


Fluoride 1995; 28(4):193-200

Changes of the human erythrocyte membrane protein SH binding site property with exposure to fluoride and three strong mutagens

Wang YY, Li XJ, Xin WJ

Beijing Municipal Research Institute of Environemental Protection, Fu Wai Avenue, Beijing 100037, China

Summary: The effects of three strong mutagens (potassium bichromate, mitomycin C, and colchicine) and fluoride on the human erythrocyte membrane protein SH binding site property have been studied by using the maleimide nitroxide-ESR technique. The results indicate that in singular and combined treatments with mutagens, the ratio of weakly to strongly immobilized component protein is altered. It is possible that the inhibition in the cytogenetic response is induced by the interaction of fluoride with the other chemicals. There is a dose and temperature dependence of both the singular and the combined action of the mutagen on the membrane protein.


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8526925&dopt=Abstract

Biochem Biophys Res Commun 1995 Dec 5;217(1):286-91

The Ca(2+)-dependent activation by fluoride of human red cell membrane sodium permeability: evidence for a chemically activated tetrodotoxin-sensitive Na+ channel.

Varecka L, Peterajova E, Sevcik J.

Department of Microbiology, Biochemistry and Biology, Slovak Technical University, Bratislava, Slovakia.

Fluoride (NaF) (5-15 mM) activated the 22Na+ uptake by human red blood cells (RBC). The effect was Ca(2+)-dependent. Sr2+, but not Ba2+, Mg2+, Mn2+, substituted Ca2+ in supporting the 22Na+ uptake. The NaF-induced 22Na+ uptake was sensitive to tetrodotoxin (TTX), pertussis toxin but not to amiloride nor valinomycin. The value of the influx was 8.6 +/- 5.0 mmol/l cells. Thus, the TTX-sensitive Na(+)-transport system is present in the RBC membrane in an inactive form which could be activated with NaF by a mechanism involving G-protein(s) but not the depolarization.

PMID: 8526925 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8749036&dopt=Abstract

Eur J Pharmacol 1995 Dec 12;287(2):197-200

Interactions of N-ethylmaleimide and aluminium fluoride with GABAB receptor function in rat neocortical slices.

Ong J, Kerr DI.

Department of Anaesthesia and Intensive Care, The University of Adelaide, Adelaide, South Australia 5005, Australia.

Interactions of N-ethylmaleimide and aluminium fluoride (AlF - 4) with GABAB receptors have been examined using spontaneously discharging rat neocortical slices. The suppression of discharges by the GABAB receptor agonist baclofen (5-10 mu M) was irreversibly prevented by N-ethylmaleimide (10-50 mu M) and its analog N-phenylmaleimide (10-50 mu M), whilst superfusion of slices with NaF (10 mM) and AlCl3 (100 mu M) to form a fluoroaluminate (AlF - 4) complex markedly potentiated the action of baclofen. The lipoxygenase inhibitors, nordihydroguaiaretic acid (10-50 mu M) and eicosatetraynoic acid (10-50 mu M) or the phospholipase A2 inhibitor bromophenacylbromide (50-100 mu M) did not affect the response to baclofen. The depressant action of baclofen is evidently mediated through G-proteins, but is not dependent on arachidonic acid metabolites.

PMID: 8749036 [PubMed - indexed for MEDLINE]


Full report available free at http://www.jbc.org/cgi/content/full/270/49/29469

J Biol Chem 1995 Dec 8;270(49):29469-75

Primary structure of a gamma subunit of G protein, gamma 12, and its phosphorylation by protein kinase C.

Morishita R, Nakayama H, Isobe T, Matsuda T, Hashimoto Y, Okano T, Fukada Y, Mizuno K, Ohno S, Kozawa O, et al.

Department of Biochemistry, Aichi Human Service Center, Japan.

