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Nutritional treatment of genome instability: a paradigm shift in disease prevention and in the setting of recommended dietary allowances

Published online by Cambridge University Press:  01 November 2007

Michael Fenech*
Affiliation:
Cooperative Research Centre for Diagnostics, Genome Stability Project, CSIRO Health Sciences and Nutrition, PO Box 10041, Adelaide BC, SA 5000, Australia
*
Corresponding author: Dr Michael Fenech, fax +61 8 8303 8880, email Michael.Fenech@csiro.au
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Abstract

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The link between genome instability and adverse health outcomes during the various stages of life, such as infertility, fetal development and cancer, is briefly reviewed against a background of evidence indicating that genome instability, in the absence of overt exposure to genotoxins, is itself a sensitive marker of nutritional deficiency. The latter is illustrated with cross-sectional and dietary intervention data obtained using the micronucleus assay, an efficient biomarker for diagnosing genome instability and nutritional deficiency. The concept of recommended dietary allowances for genome stability and how this could be achieved is discussed together with the emerging field of nutritional genomics for genome stability. The review concludes with a vision for a disease-prevention strategy based on the diagnosis and nutritional treatment of genome instability, i.e. ‘Genome Health Clinics’.

Type
Research Article
Copyright
Copyright © CABI Publishing 2003

References

Abramsson-Zetterberg, L, Zetterberg, G, Bergqvist, M & Grawe, J (2000) Human cytogenetic biomonitoring using flow-cytometric analysis of micronuclei in transferrin-positive immature peripheral blood reticulocytes. Environmental and Molecular Mutagenesis 36, 2231.3.0.CO;2-U>CrossRefGoogle ScholarPubMed
Ambrosone, CB, Freudenheim, JL, Thompson, PA, Bowman, E, Vena, JE, Marshall, JR, Graham, S, Laughlin, R, Nemoto, T & Shields, PG (1999) Managanese superoxide dismutase (MnSOD) genetic polymorphisms, dietary antioxidants and risk of breast cancer. Cancer Research 59, 602606.Google Scholar
Ames, BN (1998) Micronutrients prevent cancer and delay ageing. Toxicology Letters 102–103, 518.CrossRefGoogle Scholar
Ames, BN (1999) Cancer prevention and diet: help from single nucleotide polymorphisms. Proceedings of the National Academy of Sciences USA 96, 1221612218.CrossRefGoogle ScholarPubMed
Ames, BN (2001) DNA damage from micronutrient deficiencies is likely to be a major cause of cancer. Mutation Research 475, 720.CrossRefGoogle Scholar
Ames, BN, Elson-Schwab, I & Silver, EA (2002) High dose vitamin therapy stimulates variant enzymes with deceased co-enzyme binding affinity (increased K(m)): relevance to genetic disease and polymorphisms. American Journal of Clinical Nutrition 75, 616658.CrossRefGoogle Scholar
Ames, BN & Wakimoto, P (2002) Are vitamin and mineral deficiencies a major cancer risk?. Nature Reviews. Cancer 2, 694704.CrossRefGoogle ScholarPubMed
Baria, K, Warren, C, Eden, OB, Roberts, SA, West, CM & Scott, D (2002) Chromosomal radiosensitivity in young cancer patients: possible evidence of genetic predisposition. International Journal of Radiation Biology 78, 341346.CrossRefGoogle ScholarPubMed
Biedler, JL & Spengler, BA (1976) Metaphase chromosome anomaly: association with drug resistance and cell-specific products. Science 191, 185187.CrossRefGoogle ScholarPubMed
Blount, BC & Ames, BN (1995) DNA damage in folate deficiency. Baillere's Clinical Haematology 8, 461478.CrossRefGoogle ScholarPubMed
