Fluoride‐induced genotoxicity in mouse bone marrow cells: effect of buthionine sulfoximine and N‐acetyl‐ l‐cysteine

A significant level of reactive oxygen species generation was observed in sodium fluoride (NaF) treated mouse bone marrow cells (BMCs). Reduced glutathione (GSH) as a free radical scavenger could be an important determining factor in F‐induced genotoxicity. We therefore attempted to monitor GSH to understand the mechanism of NaF‐induced genotoxicity. NaF was injected intra‐peritoneally in normal, buthionine sulfoximine (BSO) or N‐acetyl‐ l‐cysteine (NAC) treated mice (n = 5). After 13 h of NaF‐treatment BMCs were collected to harvest them at the same divisional cycle and processed for analysis of cell cycle, induction of apoptosis and chromosomal aberrations (CAs). Level of GSH was also measured concomitantly. NaF induced significant CAs in all treatment groups except at 2.5 mg NaF kg−1 body weight. BSO‐treatment alone induced significantly high frequency of CAs. BSO treatment prior to injection of 2.5–7.5 mg NaF kg−1 b.w. was found to increase the frequency of CAs, significantly when compared with the positive control group, but the level was not significant in case of higher doses of NaF treatment (15 and 30 mg kg−1 b.w.). NaF‐treated cells also showed a higher population of Annexin‐V positive cells. NAC pre‐treatment significantly reduced the extent of NaF‐induced CAs, which clearly indicates the involvement of GSH in the NaF response. However, further study is warranted to evaluate the low synergistic effect of BSO on higher doses of NaF‐induced CAs. Copyright © 2010 John Wiley & Sons, Ltd.

[1]  S. Chouhan,et al.  Fluoride‐induced changes in haem biosynthesis pathway, neurological variables and tissue histopathology of rats , 2010, Journal of applied toxicology : JAT.

[2]  S. Chouhan,et al.  Effects of fluoride on the tissue oxidative stress and apoptosis in rats: biochemical assays supported by IR spectroscopy data. , 2008, Toxicology.

[3]  S. Flora,et al.  Effects of individual and combined exposure to sodium arsenite and sodium fluoride on tissue oxidative stress, arsenic and fluoride levels in male mice. , 2006, Chemico-biological interactions.

[4]  Wei Wei,et al.  A dual effect of N-acetylcysteine on acute ethanol-induced liver damage in mice. , 2006, Hepatology research : the official journal of the Japan Society of Hepatology.

[5]  Ling He,et al.  DNA damage, apoptosis and cell cycle changes induced by fluoride in rat oral mucosal cells and hepatocytes. , 2006, World journal of gastroenterology.

[6]  A. Hirner,et al.  Uptake of inorganic and organic derivatives of arsenic associated with induced cytotoxic and genotoxic effects in Chinese hamster ovary (CHO) cells. , 2004, Toxicology and applied pharmacology.

[7]  D. Shanthakumari,et al.  Effect of fluoride intoxication on lipidperoxidation and antioxidant status in experimental rats. , 2004, Toxicology.

[8]  Guoyao Wu,et al.  Glutathione metabolism and its implications for health. , 2004, The Journal of nutrition.

[9]  H. Hwang,et al.  Cytotoxicity and apoptosis induction of sodium fluoride in human promyelocytic leukemia (HL-60) cells. , 2002, Environmental toxicology and pharmacology.

[10]  S. De Flora,et al.  Mechanisms of N-acetylcysteine in the prevention of DNA damage and cancer, with special reference to smoking-related end-points. , 2001, Carcinogenesis.

[11]  S. Deb,et al.  Genotoxic effect of arecoline given either by the peritoneal or oral route in murine bone marrow cells and the influence of N-acetylcysteine. , 1999, Cancer letters.

[12]  G. Arendash,et al.  Evidence That Oxidative Stress Is Associated with the Pathophysiology of Inherited Hydrocephalus in the H-Tx Rat Model , 1999, Experimental Neurology.

[13]  J. Jeng,et al.  Cytotoxicity of sodium fluoride on human oral mucosal fibroblasts and its mechanisms , 1998, Cell Biology and Toxicology.

[14]  G. Dallner,et al.  Influence of chronic fluorosis on membrane lipids in rat brain. , 1998, Neurotoxicology and teratology.

[15]  C. Klaassen,et al.  Does hepatic ATP depletion impair glycine conjugation in vivo? , 1996, Drug metabolism and disposition: the biological fate of chemicals.

[16]  X. Shi,et al.  Generation of free radicals from model lipid hydroperoxides and H2O2 by Co(II) in the presence of cysteinyl and histidyl chelators. , 1993, Chemical research in toxicology.

[17]  B. Vojnovic,et al.  The effects of counter-ion condensation and co-ion depletion upon the rates of chemical repair of poly(U) radicals by thiols. , 1991, International journal of radiation biology.

