An altered antioxidant balance occurs in Down syndrome fetal organs: Implications for the “gene dosage effect” hypothesis

  • J. B. de Haan
  • B. Susil
  • M. Pritchard
  • I. Kola
Part of the Journal of Neural Transmission Supplement 67 book series (NEURAL SUPPL, volume 67)


Down syndrome (DS) is the congenital birth defect responsible for the greatest number of individuals with mental retardation. It arises due to trisomy of human chromosome 21 (HSA21) or part thereof. To date there have been limited studies of HSA21 gene expression in trisomy 21 conceptuses. In this study we investigate the expression of the HSA21 antioxidant gene, Cu/Zn-superoxide dismutase-1 (SOD1) in various organs of control and DS aborted conceptuses. We show that SOD1 mRNA levels are elevated in DS brain, lung, heart and thymus. DS livers show decreased SOD1 mRNA expression compared with controls. Since non-HSA21 antioxidant genes are reported to be concomitantly upregulated in certain DS tissues, we examined the expression of glutathione peroxidase-1 (GPX1) in control and DS fetal organs. Interestingly, GPX1 expression was unchanged in the majority of DS organs and decreased in DS livers. We examined the SOD1 to GPX1 mRNA ratio in individual organs, as both enzymes form part of the body’s defense against oxidative stress, and because a disproportionate increase of SOD1 to GPX1 results in noxious hydroxyl radical damage. All organs investigated show an approximately 2-fold increase in the SOD1 to GPX1 mRNA ratio. We propose that it is the altered antioxidant ratio that contributes to certain aspects of the DS phenotype.


Down Syndrome Gene Dosage Effect Slot Blot SOD1 mRNA Down Syndrome Group 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