Blount, BC, Mack, MM, Wehr, CM, MacGregor, JT, Hiatt, RA, Wang, G, Wickramasinghe, SN, Everson, RB & Ames, BN (1997) Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proceedings of the National Academy of Sciences USA 94, 32903295.CrossRefGoogle ScholarPubMed
Bonassi, S, Fenech, M, Lando, C, Lin, YP, Ceppi, M, Chang, WP, Holland, N, Kirsch-Volders, M, Zeiger, E, Ban, SY, Barale, R & Bigatti, MP (2001) HUman MicroNucleus Project: International data base comparison for results with the cytokinesis-block micronucleus assay in human lymphocytes: I effect of laboratory protocol, scoring criteria and host factors on the frequency of micronuclei. Environmental and Molecular Mutagenesis 37, 3145.3.0.CO;2-P>CrossRefGoogle Scholar
Bonassi, S, Hagmar, L, Stromberg, U, Montagud, AH, Tinnerberg, H, Forni, A, Heikkila, P, Wanders, S, Wilhardt, P, Hansteen, IL, Knudsen, LE & Norrpa, H (2000) Chromosomal aberrations in lymphocytes predict human cancer independently of exposure to carcinogens. Cancer Research 60, 16191625.Google ScholarPubMed
Boveri, M (1929) In The Origin of Malignant Tumours. pp Baltimore, MD: Waverley Press.Google Scholar
Brison, O (1993) Gene amplification and tumor progression. Biochimica et Biophysica Acta 1155, 2541.Google ScholarPubMed
Brody, LC, Conley, M, Cox, C, Kirke, PN, McKeever, MP, Mills, JL, Molloy, AM, O'Leary, VB, Parle-McDermott, A, Scott, JM & Swanson, DA (2002) A Polymorphism, R653Q, in the trifunctional enzyme methylenetetrahydrofolate dehydrogenase/ methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase is a maternal genetic risk factor for neural tube defects: Report of the Birth Defects Research Group. American Journal of Human Genetics 71, 12071215.CrossRefGoogle ScholarPubMed
Centers for Disease Control (1992) Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. Morbidity and Mortality Weekly Report 41, 17.Google Scholar
Chen, J, Giovannucci, EL & Hunter, DJ (1999) MTHFR polymorphisms, methyl-replete diets and risk of colorectal carcinoma and adenoma among U.S. men and women: an example of gene-environment interactions in colorectal tumorigenesis. Journal of Nutrition 129, 560S564S.CrossRefGoogle ScholarPubMed
Claycombe, KJ & Meydani, SN (2001) Vitamin E and genomic stability. Mutation Research 475, 3744.CrossRefGoogle Scholar
Coquelle, A, Pipiras, E, Toledo, F, Buttin, G & Debattisse, M (1997) Expression of fragile sites triggers intrachromosomal mammalian gene amplification and sets boundaries to early amplicons. In Cell 89 215225.CrossRefGoogle ScholarPubMed
Cravo, M, Fidalgo, P, Pereira, AD, Gouveia-Oliviera, A, Chaves, P, Selhub, J, Mason, JB, Mira, FC, Leitao, CN (1994) DNA methylation as an intermediate biomarker in colorectal cancer: modulation by folic acid supplementation. European Journal of Cancer Prevention 3, 473479.CrossRefGoogle ScholarPubMed
Crott, JW & Fenech, M (1999) Effect of vitamin C supplementation on chromosome damage, apoptosis and necrosis ex vivo. Carcinogenesi 20, 10351041.CrossRefGoogle ScholarPubMed
Crott, JW, Mashiyama, ST, Ames, BN & Fenech, M (2001) Methylenetetrahydrofolate reductase C677T polymorphism does not alter folic acid deficiency-induced uracil incorporation into primary human lymphocyte DNA in vitro. Carcinogenesis 22, 10191025.CrossRefGoogle Scholar
Crott, JW, Mashiyama, ST, Ames, BN & Fenech, M (2001) Folic acid deficiency increases chromosome breakage and rearrangement, gene amplification and DNA-uracil content in human lymphocytes in vitro: effect of MTHFR C677T polymorphism. Cancer Epidemiology, Biomarkers and Prevention 10, 10891096.Google Scholar
