1990 Fluoride Abstracts. Part 1. Fluoride Action Network Pesticide Project.

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12637966&dopt=Abstract

Natl Toxicol Program Tech Rep Ser 1990 Dec;393:1-448

NTP Toxicology and Carcinogenesis Studies of Sodium Fluoride (CAS No. 7681-49-4)in F344/N Rats and B6C3F1 Mice (Drinking Water Studies).

National Toxicology Program. (No authors listed)

Sodium fluoride is a white, crystalline, water-soluble powder used in municipal water fluoridation systems, in various dental products, and in a variety of industrial applications. Toxicology and carcinogenesis studies were conducted with F344/N rats and B6C3F1 mice of each sex by incorporating sodium fluoride into the drinking water in studies lasting 14 days, 6 months, and 2 years. In addition, genetic toxicology studies were performed with Salmonella typhimurium, with mouse L5178Y cells, and with Chinese hamster ovary cells.

14-Day Studies: Rats and mice received sodium fluoride in drinking water at concentrations as high as 800 ppm. (Concentrations are expressed as sodium fluoride; fluoride ion is 45% of the sodium salt by weight.) In the high-dose groups, 5/5 male and 5/5 female rats and 2/5 male mice died; one female rat was given 400 ppm in the drinking water also died before the end of the studies. No gross lesions were attributed to sodium fluoride administration.

6-Month Studies: Rats received concentrations of sodium fluoride in drinking water as high as 300 ppm, and mice as high as 600 ppm. No rats died during the studies; however, among the mice, 4/9 high-dose males, 9/11 high-dose females, and 1/8 males in the 300 ppm group died before the end of the studies. Weight gains were less than those of controls for rats receiving 300 ppm and mice receiving 200 to 600 ppm. The teeth of rats and mice receiving the higher doses of sodium fluoride were chalky white and chipped or showed unusual wear patterns. Mice and male rats given the higher concentrations had microscopic focal degeneration of the enamel organ. Rats receiving 100 or 300 ppm sodium fluoride had minimal hyperplasia of the gastric mucosa of the stomach, and one high-dose rat of each sex had an ulcer. Acute nephrosis and/or lesions in the liver and myocardium were observed in mice that died early, and minimal alterations in bone growth/remodeling were observed in the long bones of mice receiving sodium fluoride at concentrations of 50 to 600 ppm.

The sodium fluoride concentrations selected for the 2-year studies in both rats and mice were 0, 25, 100, and 175 ppm in the drinking water. These concentrations were selected based on the decreased weight gain of rats at 300 ppm and of mice at 200 ppm and above, on the incidence of gastric lesions in rats at 300 ppm in the 6-month studies, and on the absence of significant toxic effects at sodium fluoride concentrations as high as 100 ppm in an earlier 2-year study.

Body Weights and Survival in the 2-Year Studies: Mean body weights of dosed and control groups of rats and mice were similar throughout the 2-year studies. Survival of rats and mice was not affected by sodium fluoride administration. Survival rates after 2 years were: male rats-control, 42/80; 25 ppm, 25/51; 100 ppm, 23/50; 175 ppm, 42/80; female rats-59/80; 31/50; 34/50; 54/81; male mice-58/79; 39/50; 37/51; 65/80; female mice-53/80; 38/52; 34/50; 52/80.

Neoplastic and Nonneoplastic Effects in the 2-Year Studies: The teeth of rats and mice has a dose-dependent whitish discoloration, and male rats had an increased incidence of tooth deformities and attrition leading on occasion to malocclusion. The teeth of male and, to a lesser degree, female rats had areas of microscopic dentine dysplasia and degeneration of ameloblasts. Dentine dysplasia occurred in both dosed and control groups of male and female mice; the incidence of this lesion was significantly greater in high-dose than in control male mice. Osteosclerosis of long bones was increased in female rats given drinking water containing 175 ppm sodium fluoride. No other significant nonneoplastic lesions in rats or mice appeared related to sodium fluoride administration. Osteosarcomas of bone were observed in 1/50 male rats in the 100 ppm group and in 3/80 male rats in the 175 ppm group. None were seen in the control or 25 ppm dose groups. One other 175 ppm male rat had an extraskeletal osteosarcoma arising in the subcutaneous tissue. Osteosarcomas occur in historical control male rats at an incian incidence of 0.5&percnt; (range 0-6&percnt;). The historical incidence is not directly comparable with the incidences observed in this study because examination of bone was more comprehensive in the sodium fluoride studies than in previous NTP studies of other chemicals, and the diet used in previous studies was not controlled for fluoride content. In the current study, although the pairwise comparison of the incidence in the 175 ppm group versus that in the controls was not statistically significant, osteosarcomas occurred with a statistically significant dose-response trend, leading to the conclusion that a weak association may exist between the occurrence of these neoplasms and the administration of sodium fluoride. No other neoplastic lesions in rats or mice were considered possibly related to chemical administration.

Genetic Toxicology: Sodium fluoride was negative for gene mutation induction in Salmonella typhimurium strains TA100, TA1535, TA1537, and TA98 with and without S9. In two laboratories, sodium fluoride was tested for induction of trifluorothymidine resistance in mouse L5178Y lymphoma cells; results were positive both with and without S9. Sodium fluoride was tested for cytogenetic effects in Chinese hamster ovary (CHO) cells in two laboratories. In the first laboratory, the sister chromatid exchange (SCE) test was negative with and without S9, and the chromosomal aberration (Abs) test was positive in the absence of S9; in the second laboratory, the SCE test was positive with and without S9, but no induction of Abs was observed. The laboratory that reported a negative result for Abs tested at doses below that shown to be positive at the other laboratory. Similarly, the positive SCE result was obtained at a higher dose and longer harvest time than used by the laboratory reporting the negative SCE response.

Conclusions: Under the conditions of these 2-year dosed water studies, there was equivocal evidence of carcinogenic activity of sodium fluoride in male F344/N rats, based on the occurrence of a small number of osteosarcomas in dosed animals. "Equivocal evidence" is a category for uncertain findings defined as studies that are interpreted as showing a marginal increase of neoplasms that may be related to chemical administration. There was no evidence of carcinogenic activity in female F344/N rats receiving sodium fluoride at concentrations of 25, 100, or 175 ppm (11, 45, or 79 ppm fluoride) in drinking water for 2 years. There was no evidence of carcinogenic activity of sodium fluoride in male or female mice receiving sodium fluoride at concentrations of 25, 100, or 175 ppm in drinking water for 2 years. Dosed rats had lesions typical of fluorosis of the teeth and female rats receiving drinking water containing 175 ppm sodium fluoride had increased osteosclerosis of long bones.

PMID: 12637966 [PubMed - as supplied by publisher]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1964844&dopt=Abstract
Brain Res 1990 Dec 24;537(1-2):93-101

Multiple actions of fluoride ions upon the phosphoinositide cycle in the rat brain.

Tiger G, Bjorklund PE, Brannstrom G, Fowler CJ.

Department of Pharmacology, University of Umea, Sweden.

The effects of sodium fluoride upon basal and agonist-stimulated inositol phospholipid breakdown have been investigated in rat brain miniprisms. NaF concentration dependently increased basal inositol phospholipid breakdown, with a maximum effect being seen at 20 mM. NaF reduced the inositol phospholipid breakdown responses to stimulation by carbachol, noradrenaline, serotonin and quisqualate, but not to the stimulation produced by raising the assay [K+] from 6 to 18 mM. More detailed study demonstrated NaF to have a 'levelling' effect, reducing all InsP/(Lipid + InsP) values greater than 0.15 (i.e. produced by carbachol at raised [K+], noradrenaline and by 50 mM K+) to about this value. Time-course experiments indicated that NaF treatment reduced the rate of carbachol-stimulated inositol phospholipid breakdown up to this InsP/(Lipid + InsP) level and thereafter blocked further breakdown. Inhibitory effects upon carbachol-stimulated inositol phospholipid breakdown were not seen with forskolin, sodium nitroprusside or 8BrcGMP. Under conditions where there is no de novo synthesis of phosphoinositides from [3H]myo-inositol, NaF reduced the total Lipid + InsP labelling by about 20%. NaF in addition inhibits the activity of Ins(1,4)P2-phosphatase in cerebral cortical homogenates. It is concluded that fluoride ions inhibit agonist-stimulated inositol phospholipid breakdown via actions not only on G-proteins but also on phosphoinositide-specific phospholipase C substrate availability.