We have determined the primary structure of a novel gamma subunit (gamma 12, previously designated gamma S1) of G protein purified from bovine spleen. The mature gamma 12 protein composed of 68 amino acids had acetylated serine at the N terminus and geranylgeranylated/carboxylmethylated cysteine at the C terminus. This was consistent with the C-terminal prenylation signal in the amino acid sequence, which was predicted from gamma 12 cDNA isolated from a bovine spleen cDNA library. Western blots with the specific antibody against gamma 12 showed that gamma 12 is present in all tissues examined. Among various gamma subunits (gamma 1, gamma 2, gamma 3, gamma 7, and gamma 12), gamma 12 has a unique property to be phosphorylated by protein kinase C. The phosphorylated amino acid residue was Ser1 (or Ser2). The phosphorylated beta gamma 12 associated with Go alpha more tightly than the unphosphorylated form. Exposure of Swiss 3T3 and aortic smooth muscle cells to phorbol 12-myristate 13-acetate and NaF induced phosphorylation of gamma 12. Stimulation of aortic smooth muscle cells with natural vasoactive agents such as angiotensin II and vasopressin also induced phosphorylation of gamma 12. The extent of phosphorylation of beta gamma 12 in vitro was suppressed by a complex formation with Go alpha, which was relieved by the addition of guanosine 5'-O-(3-thiotriphosphate) or aluminum fluoride. These results strongly suggest that gamma 12 is phosphorylated by protein kinase C during activation of receptor(s) and G protein(s) in living cells.

PMID: 7493986 [PubMed - indexed for MEDLINE]


Full report available free at: http://www.jbc.org/cgi/content/full/270/34/19998

J Biol Chem 1995 Aug 25;270(34):19998-20003

Androgen receptor antagonist versus agonist activities of the fungicide vinclozolin relative to hydroxyflutamide.

Wong C, Kelce WR, Sar M, Wilson EM.

Department of Biology, University of North Carolina, Chapel Hill 27599, USA.

The mechanism of antiandrogenic activity of vinclozolin (3-(3,5-dichlorophenyl)-5-methyl-5-vinyloxazolidine-2,4-dione), a dicarboximide fungicide under investigation for its potential adverse effects on human male reproduction, was investigated using recombinant human androgen receptor (AR). The two primary metabolites of vinclozolin in plants and mammals are M1 (2-[[3,5-dichlorophenyl)-carbamoyl]oxy]-2-methyl-3-butenoic acid) and M2 (3',5'-dichloro-2-hydroxy-2-methylbut-3-enanilide). Both metabolites, in a dose-dependent manner, target AR to the nucleus and inhibit androgen-induced transactivation mediated by the mouse mammary tumor virus promoter. M2 is a 50-fold more potent inhibitor than M1 and only 2-fold less than hydroxyflutamide. In the presence of dihydrotestosterone (50 nM), M2 (0.2-10 microM) inhibits androgen-induced AR binding to androgen response element DNA. In the absence of dihydrotestosterone, concentrations of 10 microM M2 or hydroxyflutamide promote AR binding to androgen response element DNA and activation of transcription. Agonist activities of M2 and hydroxyflutamide occur at 10-fold lower concentrations with the mutant AR (Thr877 to Ala) endogenous to LNCaP human prostate cancer cells. The results indicate that androgen antagonists can act as agonists, depending on ligand binding affinity, concentration, and the presence of competing natural ligands.

PMID: 7650017 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7770008&dopt=Abstract

Microbios 1995;81(329):231-9

Effects of G-protein activator fluorides, protein kinase C activator phorbol ester and protein kinase inhibitor on insulin binding and hormonal imprinting of Tetrahymena.

Kovacs P, Csaba G.

Department of Biology, Semmelweis University of Medicine, Budapest, Hungary.

AlCl3, BeCl2 and NaF do not influence the insulin binding of Tetrahymena immediately after treatment, but 24 h later insulin binding is decreased or increased by NaF in a dose-dependent manner, AlCl3 barely influences the binding, and BeCl2 increases it. The effect of all the three fluorides is dose-dependent. While NaF and AlF4 decrease binding at low doses and increase the binding at higher doses, BeF3 increases the insulin binding enormously. NaF does not permit insulin imprinting to be developed, AlF4 inhibits or amplifies the imprinting in a dose-dependent manner, while BeF3 allows imprinting to develop. After 24 h the protein kinase C (PKC) activator phorbol ester (PMA) increases the insulin binding to a similar degree as does the insulin imprinting itself. There was only one dose of the three tested in which PMA inhibited the development of insulin imprinting, whereas the PKC inhibitor reduced insulin binding after 24 h, but could not inhibit insulin imprinting.