Cruz Suarez, R, Gustafsson, M & Mrabit, K (2001) IAEA Occupational Radiation Protection Programme. Radiat Prot Dosimetry 96, 1720.CrossRefGoogle ScholarPubMed
Dreosti, IE (2001) Zinc and the gene. Mutation Research 475, 161168.CrossRefGoogle ScholarPubMed
Duesberg, P, Stindl, R & Helmann, R (2000) Explaining high mutation rates of cancer cells to drug and multidrug resistance by chromosome reassortments that are catalysed by aneuploidy. Proceedings of the National Academy of Sciences USA 97, 1429514300.CrossRefGoogle Scholar
Duthie, SJ & Hawdon, A (1998) DNA instability (strand breakage, uracil misincorporation, and defective repair) is increased by folic acid depletion in human lymphocytes in vitro. FASEB Journal 12, 14911497.CrossRefGoogle ScholarPubMed
Everson, RB, Wehr, CM, Erexson, GL & MacGregor, JT (1988) Association of marginal folate depletion with increased human chromosomal damage in vivo: demonstration by analysis of micronucleated erythrocytes. Journal of the National Cancer Institute 80, 525529.CrossRefGoogle ScholarPubMed
Fenech, M (2000) The in vitro micronucleus technique. Mutation Research 455, 8195.CrossRefGoogle ScholarPubMed
Fenech, M (2001) The role of folic acid and vitamin B12 in genomic stability of human cells. Mutation Research 475, 5768.CrossRefGoogle ScholarPubMed
Fenech, M (2002) Chromosomal biomarkers of genomic instability relevant to cancer. Drug Discovery Today 7, 11281137.CrossRefGoogle ScholarPubMed
Fenech, M, Aitken, C & Rinaldi, J (1998) Folate, vitamin B12, homocysteine status and DNA damage in young Australian adults. Carcinogenesis 19, 11631171.CrossRefGoogle ScholarPubMed
Fenech, M, Dreosti, I & Aitken, C (1997) Vitamin-E supplements and their effect on Vitamin-E status in blood and genetic damage rate in peripheral blood lymphocytes. Carcinogenesis 18, 359364.CrossRefGoogle ScholarPubMed
Fenech, M, Dreosti, IE & Rinaldi, JR (1997) Folate, vitamin B12, homocysteine status and chromosome damage rate in lymphocytes of older men. Carcinogenesis 18, 13291336.CrossRefGoogle ScholarPubMed
Fenech, M, Ferguson, LR (editors) (2001) Micronutrients and genomic stability. Mutation Research 475, 16.CrossRefGoogle ScholarPubMed
Fenech, M, Holland, N, Chang, WP, Zeiger, E & Bonassi, S (1999) The HUman MicroNucleus project – an international collaborative study on the use of the micronucleus technique for measuring DNA damage in humans. Mutation Research 428, 271283.CrossRefGoogle Scholar
Fenech, M & Morley, AA (1986) Cytokinesis-block micronucleus method in human lymphocytes: effects of in vivo ageing and low dose X-irradiation. Mutation Research 161, 193198.CrossRefGoogle ScholarPubMed
Fenech, M & Rinaldi, J (1995) A comparison of lymphocyte micronuclei and plasma micronutrients in vegetarians and non-vegetarians. Carcinogenesis 16, 223230.CrossRefGoogle ScholarPubMed
Fraga, CG, Motchnik, PA, Shigenaga, MK, Helbock, HJ, Jacob, RA & Ames, BN (1991) Ascorbic acid protects against endogenous oxidative DNA damage in human sperm. Proceedings of the National Academy of Sciences USA 88, 1100311006.CrossRefGoogle ScholarPubMed
Gaziev, AI, Sologub, GR, Fomenko, LA, Zaichkina, SI, Kosyakova, NI & Bradbury, RJ (1996) Effect of vitamin-antioxidant micronutrients on the frequency of spontaneous and in vitro gamma-ray-induced micronuclei in lymphocytes of donors: the age factor. Carcinogenesis 17, 493499.CrossRefGoogle ScholarPubMed
Giovannucci, E (2002) Epidemiological studies of folate and colorectal neoplasia: a review. Journal of Nutrition 132, 2350s2355s.CrossRefGoogle ScholarPubMed