PMID: 1964844 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2155122&dopt=Abstract
Eur J Pharmacol 1990 Jan 23;188(1):51-62

Effect of monovalent ions upon G proteins coupling muscarinic receptors to phosphoinositide hydrolysis in the rat cerebral cortex.

Tiger G, Bjorklund PE, Cowburn RF, Garlind A, O'Neill C, Wiehager B, Fowler CJ.

Department of Pharmacology, University of Umea, Sweden.

It has been suggested that K+, Li+ and Fl- affect the function of G proteins coupled to signal transducing enzymes. Lithium, at concentrations which were found to reduce forskolin-stimulated adenylate cyclase activity, was without effect on either membrane [3H]phosphatidylinositol-4,5-bisphosphate ([3H]PIP2) hydrolysis measured in the absence or presence of 5'-guanylyl-imidodiphosphate (Gpp(NH)p), or (at greater than or equal to 2.3 mM Li+) upon the stimulation of rat cerebral cortical inositol phospholipid breakdown by either carbachol, noradrenaline or NaF measured at either 6 or 18 mM K+. The increase in assay [K+] greatly enhanced the inositol phospholipid response to carbachol but not to NaF. The inhibitory effect of carbachol upon forskolin-stimulated adenylate cyclase was not affected by raising the [K+] from 6 to 18 mM. At 6 mM K+ (both in the absence and presence of 15 microM AlCl3), the effects of carbachol and NaF upon inositol phospholipid breakdown were essentially additive, whereas at 18 mM K+, the breakdown response to carbachol (antagonised by pirenzepine with a pA2 value of 7.6) was similar in the absence and presence of NaF. It is concluded that in the rat cerebral cortex:
(a) Li+ does not affect the function of either the phosphoinositide-specific phospholipase C enzyme itself or the Gp coupled to this enzyme;
(b) the difference between the additivity between NaF and carbachol seen at different assay [K+] may reflect the K(+)-dependent changes in the tetrodotoxin-resistant and tetrodotoxin-sensitive pathways of carbachol stimulation of inositol phospholipid breakdown reported by Gurwitz and Sokolovsky (1987, Biochemistry 26, 633); and
(c) the effect of K+ on muscarinic receptor-coupled inositol phospholipid breakdown is not found for muscarinic receptors inhibitorily coupled to adenylate cyclase. Evidence is also presented to suggest that NaF affects the dephosphorylation of the formed [3H]inositol polyphosphates.

PMID: 2155122 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2163621&dopt=Abstract
Biochem J 1990 Jun 15;268(3):733-7

Dual effect of fluoride on phosphoinositide metabolism in rat brain cortex.
Stimulation of phospholipase C and inhibition of polyphosphoinositide synthesis.

Claro E, Wallace MA, Fain JN.

Department of Biochemistry, University of Tennessee, Memphis 38163.

We have studied the effects of fluoride, guanosine 5'-[gamma-thio]triphosphate (GTP[S]) and carbachol on phospholipase C and polyphosphoinositide synthesis. The experimental system consisted of membranes from rat brain cortex, with exogenous [3H]phosphatidylinositol ([3H]PtdIns) as substrate. In such systems, we have not found evidence to support carbachol and/or GTP[S] stimulation of PtdIns phosphorylation. Fluoride inhibited synthesis of PtdIns4P and PtdIns(4,5)P2 from PtdIns. Consequently, under conditions where breakdown of polyphosphoinositides by phospholipase C was dependent on PtdIns kinase activity, fluoride inhibited activation by GTP[S] plus carbachol of phospholipase C. When conditions allowed direct breakdown of PtdIns and precluded PtdIns kinase activity, the stimulatory effects of fluoride and GTP[S] plus carbachol on phospholipase C activity were additive.

PMID: 2163621 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2156022&dopt=Abstract
J Neurochem 1990 Apr;54(4):1426-32

Guanosine 5'-O-thiotriphosphate and sodium fluoride activate polyphosphoinositide hydrolysis in rat cortical membranes by distinct mechanisms.

Li PP, Sibony D, Warsh JJ.

Section of Biochemical Psychiatry, Clarke Institute of Psychiatry, Toronto, Ontario, Canada.

NaF and guanosine 5'-O-thiotriphosphate [GTP(S)] stimulated the accumulation of [3H]inositol monophosphate ([3H]InsP) in rat brain cortical membranes, with half-maximal stimulation at 2 mM and 1 microM, respectively. Calcium also increased basal [3H]InsP formation over a range of concentrations from 10(-7) to 10(-4) M. The stimulatory effect of GTP(S) (30 microM) on [3H]InsP production was insensitive to Ca2+, whereas NaF-evoked [3H]InsP formation was dependent on Ca2+ concentrations. Guanosine 5'-O-thiodiphosphate significantly attenuated GTP(S)- but not NaF-stimulated [3H]InsP production. Coincubation of GTP(S) (30 microM) and submaximal concentrations of NaF (1 or 3 mM) stimulated [3H]InsP formation to a degree that was nearly additive with that produced by either drug alone. However, the resultant accumulation of [3H]InsP in the presence of maximally effective concentrations of GTP(S) and NaF was not different from that produced by NaF alone. Incubation of cortical membranes with GTP(S) and NaF for 1 min stimulated the accumulation of [3H]inositol bisphosphate (InsP2) but not [3H]InsP. [3H]InsP2 production elicited by GTP(S) was markedly enhanced by the muscarinic cholinergic agonist carbachol. In contrast, NaF-stimulated [3H]InsP2 formation was not potentiated by carbachol. Our findings of different characteristics of GTP(S) and fluoride activation of polyphosphoinositide (PPI) hydrolysis suggest that separate regulatory mechanisms are involved in these two modes of stimulation in brain membranes. Activation of PPI hydrolysis by fluoride may be mediated by a direct stimulation of PPI phosphodiesterase or by activating a putative guanine nucleotide regulatory protein at a location distinct from the GTP-binding site.

PMID: 2156022 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1690266&dopt=Abstract
J Neurochem 1990 Apr;54(4):1130-5

Modulation of gamma-aminobutyric acid release in cerebral cortex by fluoride, phorbol ester, and phosphodiesterase inhibitors: differential sensitivity of acetylcholine release to fluoride and K+ channel blockers.

Gardiner IM, de Belleroche J.

Department of Biochemistry, Charing Cross and Westminster Medical School, London, England.