human Cu/Zn-superoxide dismutase


human selenium-dependent glutathione peroxidase


Down syndrome


human chromosome 21


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  1. Anneren KG, Epstein CJ (1987) Lipid peroxidation and superoxide dismutase-1 and glutathione peroxidase activities in trisomy 16 fetal mice and human trisomy 21 fibroblasts. Pediatr Res 21: 88–92PubMedCrossRefGoogle Scholar
  2. Avraham KB, Sugarman H, Rotshenker S, Groner Y (1991) Down’s syndrome: morphological remodelling and increased complexity in the neuromuscular junction of transgenic CuZn-superoxide dismutase mice. J Neurocytol 20: 208–215PubMedCrossRefGoogle Scholar
  3. Bar-Peled O, Korkotian E, Segal M, Groner Y (1996) Constitutive overexpression of Cu/Zn superoxide dismutase exacerbates kainic acid-induced apoptosis of transgenicCu/Zn superoxide dismutase neurons. Proc Natl Acad Sci 93: 8530–8535PubMedCrossRefGoogle Scholar
  4. Brooksbank BWL, Balazs R (1984) Superoxide dismutase, glutathione peroxidase and lipoperoxidation in Down’s Syndrome fetal brain. Dev Brain Res 16: 37–44CrossRefGoogle Scholar
  5. Ceballos I, Nicole A, Briand P, Grimber G, Delacourte A, Flament S, Blouin JL, Thevenin M, Kamoun P, Sinet M (1991) Expression of human Cu-Zn superoxide dismutase gene in transgenic mice: model for gene dosage effect in Down syndrome. Free Rad Res Commun 12–13: 581–589CrossRefGoogle Scholar
  6. Ceballos-Picot I, Nicole A, Clement M, Bourre JM, Sinet PM (1992) Age-related changes in antioxidant enzymes and lipid peroxidation in brains of control and transgenic mice overexpressing copper-zinc superoxide dismutase. Mutat Res 275: 281293Google Scholar
  7. Chada S, Le Beau MM, Casey L, Newburger PE (1990) Isolation and chromosomal localization of the human glutathione peroxidase gene. Genomics 6: 268–271PubMedCrossRefGoogle Scholar
  8. Chaushu S, Yefenof E, Becker A, Shapira J, Chaushu G (2002) Severe impairment of secretory Ig production in parotid saliva of Down syndrome individuals. J Dent Res 81: 308–312PubMedCrossRefGoogle Scholar
  9. Cheon MS, Kim SH, Yaspo ML, Blasi F, Aoki Y, Melen K, Lubec G (2003a) Protein levels of genes encoded on chromosome 21 in fetal Down syndrome brain. Challenging the gene dosage effect hypothesis, part I. Amino Acids 24: 111–117Google Scholar
  10. Cheon MS, Bajo M, Kim SH, Claudio JO, Stewart AK, Patterson D, Kruger WD, Kondoh H, Lubec G (2003b) Protein levels of genes encoded on chromosome 21 in fetal Down syndrome brain. Challenging the gene dosage effect hypothesis, part II Amino Acids 24: 119–125Google Scholar
  11. Cheon MS, Kim SH, Ovod V, Kopitas Jerala N, Morgan JI, Hatefi Y, Ijuin T, Takenawa Y, Lubec G (2003c) Protein levels of genes encoded on chromosome 21 in fetal Down syndrome brain. Challenging the gene dosage effect hypothesis, part III Amino Acids 24: 127–134Google Scholar
  12. Davies KJA (1987) Protein damage and degradation by oxygen radicals. J Biol Chem 262: 9895–9901PubMedGoogle Scholar
  13. de Haan JB, Newman JD, Kola I (1992) Cu/Zn superoxide dismutase mRNA and enzyme activity, and susceptibility to lipid peroxidation, increases with aging in murine brains. Mol Brain Res 13: 179–186PubMedCrossRefGoogle Scholar
  14. de Haan JB, Tymms MJ, Cristiano F, Kola I (1994) Expression of copper/zinc superoxide dismutase and glutathione peroxidase in organs of developing mouse embryos, fetuses and neonates. Pediatr Res 35: 188–196PubMedCrossRefGoogle Scholar
  15. de Haan JB, Cristino C, Iannello R, Bladier C, Kelner MJ, Kola I (1996) Elevation in the ratio of Cu/Zn-superoxide dismutase to glutathione peroxidase activity induces features of cellular senescence and this effect is mediated by hydrogen peroxide. Hum Mol Genet 5: 283–292PubMedCrossRefGoogle Scholar
  16. Delabar JM, Nicole A, D’Auriol L, Jacob Y, Meunier-Rotival M, Galibert F, Sinet PM, Jerome H (1987) Cloning and sequencing of a rat CuZn superoxide dismutase cDNA: correlation between CuZn superoxide dismutase mRNA levels and enzyme activity in rat and mouse tissues. Eur J Biochem 166: 181–187PubMedCrossRefGoogle Scholar
  17. De La Torre R, Casado A, Lopez-Fernandez E, Carrascosa D, Ramirez V, Saez J (1996) Overexpression of copper-zinc superoxide dismutase in trisomy 21. Experientia 52: 871–873CrossRefGoogle Scholar
  18. Diomede L, Salmona M, Albani D, Bianchi M, Bruno A, Salmona S, Nicolini U (1999) Alteration of SREBP activation in liver of trisomy 21 fetuses. Biochem Biophys Res Commun 260: 499–503PubMedCrossRefGoogle Scholar