Gisselson, D, Bjork, J, Hoglund, M, Mertens, F, Dal Cin, P, Akerman, M & Mandahl, N (2001) Abnormal nuclear shape in solid tumours reflects mitotic instability. American Journal of Pathology 158, 199206.CrossRefGoogle Scholar
Green, NS (2002) Folic acid supplementation and prevention of birth defects. Journal of Nutrition 132, Suppl., 2356S2360S.CrossRefGoogle ScholarPubMed
Griffin, CS (2002) Aneuploidy, centrosome activity and chromosome instability in cells deficient in homologous recombination repair. Mutation Research 504, 149155.CrossRefGoogle ScholarPubMed
Griffin, CS, Simpson, PJ, Wilson, CR & Thacker, J (2000) Mammalian recombination-repair genes XRCC2 and XRCC3 promote correct chromosome segregation. Nature Cell Biology 2, 757761.CrossRefGoogle ScholarPubMed
Hageman, GJ & Stierum, RH (2001) Niacin, poly(ADP-ribose) polymerase-1 and genoic stability. Mutation Research 475, 4556.CrossRefGoogle ScholarPubMed
Halliwell, B (2001) Vitamin C and genomic stability. Mutation Research 475, 2935.CrossRefGoogle ScholarPubMed
Hartwig, A (2001) Role of magnesium in genomic stability. Mutation Research 475, 113121.CrossRefGoogle ScholarPubMed
Ho, E & Ames, BN (2002) Low intracellular zinc induces oxidative DNA damage, disrupts p53, NfkappaB and AP1 binding and affects DNA repair in a rat glioma cell line. Proceedings of the National Academy of Sciences USA 99, 1677016775.CrossRefGoogle Scholar
Holliday, R (1995) In Understanding Ageing. Cambridge, UK: Cambridge University Press.CrossRefGoogle Scholar
Honma, M, Tadokoro, S, Sakamoto, H, Tanabe, H, Sugimoto, M, Furuichi, Y, Satoh, T, Sofuni, T, Goto, M & Hayashi, M (2002) Chromosomal instability in B-lymphoblasotoid cell lines from Werner and Bloom syndrome patients. Mutation Research 520, 1524.CrossRefGoogle ScholarPubMed
Hsia, KT, Millar, MR, King, S, Selfridge, J, Redhead, NJ, Melton, DW & Saunders, PT (2003) DNA repair gene Ercc1 is essential for normal spermatogenesis and oogenesis and for functional integrity of germ cell DNA in the mouse. Development 130, 369378.CrossRefGoogle ScholarPubMed
Jacky, PB, Beek, B & Sutherland, GR (1983) Fragile sites in chromosomes: possible model for the study of spontaneous chromosome breakage. Science 220, 6970.CrossRefGoogle Scholar
Jacob, RA, Gretz, DM, Taylor, PC, James, SJ, Pogribny, IP, Miller, BJ, Henning, SM & Swendseid, ME (1998) Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women. Journal of Nutrition 128, 12041212.CrossRefGoogle ScholarPubMed
Joenje, H & Patel, JK (2001) The emerging genetic and molecular basis of Fanconi anaemia. Nature Reviews. Genetics 2, 446457.CrossRefGoogle ScholarPubMed
Kassie, F, Darroudi, F, Kundi, M, Schulte-Hermann, R, Knasmuller, S (2001) Khat (Catha edulis) consumption causes genotoxic effects in humans. International Journal of Cancer 92, 329332.CrossRefGoogle ScholarPubMed
Keen, CL, Zidenberg-Cherr, S (1996) Manganese. In. Present Knowledge in Nutrition. 7th ed., pp. 334343 [Zeigler, EE and Filer, LJ editors]. Washington, DC: ILSI Press.Google Scholar
Konings, EJ, Roomans, HH, Dorant, E, Goldbohm, RA, Saris, WH & van den Brandt, PA (2001) Folate intake of the Dutch population according to newly established liquid chromatography data for foods. American Journal of Clinical Nutrition 73, 765776.CrossRefGoogle ScholarPubMed
Kuramoto, K, Ban, S, Oda, K, Kimura, A & Suzuki, G (2002) Chromosomal instability and radiosensitivity in myelodysplastic syndrome. Leukemia 16, 22532258.CrossRefGoogle ScholarPubMed
Lansdorp, PM (2000) Repair of telomeric DNA prior to replicative senescence. Mechanisms of Ageing and Development 118, 2334.CrossRefGoogle ScholarPubMed