In this study we have used fluoride as a tool to investigate the involvement of G protein-coupled effector systems in the regulation of the depolarization-induced release of gamma-aminobutyric acid (GABA) from rat cerebral cortex. To distinguish among the activating effects of NaF on G proteins linked to different effectors, such as adenylate cyclase, polyphosphoinositide phospholipase C, and K+ channels, agents specific to these effectors have been used in parallel. NaF induced a marked dose-dependent facilitation of the K(+)-evoked release of [14C]GABA, with an EC50 of 1.26 mM, increasing release by 103% at 5 mM NaF. No effect on basal release was seen up to 3 mM NaF, and no modulation of [3H]acetylcholine (ACh) release was seen up to 5 mM NaF. Phorbol 12,13-diacetate (PDA) produced a similar dose-dependent facilitation of the K(+)-evoked release of [14C]GABA, potentiating the release of [14C]GABA by 50% at 10 microM PDA. The phosphodiesterase inhibitors, 3-isobutyl-1-methylxanthine (IBMX) and theophylline, inhibited the K(+)-evoked release of [14C]GABA, and IBMX reversed the NaF facilitation of GABA release in a dose-dependent manner (pA2 2.57). The K+ channel blocker (IA current) tetrahydroaminoacridine (THA), which markedly inhibits the K(+)-evoked release of [14C]GABA, also reversed the NaF facilitatory effect, but the release of [3H]ACh was less sensitive to the inhibitory effect of THA. On the other hand, the K+ channel blocker, tetraethylammonium, which has no effect on the release of [14C]GABA, caused a significant facilitation of K(+)-evoked release of [3H]ACh. From these studies, it is concluded that GABA release in cerebral cortex is subject to regulation by G protein-linked effector systems that are distinct from those affecting the release of [3H]ACh in cerebral cortex.

PMID: 1690266 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2159821&dopt=Abstract
Brain Res 1990 Jan 22;507(2):181-8

Aluminum fluoride reveals a phosphoinositide system within the suprachiasmatic region of rat hypothalamus.

Nadakavukaren JJ, Welsh DK, Reppert SM.

Laboratory of Developmental Chronobiology, Children's Service, Massachusetts General Hospital, Boston 02114.

The phosphoinositide (PI) transduction system has proven to be of major importance in several regions of mammalian brain. In this report, we examined in rats whether a PI system is present in the hypothalamic suprachiasmatic nuclei (SCN), the site of a biological clock that generate circadian rhythms. Autoradiographic localization of phorbol ester binding revealed moderate levels of protein kinase C, a component of the PI system, in the SCN. Hypothalamic explants containing SCN showed substantial incorporation of [3H]myoinositol into lipids. AlF4-, a non-specific activator of G proteins, produced a dose-dependent increase in inositol monophosphate (IP1) levels in the explants in calcium-free medium, with a maximum increase of 216% of control at 50 mM NaF. Medium containing 1.8 mM calcium stimulated a similar increase in IP1 levels, but the stimulatory effects of AlF4- and calcium were not additive, so that the effect of Al4- was obscured in medium containing calcium. AlF4- stimulated accumulation of IP1, as well as inositol bis-, and trisphosphate, over a 40-min time course in the presence and absence of lithium (10 mM LiCl). Lithium, a known inhibitor of phosphatases in the inositol phosphate recycling pathway, raised levels of all 3 inositol phosphates in SCN explants both at baseline (without A1F4-) and after 30 min AlF4- stimulation. The results show the existence of a lithium-sensitive PI system within the suprachiasmatic region of the rat hypothalamus.

PMID: 2159821 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2171506&dopt=Abstract
Biochem Biophys Res Commun 1990 Sep 28;171(3):1087-92

The effect of new potent selective inhibitors of protein kinase C on the neutrophil respiratory burst.

Twomey B, Muid RE, Nixon JS, Sedgwick AD, Wilkinson SE, Dale MM.

Department of Pharmacology, University College London, UK.

New potent inhibitors of protein kinase C were found to inhibit protein kinase C isolated from rat brain and human neutrophils, with a large degree of selectivity over cAMP-dependent kinase and Ca2+/calmodulin-dependent kinase. These novel compounds were potent inhibitors of the fluoride, diC8- and formyl-methionyl-leucyl-phenylalanine-mediated respiratory bursts in intact neutrophils. The opsonized zymosan-stimulated burst was only marginally affected by the compounds. These results differ from those obtained in studies with H7 and CI, (which are less potent and less specific protein kinase C inhibitors) and are consistent with the hypothesis that protein kinase C has a role in the transduction mechanism for the neutrophil oxidative burst stimulated with fluoride, formyl-methionyl-leucyl-phenylalanine and diC8.

PMID: 2171506 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2109044&dopt=Abstract
J Neurochem 1990 May;54(5):1632-8

Guanine nucleotide-binding protein regulation of microsomal phospholipase D activity of canine cerebral cortex.

Qian Z, Reddy PV, Drewes LR.

Department of Biochemistry, School of Medicine, University of Minnesota, Duluth 55812.

The hydrolytic activity of microsomal phospholipase D from canine cerebral cortex was measured by a radiochemical assay using 1,2-dipalmitoyl-sn-glycerol-3-phosphoryl[3H]choline and 1-palmitoyl-2-[9,10(n)-3H]palmitoyl-sn-glycerol-3-phosphorylcholine as the exogenous substrates. Of several detergents tested, Triton X-100 was found to be the most effective in allowing expression of phospholipase D hydrolytic activity. The microsomal phospholipase D does not require any metal ion for its hydrolytic activity. Calcium and magnesium were slightly inhibitory between concentrations of 1 and 4 mM, but zinc was greatly inhibitory, causing a loss of greater than 90% activity at the 4 mM concentration. Non-hydrolyzable guanine nucleotide analogues such as guanosine 5'-(3-O-thio)triphosphate and guanyl-5'-yl-(beta, gamma-methylene)diphosphonate but not guanosine 5'-(2-thio)diphosphate were able persistently to stimulate phospholipase D hydrolytic activity at micromolar concentrations. Guanosine 5'-(2-thio)diphosphate was capable of partially blocking guanosine 5'-(3-O-thio)triphosphate stimulation of phospholipase D. Aluminum fluoride was able to cause a two- to threefold increase in hydrolytic activity of the phospholipase D. Cholera toxin had a stimulatory effect on the hydrolytic activity of phospholipase D, whereas islet-activating protein pertussis toxin had no effect. These results indicate that regulation of microsomal phosphatidylcholine phospholipase D activity by the guanine nucleotide-binding protein(s) in canine cerebral cortex may play an important role in signal transduction processes as well as in brain choline metabolism.

PMID: 2109044 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2115460&dopt=Abstract
Biochem Soc Trans 1990 Jun;18(3):424-6

Preferential binding of a chick brain tau isoform to microtubules assembled in the presence of aluminium fluoride.

Burns RG.

Biophysics Section, Blackett Laboratory, Imperial College of Science, Technology and Medicine, London, U.K.

PMID: 2115460 [PubMed - indexed for MEDLINE]

Fluoride 1990; 23(2):83-91
Effects of fluoride on Drosophila melanogaster in relation to survival and mutagenicity

B Dominok and GW Miller *

* Biology Department, Utah State University, Logan, Utah 84322, USA

Summary: Drosophilia melanogaster (D.m.) genotype Oregon R was treated with 0.01% to 4.8% NaF for 24 hours to determine the survival rate (toxicity test) and the level of inducting sex-linked lethal mutations. As a control NaCl was used at the same molar solution. The results indicated a decrease in survival of flies at concentrations above 0.05% NaF.

At 0.1% (22.8 mM) NaF, survival was about 50%. Examinations of 856 male D.m. treated with 0.1% NaF for 24 hours showed 1.4% sex-linked recessive lethal mutations at the F2 progeny; 637 males of the F2 offspring treated with 0.138% NaCl (23.8% mM) showed no recessive lethals. Possible mutagenicity of fluoride is suggested. D.m. tested with 23.8 mM NaF or 23.8 mM NaCl for 24 hours contained 360 and 1.7 µg fluoride per gram dry weight, respectively.

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Mutat Res 1990 Jul;244(3):209-14

Induction of chromosomal aberrations in male mouse germ cells by uranyl fluoride containing enriched uranium.

Hu QY, Zhu SP.

Department of Radiotoxicology, Suzhou Medical College, Jiangsu, China.