  19. Epstein CJ, Avraham KB, Lovett M, Smith S, Elroy-Stein O, Rotman G, Bry C, Groner Y (1987) Transgenic mice with increased Cu/Zn-superoxide dismutase activity: animal model of dosage effects in Down syndrome. Proc Natl Acad Sci USA 84: 8044–8048PubMedCrossRefGoogle Scholar
  20. Feaster WW, Kwok LW, Epstein C (1977) Dosage effects for superoxide dismutase-1 in nucleated cells aneuploid for chromosome 21. Am J Hum Genet 29: 563–570PubMedGoogle Scholar
  21. Fong C, Brodeur GM (1987) Down’s syndrome and leukemia: epidemiology, genetics,cytogenetics and mechanisms of leukemogenesis. Cancer Genet Cytogenet 28: 55–76PubMedCrossRefGoogle Scholar
  22. Fridovich I (1978) The biology of oxygen radicals. Science 201: 875–880PubMedCrossRefGoogle Scholar
  23. Frischer H, Chu LK, Ahmad T, Justice P, Smith GF (1981) Superoxide dismutase and glutathione peroxidase abnormalities in erthyrocytes and lymphoid cells in Down syndrome. In: Brewer GJ (ed) The Red Cell: Fifth Ann Arbor Conference. AL Liss, New York, pp 269–283Google Scholar
  24. Fuentes JJ, Genesca L, Kingsbury TJ, Cunningham KW, Perez-Riba M, Estivill X, de la Luna S (2000) DCSR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways. Hum Mol Genet 9: 1681–1690Google Scholar
  25. Gilles L, Ferradini C, Foos J, Pucheault J, Allard D, Sinet PM, Jerome H (1976) The estimation of red cell superoxide dismutase activity by pulse radiolysis in normal and trisomic cells. Hum Genet 31: 197–202CrossRefGoogle Scholar
  26. Greber-Platzer S, Scatzmann-Turhani D, Wollenek G, Lubec G (1999a) Evidence against the current hypothesis of “gene dosage effects” of trisomy 21: ets-2, encoded on chromosome 21 is not overexpressed in hearts of patients with Down syndrome. Biochem Biophys Res Commun 254: 395–399PubMedCrossRefGoogle Scholar
  27. Greber-Platzer S, Schatzmann-Turhani D, Cairns N, Balcz B, Lubec G (1999b) Expression of the transcription factor ETS2 in brains of patients with Down Syndrome-evidence against the overexpression-gene dosage hypothesis. J Neural Transm 57: 270–281Google Scholar
  28. Gulesserian T, Engidawork E, Fountoulakis M, Lubec G (2001a) Antioxidant proteins in fetal brain: superoxide dismutase-1 (SOD1) protein is not overexpressed in fetal Down syndrome. J Neural Transm 61: 71–84Google Scholar
  29. Gulesserian T, Seidl R, Hardmeier R, Cairns N, Lubec G (2001b) Superoxide dismutase SOD1, encoded by chromosome 21, but not SOD2 is overexpressed in brains of patients with Down syndrome. J Invest Med 49: 41–46CrossRefGoogle Scholar
  30. Hall B (1965) Delayed ontogenesis in human trisomy syndromes. Hereditas (Lund) 52: 334–344CrossRefGoogle Scholar
  31. Holtzman DM, Bayney RM, Li Y, Khosrovi H, Berger CN, Epstein CJ, Mobley WC (1992) Dysregulation of gene expression in mouse trisomy 16, an animal model of Down syndrome. EMBO J 11: 619–627PubMedGoogle Scholar
  32. Imlay JA, Chin SM, Linn S (1988) Toxic DNA damage by hydrogen peroxide through the Fenton reaction in vivo and in vitro. Science 240: 640–642PubMedCrossRefGoogle Scholar
  33. Keiner MJ, Bagnell R (1990) Alteration of growth rate and fibronectin by imbalances in superoxide dismutase and glutathione peroxidase activity. Biol Reactive Intermediates IV: 305–309Google Scholar
  34. Keiner MJ, Bagnell R, Montoya M, Estes L, Uglik SF, Cerutti P (1995) Transfection with human copper-zinc superoxide dismutase induces bidirectional alterations in other antioxidant enzymes, proteins, growth factor response, and paraquat resistance. Free Rad Biol Med 18: 497–506CrossRefGoogle Scholar
  35. Kola I, Cristiano F, de Haan JB, Sumarsono S, Thomas R, Corrick C, Tymms M (1993) Genes, embryogenesis and Down syndrome. In: Moeloek F, Affandi B, Trounson AO (eds) Advances in human reproduction, vol 38. Parthenon Publishing Group, pp 309–320Google Scholar
  36. Lemieux N, Malfoy B, Forrest GL (1993) Human carbonyl reductase (CBR) localized to band 21q22.1 by high-resolution fluorescence in situ hybridization displays gene dosage effects in trisomy 21 cells. Genomics 15: 169–172PubMedCrossRefGoogle Scholar
  37. Mann DMA, Esiri MM (1989) The pattern of acquisition of plaques and tangles in the brains of patients under 50 years of age with Down’s Syndrome. J Neurol Sci 89: 169179Google Scholar
  38. Meyer M, Schreck R, Baeuerle PA (1993) H2O2 and antioxidants have opposite effects on activation of NF-,B and AP-1 in intact cells: AP-1 as secondary antioxidant-responsive factor. EMBO J 12: 2005–2015PubMedGoogle Scholar