Lessin, LS & Bessis, M (1972) Morphology of the erythron. In. Hematology. pp. 6293 [Williams, WJ, Beutler, E, Erslev, EJ and Rundles, RW editors]. New York, NY: Mcgraw-Hill.Google Scholar
Li, RH, Sonik, A, Stindl, R, Rasnick, D & Duesberg, P (2000) Aneuploidy vs gene mutation hypothesis of cancer: recent study claims mutation but is found to support aneuploidy. Proceedings of the National Academy of Sciences USA 97, 32363241.CrossRefGoogle ScholarPubMed
Lindahl, T & Wood, RD (1999) Quality control by DNA repair. Science 286, 18971905.CrossRefGoogle ScholarPubMed
Liu, L, Blasco, M, Trimarchi, J & Keefe, D (2002) An essential role for functional telomeres in mouse germ cells during fertilization and early development. Developmental Biology 249, 7484.CrossRefGoogle ScholarPubMed
Ma, C, Martin, S, Trask, B & Hamlin, JL (1993) Sister chromatid fusion initiates amplification of the dihydrofolate reductase gene in Chinese hamster cells. Genes and Development 7, 605620.CrossRefGoogle ScholarPubMed
McClintock, B (1942) The fusion of broken ends of chromosomes following nuclear fusion. Proceedings of the National Academy of Sciences USA 28, 458463.CrossRefGoogle ScholarPubMed
MacGregor, JT (1990) Dietary factors affecting spontaneous chromosomal damage in man. Progress in Clinical and Biological Research 347, 139153.Google ScholarPubMed
MacGregor, JT, Schlegel, R, Wehr, CM, Alperin, P & Ames, BN (1990) Cytogenetic damage induced by folate deficiency in mice is enhanced by caffeine. Proceedings of the National Academy of Sciences USA 87, 99629965.CrossRefGoogle ScholarPubMed
Majer, BJ, Laky, B, Knasmuller, S & Kassie, F (2001) Use of the micronucleus assay with exfoliated cells as a biomarker for monitoring individuals at elevated risk of genetic damage in chemoprevention trials. Mutation Research 489, 147172.CrossRefGoogle ScholarPubMed
Melnyk, S, Pogribna, M, Miller, BJ, Basnakian, AG, Pogribny, IP & James, SJ (1999) Uracil misincorporation, DNA strand breaks, and gene amplification are associated with tumorigenic cell transformation in folic acid deficient/repleted Chinese hamster ovary cells. Cancer Letters 146, 3544.CrossRefGoogle ScholarPubMed
Migliore, L, Botto, N, Scarpato, R, Petrozzi, L, Cipriani, G & Bonucelli, U (1999) Preferential occurrence of chromosome 21 segregation in peripheral blood lymphocytes of Alzheimer disease patients. Cytogenetics and Cell Genetics 87, 4146.CrossRefGoogle ScholarPubMed
Migliore, L, Scarpato, R, Coppede, F, Petrozzi, L, Bonucelli, U & Rodilla, V (2001) Chromosome and oxidative damage biomarkers in lymphocytes of Parkinson's disease patients. International Journal of Hygiene and Environmental Health 204, 6166.CrossRefGoogle ScholarPubMed
Moore, LE, Warner, ML, Smith, AH, Kalman, D & Smith, MT (1996) Use of the fluorescent micronucleus assay to detect the genotoxic effects of radiation and arsenic exposure in exfoliated human epithelial cells. Environmental and Molecular Mutagenesis 27, 176–84.3.0.CO;2-D>CrossRefGoogle ScholarPubMed
Narula, A, Kilen, S, Ma, E, Kroeger, J, Goldberg, E & Woodruff, TK (2002) Smad4 overexpression causes germ cell ablation and leydig cell hyperplasia in transgenic mice. American Journal of Pathology 161, 17231734.CrossRefGoogle ScholarPubMed
Nathanson, KL, Wooster, R, Weber, BL & Nathanson, KN (2001) Breast cancer genetics: what we know and what we need. Nature Medicine 7, 552556.CrossRefGoogle ScholarPubMed
Ng, JM, Vrieling, H, Sugasawa, K, Ooms, MP, Grootegoed, JA, Vreeburg, JT, Visser, P, Beems, RB, Gorgels, TG, Hanaoka, F, Hoeijmakers, JH & van der Horst, GT (2002) Developmental defects and male sterility in mice lacking the ubiquitin-like DNA repair gene mHR23B. Molecular and Cellular Biology 22, 12331245.CrossRefGoogle ScholarPubMed