Cytogenetic damage induced by a wide range of concentrations of uranyl fluoride injected into mouse testes was evaluated by determining the frequencies of chromosomal aberrations in spermatogonia and primary spermatocytes. Breaks, gaps and polyploids were observed in spermatogonia. The frequencies of the significant type of aberration, breaks, were induced according to the injected doses of uranyl fluoride. Primary spermatocytes were examined for fragments, univalents and multivalents. The multivalents observed in this study resulted either from chromatid interchanges or from reciprocal translocations. The reciprocal translocations were induced in spermatogonia and recorded in primary spermatocytes. For primary spermatocytes the incidence of aberrant cells largely depended on the administered dose. Sampling time after treatment could affect the frequencies of chromosomal aberrations in male mouse germ cells.

PMID: 2366813 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2307151&dopt=Abstract
Environ Mol Mutagen 1990;15(2):71-7

Sodium fluoride is a less efficient human cell mutagen at low concentrations.

Crespi CL, Seixas GM, Turner T, Penman BW.

Gentest Corporation, Woburn, Massachusetts 01801.

Sodium fluoride was found to induce gene-locus mutations at the thymidine kinase (tk) and hypoxanthine guanine phosphoribosyl transferase (hgprt) loci in human lymphoblastoid cells. A single, 28 hr exposure to up to 600 micrograms/ml sodium fluoride induced a concentration-dependent increase in mutant fraction at both gene loci and reduced cell survival to 12% relative to negative control cultures. When cells were exposed to sodium fluoride concentrations that were only minimally toxic using a 20 day treatment protocol, no detectable induction of mutation was observed at the hgprt locus, and induction of mutation was observed at the tk locus only for treatment with 65 micrograms/ml sodium fluoride; exposure to 50 and 35 micrograms/ml sodium fluoride did not induce detectable mutation. The assay protocol used was of sufficient statistical sensitivity to detect the level of mutation predicted based on a linear extrapolation of data obtained from a 28 hour exposure. The implications of these observations with regard to the extrapolability of mutagenicity data to low concentrations are discussed.

PMID: 2307151 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2165827&dopt=Abstract
Biol Reprod 1990 Aug;43(2):323-34

Orthovanadate and fluoroaluminate stimulate inositol phosphate production and in vitro ovulation in goldfish (Carassius auratus) follicles.

Ranjan M, Goetz FW.

University of Notre Dame, Department of Biological Sciences, Indiana 46556.

Both sodium orthovanadate and fluoroaluminate were found to stimulate in vitro ovulation in intact goldfish follicles, suggesting the involvement of G-proteins in ovulation. Although orthovanadate was able to stimulate cAMP production, it probably stimulates ovulation by some other mechanism since cAMP blocks ovulation in this species. These agents also stimulated the accumulation of labeled inositol phosphate in follicle walls. The time course of inositol phosphate production showed a slightly delayed and continuous accumulation for isomers of inositol mono-, bis-, and trisphosphates. No change was observed in inositol tetrakisphosphate levels over time. The accumulation of inositol phosphates in response to orthovanadate was also dose-dependent. Lithium chloride (10 mM) caused varying increases in the levels of most isomers and a decrease in ins-3,4-P2. Inositol phosphate production varied significantly with changes in the maturational stage of follicles. Peak production was observed in follicles 7-8 h after hCG treatment, which corresponds almost exactly with the time of ovulation. This correlation of maximal inositol phosphate production with the time of ovulation, along with the stimulation of ovulation by diacylglycerols, a phorbol ester, and the G-protein-stimulating agents, orthovanadate and fluoroaluminate, suggests a role for polyphosphatidylinositol hydrolysis in ovulation.

PMID: 2165827 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2182701&dopt=Abstract
J Gynecol Obstet Biol Reprod (Paris) 1990;19(2):171-5

[The passage of fluoride across the placenta. An intra-uterine study]

[Article in French]

Forestier F, Daffos F, Said R, Brunet CM, Guillaume PN.

Service de Medecine et de Biologie foetales, Institut de Puericulture de Paris.

Until now, transplacental passage of fluoride could only be checked during delivery. Recent developments in fetal blood sampling techniques in utero have made it possible to study its passage in pregnancy. Two tablets of 2.212 mg of sodium fluoride (Zymafluor) were given to 11 women with an average age of 27 1/2 years whose pregnancies on an average had lasted 22 weeks. They were having prenatal diagnosis by ultrasound guided fetal blood sampling in any case. The levels of fluoride were measured by the use of a specific electrode before the mother took fluoride and 40 minutes after she had taken it in both maternal and fetal blood samples. The results were compared with a controlled group of 11 pregnant women with similar characteristics: maternal age, duration of pregnancy and basal maternal fluoride levels. Fetal blood levels of fluorides in mothers who had taken sodium fluoride was statistically higher than in the controlled group (2.6 mumol/l and less than 1 mumol/l); this demonstrates in a statistically significant way that fluoride passes across the placenta in the fifth and sixth months of pregnancy which is the time when the milk teeth start to develop in the uterus.

PMID: 2182701 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2161489&dopt=Abstract
Mol Biol (Mosk) 1990 Jan-Feb;24(1):104-16 Related Articles, Links

[Interaction of dNTP-binding sites of human DNA polymerase alpha and The Klenow fragment of Escherichia coli DNA polymerase I with nucleotides, pyrophosphate and their analogs]

[Article in Russian]

Nevinskii GA, Potapova IA, Tarusova NB, Khalabuda OV, Khomov VV.

AMP and NaF each taken separately were shown to activate DNA polymerization catalyzed by Klenow fragment of DNA polymerase I by means of interaction of AMP or NaF with 3'----5'-exonuclease center of the enzyme. In the presence of NaF which is a selective inhibitor of 3'----5'-exonuclease center, AMP is an inhibitor of polymerization competitive with respect to dATP. Ki values and the pattern of inhibition with respect to dATP were determined for AMP, ADP, ATP, carboxymethylphosphonyl-5'-AMP, Pi, PPi, PPPi, methylenediphosphonic acid and its ethylated esters, phosphonoformic acid, phosphonoacetic acid and its ethylated esters as well as for some bicarbonic acids in the reactions of DNA polymerization catalyzed by Klenow fragment of DNA polymerase I (in the presence of NaF) and DNA polymerase alpha from human placenta in the presence of poly(dT) template and r(pA)10 primer. All nucleotides and their analogs were found to be capable of competing with dATP for the active center of the enzyme. Most of the analogs of PPi and phosphonoacetic acid are inhibitors of Klenow fragment competitive with respect to dATP. Nowever these analogs display a mixed-type inhibition in the case of human DNA polymerase alpha. We postulated a similar mechanism of interaction for dNTP with both DNA-polymerases. It is suggested that each phosphate group of PPi makes equal contribution to the interaction with DNA polymerases and that the distance between the phosphate groups is important for this interaction. beta-phosphate of NTP or dNTP is suggested to make negligible contribution to the efficiency of the formation of enzyme complexes with dNTP. beta-phosphate is likely to be an essential point of PPi interaction with the active center of proteins during the cleavage of the alpha-beta-phosphodiester bond of dNTP in the reaction of DNA polymerization.

PMID: 2161489 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2177517&dopt=Abstract
Miner Electrolyte Metab 1990;16(4):224-31

Role of guanine nucleotide binding protein, cytosolic calcium and cAMP in fluoride-induced suppression of PTH secretion.

Sugimoto T, Ritter C, Slatopolsky E, Morrissey J.

Department of Medicine, Washington University School of Medicine, St. Louis, Mo.