PMID: 7770008 [PubMed - indexed for MEDLINE]


http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7503344&dopt=Abstract

Am J Public Health 1995 Dec;85(12):1678-83

Fluoride exposure and childhood osteosarcoma: a case-control study.

Gelberg KH, Fitzgerald EF, Hwang SA, Dubrow R.

Bureau of Occupational Health, New York State Department of Health, New York State Department of Health, Albany, USA.

OBJECTIVES. This study tests the hypothesis that fluoride exposure in a nonoccupational setting is a risk factor for childhood osteosarcoma.
METHODS. A population-based case-control study was conducted among residents of New York State, excluding New York City. Case subjects (n = 130) were diagnosed with osteosarcoma between 1978 and 1988, at age 24 years or younger. Control subjects were matched to case subjects on year of birth and sex. Exposure information was obtained by a telephone interview with the subject, parent, or both.
RESULTS. Based on the parents' responses, total lifetime fluoride exposure was not significantly associated with osteosarcoma among all subjects combined or among females. However, a significant protective trend was observed among males. Protective trends were observed for fluoridated toothpaste, fluoride tablets, and dental fluoride treatments among all subjects and among males. Based on the subjects' responses, no significant associations between fluoride exposure and osteosarcoma were observed.
CONCLUSIONS. Fluoride exposure does not increase the risk of osteosarcoma and may be protective in males. The protective effect may not be directly due to fluoride exposure but to other factors associated with good dental hygiene. There is also biologic plausibility for a protective effect.

PMID: 7503344 [PubMed - indexed for MEDLINE]

Fluoride 1996; 29(4):237-240

A review of the above study by JR Lee MD

Excerpt: ... Differing conclusions are not uncommon in science, and especially in medical science since underlying causes are often exceedingly complex, subtle and heterogeneous. It is important, therefore, to examine the report's results, its test design, and the assumptions on which the test and the conclusions are bases.

Several lines of investigation suggest that fluoride intake increases the risk of cancer in general, and, in particular, the incidence of osteosarcoma in males. As the authors admit, in vivo studies show fluoride to be mutagenic, inducing chromosome aberrations, sister chromatid exchanges, cytotoxicity, and neoplastic transformation in cultured mammalian cells. The authors also agree that fluoride accumulates primarily in bones; and that children, who are actively forming bone, have a higher uptake of fluoride into bone than adults. Further, bone in knees, ankles, shoulders, and wrists, where childhood osteosarcoma most often occurs, shows a high response to fluoride (1).

In 1990, a two-year carcinogenicty study by the National Toxicology Program (NTP) found a statistically significant, dose-related increase of osteosarcoma rates in male rats, but not in mice (2). That the so-called peer review members at the tme quxotically chose to call this fluoride/osteosarcoma correlation "equivocal" (as reported by the authors of this present study) does not change the facts. This same study revealed a strong correlation of fluoride intake with nasal and oral cancer and precancerious lesions in test rats and mice. A coincidental Proctor and Gamble study reported an increased incidence of cancer in rats but this was discounted later on the basis of a concomitant viral contamination in the test rodents (3). Time trends for bone and joint cancer and osteosarcoma derived from the Surveillance, Epidemiology and End Results (SEER) data of the National Cancer Institute (NCI) revealed a positive association of osteosarcoma incidence and water fluoridation among males under 20 years of age (4). In 1993, an ecological study performed by the New Jersey Department of Health found a strong statistical association between fluoridation and osteosarcoma among young men (5). It would appear that the fluoride/osteosarcoma hypothesis is credible and convincing, if not yet "conclusive" to fluoridtion proponents.

... In the present study, something is odd about the case subjects. While it is routinely found that osteosarcoma is more common in young men than in young women, this study's list of 130 cases included only 42 males, or 32% of the total. Thus, the osteosarcoma cases used were not typical of the disease in question.

... one must question the case-control method of the study. In the case-control method, patients with the disease in question are compared to similar appearing, same-age people without the disease. In effect, patients susceptible to osteosarcoma were selected controls, i.e. those without evident osteosarcoma. Given the rarity of osteosarcoma, and the fact that the source of fluoride exposure are so ubiquitous, it would be no problem to find an equal group of healthy people living in the same communities and using the same toothpaste as those with osteosarcoma.