O'Brien, PJ, Hales, BF, Josephy, PD, Castonguay, A, Yamazoe, Y & Guengerich, FP (1996) Chemical carcinogenesis, mutagenesis, and teratogenesis. Canadian Journal of Physiology and Pharmacology 74, 565571.CrossRefGoogle ScholarPubMed
Odagiri, Y & Uchida, H (1998) Influence of serum micronutrients on the incidence of kinetochore-positive or -negative micronuclei in human peripheral blood lymphocytes. Mutation Research 415, 3545.CrossRefGoogle ScholarPubMed
Perry, ME, Rolfe, M, McIntyre, P, Commane, M & Stark, GR (1992) Induction of gene amplification by 5-aza-2′-deoxycytidine. Mutation Research 276, 189197.CrossRefGoogle Scholar
Pihan, GA, Purohit, A, Wallace, J, Knecht, H, Woda, B, Queensberry, P & Doxsey, SJ (1998) Centrosome defects and genetic instability in malignant tumours. Cancer Research 58, 39743985.Google Scholar
Pihan, GA, Purohit, A, Wallace, J, Malhotra, R, Liotta, L & Doxsey, SJ (2001) Centrosome defects can account for cellular and genetic changes that characterize prostate cancer progression. Cancer Research 61, 22122219.Google ScholarPubMed
Piyathilake, CJ, Macaluso, M, Hine, RJ, Vinter, DW, Richards, EW & Krumdieck, CL (1995) Cigarette smoking, intracellular vitamin deficiency and occurrence of micronuclei in epithelial cells of the buccal mucosa. Cancer Epidemiology, Biomarkers and Prevention 4, 751758.Google ScholarPubMed
Rosin, MP & German, J (1985) Evidence for chromosome instability in vivo in Bloom syndrome: increased numbers of micronuclei in exfoliated cells. Human Genetics 71, 187191.CrossRefGoogle ScholarPubMed
Rothfus, A, Schutz, P, Bochum, S, Volm, T, Eberhardt, E, Kreienberg, R, Vogel, W & Speit, G (2000) Induced micronucleus frequencies in peripheral blood lymphocytes as a screening test for carriers of a BRCA1 mutation in breast cancer families. Cancer Research 60, 390394.Google Scholar
Saunders, WS, Shuster, M, Huang, X, Gharaibeh, B, Enyenihi, AK, Petersen, I & Gollin, SM (2000) Chromosomal instability and cytoskeletal defects in oral cancer. Proceedings of the National Academy of Sciences USA 97, 303308.CrossRefGoogle ScholarPubMed
Scott, D, Barber, JBP, Levine, EL, Burrill, W & Roberts, SA (1998) Radiation-induced micronucleus induction in lymphocytes identifies a high frequency of radiosensitivity cases among breast cancer patients: a test for predisposition?. British Journal of Cancer 77, 614620.CrossRefGoogle ScholarPubMed
Shen, J & Loeb, LA (2001) Unwinding the molecular basis of Werner syndrome. Mechanisms of Ageing and Development 122, 921944.CrossRefGoogle ScholarPubMed
Shimizu, N, Itoh, N, Utiyama, H & Wahl, GM (1998) Selective entrapment of extrachromosomally amplified DNA by nuclear budding and micronucleation during S phase. Journal of Cell Biology 140, 13071320.CrossRefGoogle ScholarPubMed
Shimizu, N, Shimuara, T & Tanaka, T (2000) Selective elimination of acentric double minutes from cancer cells through the extrusion of micronuclei. Mutation Research 448, 8190.CrossRefGoogle ScholarPubMed
Shimura, M, Onozuka, Y, Yamaguchi, T, Hatake, K, Takaku, F & Ishizaka, Y (1999) Micronuclei formation with chromosome breaks and gene amplification caused by Vpr, an accessory gene of human immunodeficiency virus. Cancer Research 59, 22592264.Google ScholarPubMed
Skibola, CF, Smith, MT, Hubbard, A, Shane, B, Roberts, AC, Law, GR, Rollinson, S, Roman, E, Cartwright, RA & Morgan, GJ (2002) Polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and risk of adult acute lymphocytic leukemia. Blood 99, 37863791.CrossRefGoogle ScholarPubMed