In the present studies, we used fluoride and pertussis toxin, potent modulators of guanine nucleotide binding proteins (G proteins), to examine the role of G proteins, cytosolic calcium ([Ca]i) and cAMP in the regulation of PTH secretion from dispersed bovine parathyroid cells. NaF suppressed PTH secretion and cAMP content and increased [Ca]i levels in a dose-dependent manner. Prior removal of extracellular calcium with EGTA completely blocked the NaF-induced increase in [Ca]i, but did not prevent the NaF-induced inhibition of PTH secretion and cAMP content. Pretreatment with 10(-5) M verapamil or 10(-4) M diltiazem blocked neither the NaF-induced suppression of PTH secretion and cAMP content nor the increase in [Ca]i. Manganese chloride (10(-4) M) significantly inhibited the NaF-induced increase in [Ca]i, but did not block the NaF-induced suppression of PTH secretion and cAMP content. Pertussis toxin blocked neither the NaF-induced increase in [Ca]i nor suppression of PTH secretion and cAMP content. Our data suggest that
(1) NaF might stimulate a calcium channel resulting in the increase in [Ca]i by acting on a G protein in a manner resistant to the inhibition by pertussis toxin;
(2) the NaF-induced increase in [Ca]i is not directly linked to the suppression of PTH secretion, and
(3) the NaF-induced suppression of PTH secretion might be explained at least in part by the decrease in cell cAMP content.

PMID: 2177517 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2260984&dopt=Abstract
Biochem Pharmacol 1990 Dec 15;40(12):2587-96

Characterization of neuropathy target esterase using trifluoromethyl ketones.

Thomas TC, Szekacs A, Rojas S, Hammock BD, Wilson BW, McNamee MG.

Department of Biochemistry and Biophysics, University of California, Davis 95616.

Neuropathy target esterase (NTE) is a membrane-bound carboxylesterase activity which is proposed as the target site in nerve tissue for initiation of organophosphate-induced delayed neuropathy. This activity is identified as phenyl valerate hydrolysis which is resistant to treatment with paraxon and sensitive to co-incubation with paraxon and mipafox. NTE preparations were obtained, which did not contain paraxon-sensitive or mipafox-resistant hydrolases, by selective reconstitution of detergent-solubilized NTE from chick embryo brain into asolectin vesicles during gel filtration. The topography of the catalytic site of NTE was then examined by investigating the inhibition of NTE by a series of 3-alkylthio- and 3-arylthio-1,1.1-trifluoro-propan-2-ones. These trifluoromethyl ketones were found to be rapidly reversible, competitive inhibitors of NTE with I50 values 1.3 x 10(-4) M to 4.9 x 10(-8) M. Correlation of I50 values with octanol/water partition coefficients (P), in the range of log P = 1.5 to 5.9. indicated that the optimal lipophilicity for NTE substrates and inhibitors is in the range of log P = 3.0 to 3.4. Electrophilic substitution at the meta position of aromatic rings increased the inhibitory capacity of these inhibitors, whereas substitution at the ortho position reduced inhibitory capacity. These results indicate both that a large hydrophobic pocket is closely associated with the catalytic residue of NTE, and that affinity for the active site is affected by steric and electronic parameters.

PMID: 2260984 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2254952&dopt=Abstract
J Toxicol Environ Health 1990 Dec;31(4):261-73

Potentiation of organophosphorus-induced delayed neurotoxicity by phenylmethylsulfonyl fluoride.

Pope CN, Padilla S.

School of Pharmacy, Northeast Louisiana University, Monroe 71209.

It is well known that pretreatment with the serine esterase inhibitor phenylmethylsulfonyl fluoride (PMSF) can protect experimental animals from organophosphorus-induced delayed neurotoxicity (OPIDN), presumably by blocking the active site of neurotoxic esterase (NTE) such that binding and "aging" of the neuropathic OP is thwarted. We report here that while PMSF (60 mg/kg, sc) given 4 h before the neuropathic organophosphate (OP) mipafox (50 mg/kg, im) completely prevented the clinical expression of OPIDN in hens, the identical PMSF treatment markedly amplified the delayed neurotoxicity (relative to hens treated with OP only) if administered 4 h after mipafox (5 or 50 mg/kg, im). Moreover, in a separate experiment using diisopropylphosphorofluoridate (DFP) as the neurotoxicant in place of mipafox, posttreatment with PMSF 4 h after DFP (0.5 mg/kg) also accentuated the severity of ataxia. These data indicate that PMSF only protects against OPIDN if given prior to exposure to the neurotoxicant; treatment with PMSF after OP exposure critically exacerbates the delayed neurotoxicity from exposure to organophosphorus compounds.

PMID: 2254952 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2073603&dopt=Abstract
Brain Res 1990 Dec 10;535(2):205-13

Glucose-supported oxidative metabolism and evoked potentials are sensitive to fluoroacetate, an inhibitor of glial tricarboxylic acid cycle in the olfactory cortex slice.

Saito T.

Department of Physiology, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan.

Optical absorbance change was measured by reflectance spectrophotometry in the olfactory cortex slice prepared from the rat brain. Optical absorbance of the piriform area of the slice was increased by perifusion with an anoxic (N2-gassed) solution. Components of the absorbance spectrum recorded from the slice in anoxia corresponded to that of cytochromes (cyt) aa3 and c + c1, but did not to that of cyt c. Reduction of cytochromes in anoxia coincided with decrease in the amplitude of the presynaptic potential and a slower negative wave (N-wave). The reduced state of cytochromes switched to an oxidized state when a well-oxygenated solution was reintroduced. An almost complete recovery of redox state coincided with full recovery of the evoked potential. A metabolic inhibitor, 2-deoxy-D-glucose (2DG) (10 mM) or iodoacetic acid (IAA) (3 mM) caused little or slight oxidation of cytochromes, but significantly decreased the amplitude of evoked potentials. Marked oxidation of cytochromes was observed only by perifusion with a solution containing 2 DG (10 mM) and IAA (3 mM). The rate of oxygen uptake was significantly lowered by these metabolic inhibitors. When the slice was perifused with a solution containing fluoroacetate (1 or 10 mM), a selective inhibitor of glial metabolism, cytochromes shifted to oxidized levels. The amplitude of evoked potentials tended to decline by a low dose (1 mM), and significantly decreased by a high dose (10 mM) of fluoroacetate. Oxygen consumption of the slice was dose-relatedly lowered by fluoroacetate.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID: 2073603 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2364992&dopt=Abstract
Eur J Pharmacol 1990 Apr 25;179(3):307-13

Seizures induced by fluoroacetic acid and fluorocitric acid may involve chelation of divalent cations in the spinal cord.

Hornfeldt CS, Larson AA.

Department of Veterinary Biology, University of Minnesota, St. Paul, MN 55108.

Fluoroacetic and fluorocitric acid toxicity is often characterized by seizures, however the mechanism of this activity is unknown. Intrathecal (i.t.) injection of fluorocitrate in mice resulted in seizures after an average latency of 15 s, while intracerebroventricular (i.c.v.) injection produced seizures after 36.5 min, and required higher doses to achieve this effect. This indicates the probable site of fluoroacetate and fluorocitrate neurotoxicity is the spinal cord. To mimic citrate accumulation, characteristic of fluoroacetate and fluorocitrate poisoning, citric acid was injected i.t. and also found to produce seizures. The structurally unrelated compounds EDTA, EGTA, glutamic acid and lactic acid also produced seizures identical to fluorocitrate. The ability of these compounds to chelate Ca2+ correlates well with their ability to cause seizures when administered i.t. and coadministration of calcium greatly attenuated the neurotoxicity of these compounds as well as fluoroacetate and fluorocitrate. In contrast, Ca2+ was unable to inhibit seizures elicited by strychnine, suggesting calcium's ability to inhibit chelators of divalent cations is not due to a general anticonvulsant effect. These results suggest that changes in Ca2+ concentration in the spinal cord may be responsible for some forms of seizure activity.

PMID: 2364992 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2341082&dopt=Abstract
Folia Morphol (Praha) 1990;38(1):63-5

Histopathological changes in rabbit testes during experimental fluorosis.

Shashi.

Department of Zoology, Punjabi University, Patiala, India.