[18]  M. Aardema,et al.  Sodium fluoride-induced chromosome aberrations in different stages of the cell cycle: a proposed mechanism. , 1989, Mutation research.

[19]  K. S. Pillai,et al.  Effect of subacute dosage of fluoride on male mice. , 1988, Toxicology letters.

[20]  T Sofuni,et al.  Micronucleus tests in mice on 39 food additives and eight miscellaneous chemicals. , 1988, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[21]  D. Siemann,et al.  Depletion of tumour versus normal tissue glutathione by buthionine sulfoximine. , 1987, British Journal of Cancer.

[22]  M. Edgren,et al.  Compartmentalised depletion of glutathione in cells treated with buthionine sulphoximine. , 1987, The British journal of radiology.

[23]  A. Chatterjee,et al.  Modifying effect of reduced glutathione on X-ray-induced chromosome aberration and cell-cycle delay in muntjac lymphocytes in vitro , 1986 .

[24]  J. Biaglow,et al.  Glutathione depletion, radiosensitization, and misonidazole potentiation in hypoxic Chinese hamster ovary cells by buthionine sulfoximine. , 1984, Radiation research.

[25]  N. Suzuki,et al.  Cytotoxicity, chromosome aberrations and unscheduled DNA synthesis in cultured human diploid fibroblasts induced by sodium fluoride. , 1984, Mutation research.

[26]  P. Deschavanne,et al.  Survival curves of irradiated glutathione-deficient human fibroblasts: indication of a reduced enhancement of radiosensitivity by oxygen and misonidazole. , 1982, International journal of radiation oncology, biology, physics.

[27]  K. Brown,et al.  Lack of cytogenetic effects in mice or mutations in Salmonella receiving sodium fluoride. , 1979, Mutation research.

[28]  G. Obe,et al.  Suppressive activity by fluoride on the induction of chromosome aberrations in human cells with alkylating agents in vitro. , 1973, Mutation research.

[29]  S. Bhattacharya,et al.  DIFFERENTIAL IN VIVO GENOTOXIC EFFECTS OF LOWER AND HIGHER CONCENTRATIONS OF FLUORIDE IN MOUSE BONE MARROW CELLS , 2006 .

[30]  A. Chattopadhyay,et al.  IN VIVO SUPPRESSION BY FLUORIDE OF CHROMOSOME ABERRATIONS INDUCED BY MITOMYCIN-C IN MOUSE BONE MARROW CELLS , 2006 .

[31]  Shantao Liu,et al.  DNA DAMAGE INDUCED BY FLUORIDE IN RAT OSTEOBLASTS , 2006 .

[32]  Shaolin Wang,et al.  EFFECTS OF HIGH FLUORIDE AND LOW IODINE ON OXIDATIVE STRESS AND ANTIOXIDANT DEFENSE OF THE BRAIN IN OFFSPRING RATS , 2004 .

[33]  A. Chatterjee,et al.  Modulation of the clastogenic activity of gamma-irradiation in buthionine sulphoximine-mediated glutathione depleted mammalian cells. , 1999, International journal of radiation biology.

[34]  G. Kelly,et al.  Clinical applications of N-acetylcysteine. , 1998, Alternative medicine review : a journal of clinical therapeutic.

[35]  M. Shelby,et al.  Genetic toxicity of fluoride , 1993, Environmental and molecular mutagenesis.

[36]  M. Stratford,et al.  The role of non-protein sulphydryls in determining the chemical repair rates of free radical precursors of DNA damage and cell killing in Chinese hamster V79 cells. , 1992, International journal of radiation biology.

[37]  P. R. Rao,et al.  Red cell membrane alterations in human chronic fluoride toxicity. , 1991, Biochemistry international.

[38]  O. Aruoma,et al.  The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. , 1989, Free radical biology & medicine.

[39]  H. Birnboim,et al.  Simultaneous protective and damaging effects of cysteamine on intracellular DNA of leukocytes. , 1988, Free radical biology & medicine.

[40]  S. Bhunya,et al.  Genotoxic Effect of an Environmental Pollutant, Sodium Fluoride, in Mammalian in Vivo Test System , 1987 .

[41]  Deborah J. Jones,et al.  The uracil–fluoride interaction: ab initio calculations including solvation , 1982 .

[42]  H. Sies,et al.  Assay of glutathione, glutathione disulfide, and glutathione mixed disulfides in biological samples. , 1981, Methods in enzymology.

[43]  Deborah J. Jones,et al.  An unexpectedly strong hydrogen bond: ab initio calculations and spectroscopic studies of amide-fluoride systems , 1981 .

[44]  A. Meister,et al.  Translocation of intracellular glutathione to membrane-bound γ-glutamyl transpeptidase as a discrete step in the γ-glutamyl cycle: Glutathionuria after inhibition of transpeptidase , 1979 .