The fact that the two groups' drinking water and toothpaste choices are the same does not invalidate the conclusion that fluoride was a factor in the development of osteosarcoma. The study's authors apparently assume that osteosarcoma victims require higher fluroide exposure than those without the disease. An equally plausible assumption is that variable individual susceptibility exists such that equal fluroide exposure will affect only those with the requisite susceptibility. Given the rarity of the disease, this seems more probable. The susceptibility for osteosarcoma may stem from early prenatal fluoride exposure or from factors not yet kown. The later ocurrence of the cancer may require only the level of fluoride exposure common to fluoridated communties. If this assumption was correct, a case-control study such as this comparing only post-natal fluroide exposure between osteosarcoma victims ad controls would find no difference.

When polio "epidemics" were common, it was clear that only a small percentage of children in any given community developed clinically apparent poliomyelitis while well over 90% of the children showed an equal rise in polio antibodies. That is, despite equal exposure, only a few children were sufficiently susceptible to be stricken with polio. A similar scenario might well apply to the osteosarcoma problem. Since we often do not know all the factors that "cause" or "promote" a given cancer, we do not know what factors are important in selecting comparison groups. Case-control study designs are not appropriate for all ilnesses and this, one might suspect, is one of them.


(1) Gelberg KH, Fitzgerald EF, Hwang S, Dubrow R (1995). Fluoride exposure and childhood osteosarcoma: a case control study. American Journal of Public Health 85:1678-1683

(2) Maurer JK, Cheng MC, Boysen BG, Anderson RI (1990). Two-year carcinogenicity study of sodium fluroide in rats. Journal, National Cancer Institute 82:1118-1126.

(3) As presented at the NTP peer reveiw conference (1990) at Research Triangle Park, North Carolina, attended by author.

(4) Hoover RN, Devesa SS, Cantor KP, Lubin JH, Fraumen Jr JF (1991). Time trends for bone and joint cancers and osteosarcomas. Surveillance, Epidemiology and End Results (SEER) Program, National Cancer Institute. In: Review of fluoride: benefits and risks, report of the ad hoc committee on fluoride of the Committee to Coordinate Environmental health and Related Programs, US Public Health Service, pp F1-F7.

(5) Cohn PD (1992). A brief report on the association of drinking water fluoridtion and the incidence of osteosarcoma among young males. New Jersey Department of Health, Trenton, NJ, November 8.

 

From TOXNET

Iyakuhin Kenkyu 1995;26(3):190-200

[Reproductive and developmental toxicity studies of (+)-9alpha-fluoro-11beta-hydroxy-21-methoxy-16beta-methyl-17alpha-propionyloxy-1,4-pregnadiene-3,20-dione (TS-410) (IV) -- perinatal and postnatal study in rats]

[article in Japanese]

Yamada T, Inoue T, Kurihara A,Tarumoto Y

Developmental Research Laboratories, Taisho Pharmaceutical Co., Ltd., Omiya, Saitama, Japan.

English Abstract Indicator: A Abstract: (+)-9alpha-Fluoro-11beta-hydroxy-21-methoxy-16beta-methyl-17alpha-propionyloxy -1,4-pregnadiene-3,20-dione (TS-410), a new synthetic adrenocorticosteroid, was administered subcutaneously at doses of 0.003, 0.015 or 0.075 mg/kg/day to Sprague-Dawley female rats (Charles River Japan) from day 17 of gestation to day 21 after parturition in order to examine its effects on dams (F0) and their offspring (F1). 1. In dams (F0), no influence on general condition, parturition, lactation, period of gestation, body weight, food consumption, rate of delivery or number of implantation traces was observed in any of the treated groups. However, small thymus size was observed in the 0.075 mg/kg group. 2. In offspring (F1), no influence on general condition, body weight, sex ratio, rate of survival, morphological differentiation, behavior, sensory function, learning ability or reproductive ability was observed in any of the treated groups. No external anomalies attributable to the treatment were observed in any of the treated groups. However, an increase in the number of stillbirths and a decrease in birth rate were observed in the 0.075 mg/kg group. These findings suggest that the maximum no-effect dose level of TS-410 in this study was 0.015 mg/kg for general toxic effects in dams (F0), 0.075 mg/kg for reproductive toxic effects in dams (F0), and 0.015 mg/kg for offspring (F1).


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