The aim of the study was to evaluate relationship between infertility and the histological structure of the testes following the subcutaneous administration of different doses of sodium fluoride (5, 10, 20 and 50 mg/kg/day), for 100 days, to groups of six male albino rabbits; the six control animals were given 1 cc distilled water/kg b.w./day for the same length of time. Deficient maturation and differentiation of the spermatocytes and an increase in the amount of interstitial tissue were found in the experimental animals. In the higher dosage groups, spermatogenesis stopped and the seminiferous tubules became necrotic. The study thus established the existence of a definite relationship between fluorosis and testicular damage.

PMID: 2341082 [PubMed - indexed for MEDLINE

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2391140&dopt=Abstract
Indian J Pathol Microbiol 1990 Apr;33(2):113-7

Histopathological changes in rabbit ovary during experimental fluorosis.

Shashi.

Department of Zoology, Punjabi University, Patiala, India.

Albino rabbits were injected sodium fluoride solutions in the concentration of 5, 10, 20 and 50 mg/kg body weight/day subcutaneously for 100 days. The control rabbits were given 1 cc of distilled water for the same period and sacrificed. The ovary was examined for histopathological changes. Animals in control and 5 mg fluoride treated groups displayed normal follicles with oocytes and interstitial tissue in ovaries. In animals treated with 10 and 20 mg fluoride, ovary exhibited congested oocytes in the follicles, necrosis of follicle cells and interstitial oedema. The degenerative changes were most pronounced in animals treated with 50 mg fluoride, in which complete atrophy of follicles along with oocyte disintegration and marked necrosis of cells accompanied by infiltration of monocytes, lymphocytes and histiocytes in interstitial tissue occurred. The data indicate that the structural alterations in the ovary were more pronounced with the concomitant increase in the dose of fluoride.

PMID: 2391140 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2155030&dopt=Abstract
Biochim Biophys Acta 1990 Feb 23;1042(3):374-9

Effect of NaF and okadaic acid on the subcellular distribution of CTP: phosphocholine cytidylyltransferase activity in rat liver.

Hatch GM, Lam TS, Tsukitani Y, Vance DE.

Lipid and Lipoprotein Research Group, University of Alberta, Edmonton, Canada.

The effect of preincubation of rat liver post-mitochondrial supernatant with NaF and okadaic acid on the subcellular distribution of CTP: phosphocholine cytidylyltransferase activity was investigated. NaF (20 mM) inhibited the time-dependent activation of cytidylyltransferase activity in post-mitochondrial supernatant. Subcellular fractionation of the post-mitochondrial supernatant revealed that cytidylyltransferase activity in the microsomal fraction was decreased and activity in the cytosolic fraction increased with time of preincubation with NaF compared to controls. Okadaic acid is a specific and potent inhibitor of type 1 and 2A phosphoprotein phosphatases. Preincubation of cytosol with 5 microM okadaic acid inhibited the time-dependent activation of cytosolic cytidylyltransferase activity. Preincubation of post-mitochondrial supernatants with 5 microM okadaic acid inhibited the time-dependent activation of cytidylyltransferase activity by 13% at 45 min and 16% at 60 min of preincubation compared to controls. Microsomal cytidylyltransferase activity was decreased 27% at 45 min and 31% at 60 min with a corresponding retention of cytosolic cytidylyltransferase activity of 21% at 45 min and 37% at 60 min of preincubation with okadaic acid compared to controls. We postulate that the activity of the type 1 and/or type 2A phosphoprotein phosphatases affect the subcellular distribution of CTP: phosphocholine cytidylyltransferase activity in rat liver.

PMID: 2155030 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2359138&dopt=Abstract
J Natl Cancer Inst 1990 Jul 4;82(13):1118-26

Comment in:

J Natl Cancer Inst. 1990 Dec 19;82(24):1942-3.

Two-year carcinogenicity study of sodium fluoride in rats.

Maurer JK, Cheng MC, Boysen BG, Anderson RL.

Procter and Gamble Co., Miami Valley Laboratories, Cincinnati, OH 45239-8707.

To determine the carcinogenic potential of sodium fluoride (NaF), we fed Sprague-Dawley rats a diet containing NaF for up to 99 weeks. Rats receiving NaF at a dose of 4, 10, or 25 mg/kg per day added to a low-fluoride diet were compared with controls receiving either a low-fluoride diet or laboratory chow. Each treatment group consisted of 70 rats of each sex. A 30% decrement in weight gain occurred at an NaF dose of 25 mg/kg per day. Evidence of fluoride toxicity was seen in the teeth, bones, and stomach, and the incidence and severity of these changes were related to the dose of NaF and the duration of exposure. Despite clear evidence of toxicity, NaF did not alter the incidence of preneoplastic and neoplastic lesions at any site in rats of either sex. Results from this study indicate that NaF is not carcinogenic in Sprague-Dawley rats.

PMID: 2359138 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2401999&dopt=Abstract
J Reprod Fertil 1990 Jul;89(2):753-9

Investigations into the mechanism by which sodium fluoride stimulates prostaglandin production in guinea-pig uterus.

Leckie CM, Poyser NL.

Department of Pharmacology, University of Edinburgh Medical School, UK.

Sodium fluoride (10 mM) caused a slow increase in the outputs of PGF-2 alpha, 6-keto-PGF-1 alpha and, to a lesser extent, PGE-2 from the Day-7 and Day-15 guinea-pig uterus superfused in vitro. This stimulatory action of sodium fluoride was not prevented by using calcium-free Krebs' solution. There was also a faster stimulation of 6-keto-PGF-1 alpha output from the Day-7 guinea-pig uterus produced by sodium fluoride, and this quicker response was abolished by using calcium-free Krebs' solution. TMB-8 (an intracellular calcium antagonist) inhibited the stimulatory action of sodium fluoride on the outputs of PGF-2 alpha, PGE-2 and 6-keto-PGF-1 alpha from the Day-7 guinea-pig uterus. W-7 and trifluoperazine (calmodulin antagonists) and neomycin (an inhibitor of phospholipase C) had no inhibitory effect on the increases in outputs of PGF-2 alpha, PGE-2 and 6-keto-PGF-1 alpha from the Day-7 guinea-pig uterus produced by sodium fluoride. These results indicate that sodium fluoride slowly stimulates uterine PGF-2 alpha, PGE-2 and 6-keto-PGF-1 alpha synthesis in the guinea-pig uterus by mobilizing intracellular calcium by a mechanism which apparently does not involve the activation of phospholipase C or the participation of calmodulin (or a related compound). The initial, faster stimulation of 6-keto-PGF-1 alpha synthesis in the Day-7 guinea-pig uterus by sodium fluoride is dependent upon extracellular calcium.

PMID: 2401999 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2167077&dopt=Abstract
Biomed Biochim Acta 1990;49(2-3):S141-6

Phosphoinositide signalling system in human erythrocyte and its role in cell pathology.

Strunecka A, Kmonickova E, Krpejsova L, el Desouki NI, Hrusova H, Palecek J.

Department of Physiology and Developmental Biology, Faculty of Sciences, Charles University, Prague, Czechoslovakia.

Human erythrocytes contain 217.2 +/- 70.5 pmole of inositol 1,4,5-trisphosphate per ml of packed cells (n = 14). The increased generation of Ins 1,4,5P3, was induced by 1 microM A 23187, 20 microM Pb2+, and by AlF4-. Ins 1,4,5P3, Pb2+ and AlF4- evoke shape changes, disorganisation of spectrin network and vesiculation. In erythrocytes of patients with hereditary spherocytosis the level of Ins 1,4,5P3 was increased to 556.7 +/- 374 pmole per ml of packed cells. We suggest that activation of the phosphoinositide signalling system may represent a common denominator for many divergent stimuli and defects which affect shape changes of erythrocytes.

PMID: 2167077 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2114479&dopt=Abstract
J Pharmacol Exp Ther 1990 Jul;254(1):28-32

Fluoride produces endothelium-dependent relaxation and endothelium-independent contraction in coronary artery.