Skibola, CF, Smith, MY, Kane, E, Roman, E, Rollinson, S, Cartwright, RA & Morgan, G (1999) Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukaemia in adults. Proceedings of the National Academy of Sciences USA 96, 1281012815.CrossRefGoogle ScholarPubMed
Smith, DF, MacGregor, JT, Hiatt, RA, Hooper, NK, Wehr, CM, Peters, B, Goldman, LR, Yuan, LA, Smith, PA & Becker, CE (1990) Micronucleated erythrocytes as an index of cytogenetic damage in humans: demographic and dietary factors associated with micronucleated erythrocytes in splenectomised subjects. Cancer Research 50, 50495054.Google Scholar
Stark, GR (1993) Regulation and mechanisms of mammalian gene amplification. Advances in Cancer Research 61, 87113.CrossRefGoogle ScholarPubMed
Stich, HF, Rosin, MP & Vallejera, MO (1984) Reduction with vitamin A and beta-carotene administration of proportion of micronucleated buccal mucosal cells in Asian betel nut and tobacco chewers. Lancet 1, 12041206.CrossRefGoogle ScholarPubMed
Thomas, P, Umegaki, K & Fenech, M (2003) Nucleoplasmic bridges are a sensitive measure of chromosome rearrangement in the cytokinesis-block micronucleus assay. Mutagenesis 18, 187194.CrossRefGoogle ScholarPubMed
Thompson, JR, Gerald, PF, Willoughby, ML & Armstrong, BK (2001) Maternal folate supplementation in pregnancy and protection against acute lymphoblastic leukaemia in childhood: a case-control study. Lancet 358, 19351940.CrossRefGoogle ScholarPubMed
Thompson, LH & Schild, D (2002) Recombinational DNA repair and human disease. Mutation Research 509, 4978.CrossRefGoogle ScholarPubMed
Titenko-Holland, N, Jacob, RA, Shang, N, Balaraman, A & Smith, MT (1998) Micronuclei in lymphocytes and exfoliated buccal cells of postmenopausal women with dietary changes in folate. Mutation Research 417, 101114.CrossRefGoogle ScholarPubMed
Toledo, F, Le Roscouet, D, Buttin, G & Debatisse, M (1992) Co-amplified markers alternate in megabase long inverted repeats and cluster independently in interphase nuclei at early steps of mammalian gene amplification. EMBO Journal 11, 26652673.CrossRefGoogle ScholarPubMed
Trkova, M, Kapras, J, Bobkova, K, Stankova, J & Mejsnarova, B (2000) Increased micronuclei frequencies in couples with reproductive failure. Reproductive Toxicology 14, 331335.CrossRefGoogle ScholarPubMed
Venkitaraman, AR (2002) Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 108, 171182.CrossRefGoogle ScholarPubMed
Vinson, RK & Hales, BF (2002) DNA repair during organogenesis. Mutation Research 509, 7991.CrossRefGoogle ScholarPubMed
Walter, PB, Knutson, MD, Paler-Martinez, A, Lee, S, Xu, Y, Viteri, FE & Ames, BN (2002) Iron deficiency and iron excess damage mitochondria and mitochondrial DNA in rats. Proceedings of the National Academy of Sciences USA 99, 22642269.CrossRefGoogle ScholarPubMed
Wertz, PW & Squier, CA (1991) Cellular and molecular basis of barrier function in oral epithelium. Critical Reviews in Therapeutic Drug Carrier Systems 8, 237269.Google ScholarPubMed
Windle, BE & Wahl, GM (1992) Molecular dissection of mammalian gene amplification: new mechanistic insights revealed by analyses of very early events. Mutation Research 276, 199224.CrossRefGoogle ScholarPubMed
Yu, RC, Lee, TC, Wang, TC & Li, JH (1999) Genetic toxicity of cocaine. Carcinogenesis 20, 11931199.CrossRefGoogle ScholarPubMed
Zhang, S, Hunter, DJ, Hankinson, SE, Giovannucci, EL, Rosner, BA, Colditz, GA, Speizer, FE & Willett, WCA (1999) Prospective study of folate intake and the risk of breast cancer. Journal of the American Medical Association 281, 16321637.CrossRefGoogle ScholarPubMed