Cushing DJ, Sabouni MH, Brown GL, Mustafa SJ.

Department of Pharmacology, School of Medicine, East Carolina University, Greenville, North Carolina.

NaF produced endothelium-dependent relaxation and endothelium-independent contraction in porcine, bovine, canine and human coronary artery rings precontracted with either KCl or prostaglandin F2 alpha. For practical reasons the porcine coronary artery was selected to investigate the mechanisms responsible for these responses. Methylene blue, indomethacin, N-ethylmaleimide, pertussis toxin and cholera toxin all significantly attenuated the endothelium-dependent relaxation caused by fluoride. Pretreatment with deferoxamine had no effect on relaxation and superoxide dismutase/catalase potentiated the relaxation produced by fluoride. Fluoride also contracted vessels with or without the endothelium to equal tension levels and had no apparent relaxing effect on basal tone. The contraction produced by fluoride was significantly attenuated by pertussis toxin and cholera toxin; however, none of the other agents examined significantly altered contraction. Bradykinin also caused endothelium-dependent relaxation and this response was significantly attenuated by methylene blue but not indomethacin. Therefore, fluoride appears to relax the arteries by releasing an endothelium-derived relaxing factor similar to that released by bradykinin (methylene blue sensitive) and one or more prostanoid type endothelium-derived relaxing factor(s) (indomethacin sensitive). Furthermore, fluoride relaxation and contraction may be guanine nucleotide-binding regulatory protein-mediated based on sensitivity to the guanine nucleotide-binding regulatory protein modulators.

PMID: 2114479 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2164997&dopt=Abstract
No Abstract Available

Biochem Soc Trans 1990 Jun;18(3):480-1

Sodium fluoride acts as a stimulator and inhibitor of phosphoinositide hydrolysis in permeabilized rat hepatocytes.

Pittner RA, Fain JN.

Department of Biochemistry, University of Tennessee, Memphis 38163.

PMID: 2164997 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1696150&dopt=Abstract
Br J Pharmacol 1990 Jun;100(2):223-30

NaF and guanine nucleotides modulate adenylate cyclase activity in NG108-15 cells by interacting with both Gs and Gi.

Kelly E, Keen M, Nobbs P, MacDermot J.

Department of Pharmacology, Medical School, Univesity of Birmingham.

1. NaF (10 mM) produced a 2-3 fold increase in adenylate cyclase activity in homogenates of NG108-15 cells incubated in the presence of 1 microM GTP. Higher concentrations of NaF suppressed adenylate cyclase activity.
2. In the presence of the adenosine receptor agonist 5'-(N-ethyl)-carboxamidoadenosine (NECA; 100 microM) or the prostacyclin receptor agonist iloprost (10 nM), NaF produced a much smaller increase in adenylate cyclase activity, whereas in the presence of a saturating concentration of iloprost (1 microM), NaF only inhibited adenylate cyclase activity.
3. Similarly, Gpp(NH)p activated basal adenylate cyclase activity, and inhibited 1 microM iloprost-activated enzyme activity. In the presence of 10 microM forskolin, NaF or Gpp(NH)p increased adenylate cyclase activity synergistically. Analysis of concentration-effect curves indicated that NaF (2 mM) or Gpp(NH)p (100 microM) increased the potency with which forskolin activated adenylate cyclase, whilst reducing the maximum activation of adenylate cyclase by iloprost.
4. Opiate receptors mediate inhibition of adenylate cyclase, and the opiate agonist morphine (100 microM) reduced the capacity of NaF or Gpp(NH)p to inhibit iloprost-activated adenylate cyclase. Unexpectedly, pertussis toxin treatment enhanced the ability of NaF or Gpp(NH)p to inhibit iloprost-activated adenylate cyclase.
5. In the absence of GTP, NaF and Gpp(NH)p remained able both to activate basal adenylate cyclase and to be synergistic with forskolin in activating the enzyme. In contrast the ability of NaF and Gpp(NH)p to inhibit iloprost-activated adenylate cyclase was substantially lost in the absence of added GTP.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID: 1696150 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2374126&dopt=Abstract
J Reprod Fertil 1990 May;89(1):325-33

The effects of cholera toxin, pertussis toxin, sodium fluoride and alpha-interferon on prostaglandin production by the guinea-pig endometrium.

Leckie CM, Poyser NL.

Department of Pharmacology, University of Edinburgh Medical School, UK.

The outputs of prostaglandin (PG) F-2 alpha, 6-keto-PGF-1 alpha and PGE-2 from Day-7 and Day-15 guinea-pig endometrium were neither stimulated nor inhibited by cholera toxin and pertussis toxin. This indicates that PG synthesis by guinea-pig endometrium is not controlled by toxin-sensitive G-proteins. Short-term treatment of guinea-pig endometrium in culture with sodium fluoride stimulated PG output, suggesting that endometrial PG synthesis may be regulated by a fluoride-sensitive G-protein. Long-term treatment of guinea-pig endometrium in culture with sodium fluoride inhibited endometrial PG synthesis, and this was due to an inhibition of endometrial protein synthesis. Human alpha-interferon had no inhibitory effect on the outputs of PGF-2 alpha, 6-keto-PGF-1 alpha and PGE-2 from Day-15 guinea-pig endometrium in culture. It appears that the anti-luteolytic factor secreted by guinea-pig conceptus is not an alpha-interferon and is therefore probably different from ovine trophoblast protein-1.

PMID: 2374126 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2122640&dopt=Abstract
Adv Exp Med Biol 1990;275:115-24

G-proteins and phospholipase activation in endothelial cells.

Gerritsen ME, Mannix RJ.

Department of Physiology, New York Medical College, Valhalla.

ATP stimulates arachidonic acid release and prostaglandin biosynthesis (most likely via phospholipase A2 (PLA2) activation) and phospholipase C (PLC) activation in cultured rabbit coronary microvessel endothelial cells. Pertussis toxin pretreatment inhibits ATP stimulated prostaglandin release, but not ATP stimulated phosphatidylinositol turnover. In contrast, activation of G-proteins with GTP tau S or AlF4- stimulates both prostaglandin synthesis and PLC. These observations suggest that PLC activation by ATP involves a G-protein(s) that is not ADP-ribosylated by pertussis toxin and further, that ATP activation of prostaglandin biosynthesis appears to involve a different, pertussis toxin sensitive, G-protein.

PMID: 2122640 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2174691&dopt=Abstract
Cell Signal 1990;2(4):369-75

Effect of sodium fluoride on cytosolic free Ca2(+)-concentrations and cGMP-levels in endothelial cells.

Graier WF, Schmidt K, Kukovetz WR.

Institut fur Pharmakodynamik und Toxikologie, Universitatsplatz 2, Graz, Austria.

Sodium fluoride was used to investigate a possible involvement of G-proteins in the regulation of endothelial calcium channels. Incubation of cultured porcine aortic endothelial cells with sodium fluoride produced a dose-dependent increase in intracellular free calcium (EC50 approximately 5 mM). The effect strictly depended on the presence of extracellular CaCl2, indicating an enhanced influx of extracellular Ca2+ rather than a release of Ca2+ from intracellular stores. The Al3+ chelator deferoxamine abolished the stimulatory effect of sodium fluoride but did not interfere with the stimulatory effect of bradykinin. These data confirm the current hypothesis that the complex AlF-4 and not the fluoride anion activates G-proteins and exclude a direct inhibitory effect of deferoxamine on Ca2(+)-uptake. In contrast to isoproterenol and 5'-N-ethylcarboxamido-adenosine (NECA), which elevated endothelial cAMP-levels without affecting intracellular Ca2(+)-concentrations, sodium fluoride was not able to increase endothelial cAMP. This indicates that the effect of sodium fluoride on endothelial Ca2(+)-levels is not due to stimulation of a Gs-protein. Similar to its effect on cytoplasmic Ca2+, sodium fluoride also increased endothelial cGMP-levels which has recently been suggested to serve as biochemical marker for the formation of endothelium derived relaxing factor (EDRF). Thus, similar to the activation of receptor operated calcium channels, direct stimulation of a G-protein by sodium fluoride results in an increase of cytoplasmic Ca2+ and the formation of EDRF.

PMID: 2174691 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1688564&dopt=Abstract
J Clin Invest 1990 Jan;85(1):121-9

Role of lymphotoxin in expression of interleukin 6 in human fibroblasts. Stimulation and regulation.

Akashi M, Loussararian AH, Adelman DC, Saito M, Koeffler HP.

Division of Hematology/Oncology, University of California, Los Angeles 90024.

IL-6 is a cytokine with a number of biological functions, including stimulation of immunoglobulin synthesis and proliferation of early hematopoietic stem cells. We showed that lymphotoxin stimulated accumulation of IL-6 mRNA in human fibroblasts (W138) in a dose-responsive fashion; tumor necrosis factor-alpha (TNF-alpha) was about threefold more potent than lymphotoxin. Further experiments suggested that stimulation by lymphotoxin was independent of protein kinase C activity, did not require new protein synthesis, and was at least in part a result of increased stabilization of IL-6 mRNA. t1/2 of the IL-6 transcripts increased from 0.3 h in unstimulated cells to 0.85 h in cells stimulated with lymphotoxin. In addition, stimulators of protein kinase C, including phorbol esters and teleocidin, enhanced accumulation of IL-6 mRNA. Cycloheximide (CHX), inhibitor of protein synthesis, also markedly increased levels of IL-6 mRNA. Both CHX and activators of protein kinase C increased by greater than 16-fold the stability of IL-6 mRNA. Further, dose-response studies showed that sodium fluoride (NaF), activator of G-binding proteins, and ouabain, inhibitor of Na+/H+ pump, increased levels of IL-6 mRNA. NaF stimulated IL-6 mRNA levels independent of protein kinase C activity. These results suggest that stimulators of several pathways of signal transduction increase levels of IL-6 mRNA and posttranscriptional stabilization is, in part, the mechanism that many of these signals, including lymphotoxin, use to increase levels of IL-6 RNA.

PMID: 1688564 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2081095&dopt=Abstract
Cell Signal 1990;2(6):531-6

Possible involvement of protein kinase C and cyclic AMP-dependent protein kinase in the sodium fluoride-mediated inhibition of cyclic nucleotide accumulation in smooth muscle cells.

Nambi P, Aiyar N, Wu HL, Crooke ST.

Department of Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939.

Treatment of rat thoracic aortic smooth muscle cells (A-10) with sodium fluoride (NaF) resulted in inhibition of beta-adrenergic agonist--and forskolin-induced cAMP and ANF-induced cGMP accumulation and stimulation of diacylglycerol (DAG) accumulation. The concentration of NaF and treatment times required to mediate these inhibitory effects were similar to those observed for stimulation of DAG accumulation. Treatment of the cells with NaF also resulted in a loss of [3H]phorbol dibutyrate (PDBu) binding in the cytosolic portion of the cells. In addition, pre-treatment of the cells with NaF resulted in an increase in the adenylate cyclase activity. Pertussis toxin (PT) pre-treatment of the cells did not significantly affect NaF-mediated effects. Pre-treatment of the cells with protein kinase C (PKC) inhibitor staurosporin partially reversed NaF-mediated inhibition of cyclic nucleotides accumulation. These data suggest that inhibition of the formation of agonist-induced cyclic nucleotides by NaF may be due to the formation of DAG and cAMP which lead to the activation of PKC and cAMP-PK, resulting in phosphorylation of key regulatory protein(s) in the cyclic nucleotides pathway.

PMID: 2081095 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2096385&dopt=Abstract
Pharmacol Toxicol 1990 Nov;67(5):411-4

Effect of sodium fluoride on growth of human diploid cells in culture.

Oguro A, Cervenka J, Horii K.

Department of Preventive Dentistry, Niigata University School of Dentistry, Japan.

Cytotoxicity of sodium fluoride (NaF) on human diploid cells in exponential growth was investigated using
a) Flow 1000 cells, passage No. 13, obtained from skin and muscle tissues of male black foetus,
b) IMR-90 cells, passage No. 22, derived from lung tissue of female Caucasian foetus and
c) primary fibroblast-like cell cultures from 5 Japanese whole foetuses.
Diploid cells did not survive at 20 p.p.m. of ionic fluoride (F-) concentration. However, the cells were capable of proliferation with no significant impairment of growth up to 0.2 p.p.m. F-, a level which is much higher than the plasma concentration in human subjects from areas with highly fluoridated water. The growth of the cells was markedly affected by F- concentrations greater than 2 p.p.m.

PMID: 2096385 [PubMed - indexed for MEDLINE]

NOTE: Martin Rodbell (co-author of this report) 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."
Proc Natl Acad Sci U S A 1990 Feb;87(3):1208-12

Full report available free at http://www.pnas.org/cgi/reprint/87/3/1208.pdf

Isoproterenol stimulates shift of G proteins from plasma membrane to pinocytotic vesicles in rat adipocytes: a possible means of signal dissemination.

Haraguchi K, Rodbell M.

Laboratory of Cellular and Molecular Pharmacology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.

Guanine nucleotide-binding regulatory proteins (G proteins) are linked to a large number of surface membrane receptors and appear to regulate a variety of effector systems located both in the plasma membrane and in other parts of the cell. The mechanism of the disseminative actions of G proteins remains obscure. During an investigation of the fate of two types of G proteins, Gs and Gi, in rat adipocytes, we unexpectedly found that isoproterenol, which stimulates cAMP levels and lipolysis in these cells, induces parallel increases in both Gs and Gi in a low-density microsomal fraction rich in endosomes and Golgi bodies. Two plasma membrane constitutive enzymes, adenylyl cyclase and 5'-nucleotidase, are also elevated in this fraction. NaF and NaN3, metabolic inhibitors, block the redistribution process. The isoproterenol-stimulated shifts are completely reversible after removal of the hormone, indicating a recycling, endocytic process. The endocytic process seems to be fluid phase endocytosis, or pinocytosis, since isoproterenol stimulates the uptake of both fluorescent-labeled dextran and horseradish peroxidase into the same vesicles containing Gs. However, the vesicles that accumulate in response to isoproterenol seem heterogenous in properties that may reflect the lipolytic process induced by isoproterenol. It is speculated that the "pinosomes" formed in response to lipolytic hormones may continually produce signals within the cellular interior during their processing and cycling. Hence, signal production in response to hormones need not be confined to the cell membrane; circulating pinosomes may be responsible for some of the disseminative effects of hormones.

PMID: 2105498 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2384166&dopt=Abstract
FEBS Lett 1990 Jul 30;268(1):277-80

A novel magnesium-dependent mechanism for the activation of transducin by fluoride.

Antonny B, Bigay J, Chabre M.

CNRS, Institut de Pharmacologie Moleculaire et Cellulaire, Valbonne, France.

Activation of transducin-GDP by NaF is mainly mediated by aluminofluorde or beryllofluoride complexes acting as GTP gamma-phosphate analogs. In millimolar magnesium, NaF at concentrations above 3 mM is active even in the absence of aluminium or beryllium. This activation has a Hill coefficient of 3 with respect to F-, and its rate is linear with respect to Mg2+ concentrations above 2 mM. Upon fluoride dilution, inactivation rate is hundreds of times faster than for aluminofluoride-activated T alpha GDP. We propose that at high NaF concentrations, 3 hydrogen-bonded fluorides in the gamma-phosphate site of T alpha GDP entrap a magnesium counterion and this induces the transconformation to the T alpha GTP form.

PMID: 2384166 [PubMed - indexed for MEDLINE]

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