  39. Minc-Golomb D, Knobler H, Groner Y (1991) Gene dosage of CuZnSOD and Down’s syndrome• diminished prostaglandin synthesis in human trisomy 21, transfected cells and transgenic mice. EMBO J 10: 2119–2124PubMedGoogle Scholar
  40. Mirochnitchenko O, Inouye M (1996) Effect of overexpression of human Cu,Zn superoxide dismutase in transgenic mice on macrophage functions. J Immunol 156: 1578–1586Google Scholar
  41. Nabarra B, Casanova M, Paris D, Nicole A, Toyama K, Sinet PM, Ceballos I, London J (1996) Transgenic mice overexpressing the human Cu/Zn-SOD gene: ultrastructural studies of a premature thymic involution model of Down’s syndrome (Trisomy 21). Lab Invest 74: 67–626Google Scholar
  42. Neve J, Sinet PM, Molle L, Nicole A (1983) Selenium, zinc and copper levels in Down’s syndrome (trisomy 21): blood levels and relations with glutathione peroxidase and superoxide dismutase. Clin Chim Acta 133: 209–214PubMedCrossRefGoogle Scholar
  43. Neve RL, Finch EA, Dawes LR (1988) Expression of the Alzheimer amyloid precursor gene transcript in the human brain. Neuron 1: 669–677PubMedCrossRefGoogle Scholar
  44. Odetti P, Angelini G, Dapino D, Zaccheo D, Garibaldi S, Dagna-Bricarelli F, Piombo G, Perry G, Smith M, Traverso N, Tabaton M (1998) Early glycoxidation damage in brains from Down’s syndrome. Biochem Biophys Res Commun 243: 849–851PubMedCrossRefGoogle Scholar
  45. Pallister C, Jung SS, Shaw I, Nalbantoglu J, Gauthier S, Cashman NR (1997) Lymphocyte content of amyloid precursor protein is increased in Down’s syndrome and aging. Neurobiol Aging 18: 97–103PubMedCrossRefGoogle Scholar
  46. Pastor M-C, Sierra C, Dolade M, Navarro E, Brandi N, Cabre E, Mira A, Seres A (1998) Antioxidant enzymes and fatty acid status in erythrocytes of Down’s syndrome patients. Clin Chem 44: 924–929PubMedGoogle Scholar
  47. Patterson DH (1987) The causes of Down Syndrome. Sci Am 257: 42–49CrossRefGoogle Scholar
  48. Pritchard MA, Kola I (1999) The “gene dosage effect” hypothesis versus the “amplified developmental instability” hypothesis in Down syndrome. J Neural Transm 57: 293303Google Scholar
  49. Rehder H (1981) Pathology of trisomy 21, with particular reference to persistent common atrioventricular canal of the heart. In: Burgio GR, Fraccaro M, Tiepolo L, Wolf U (eds) Trisomy 21. An International Symposium. Springer, Berlin Heidelberg New York Tokyo, pp 57–73Google Scholar
  50. Rudolf AM (1984) Oxygenation in the fetus and neonate — a perspective. Semin Perinatol 8: 158–167Google Scholar
  51. Schwab M, Niemeyer C, Schwarzer U (1998) Down syndrome, transient myeloprolifera-tive disorder, and infantile liver fibrosis. Med Pediatr Oncol 31: 159–165PubMedCrossRefGoogle Scholar
  52. Shapiro BL (1994) The environmental basis of the Down syndrome phenotype. Dev Med Child Neurol 36: 84–90PubMedCrossRefGoogle Scholar
  53. Sherman L, Levanon D, Lieman-Hurwitz J, Dafni N, Groner Y (1984) Human Cu/Zn superoxide dismutase gene: molecular characterization of its two mRNA species. Nucl Acids Res 12: 9349–9365PubMedCrossRefGoogle Scholar
  54. Siegel S (1956) In: Non-parametric statistics for the behavioural sciences. International Student edition. McGraw-Hill Kogakusha LTD, Tokyo, JapanGoogle Scholar
  55. Sies H, de Groot H (1992) Role of reactive oxygen species in cell toxicology. Toxicol Lett 64–65: 547–551CrossRefGoogle Scholar
  56. Sinet PM, Michelson AM, Bazin A, Lejeune J, Jerome H (1975a) Superoxide dismutases activities of blood platelets in trisomy 21. Biochem Biophys Res Commun 67: 904–909PubMedCrossRefGoogle Scholar
  57. Sinet PM, Michelson AM, Bazin A, Lejeune J, Jerome H (1975b) Increase in glutathione peroxidase activity in erythrocytes from trisomy 21 subjects. Biochem Biophys Res Commun 67: 910–915PubMedCrossRefGoogle Scholar
  58. Stefani I, Galt J, Palmer A, Affara N, Ferguson-Smith M, Nevin NC (1988) Expression of chromosome 21 specific sequences in normal and Down’s syndrome tissues. Nucl Acids Res 16: 2885–2896PubMedCrossRefGoogle Scholar
  59. Sumarsono SH, Wilson TJ, Tymms MJ, Venter DJ, Corrick CM, Kola R, Lahoud MH, Papas TS, Seth A, Kola I (1996) Down’s syndrome-like skeletal abnormalities in Ets2 transgenic mice. Nature 379: 534–537PubMedCrossRefGoogle Scholar
  60. Tam CF, Walford RL (1980) Alteration in cyclic nucleotides and cyclase-specific activities in T lymphocytes of aging normal humans and patients with Down’s syndrome. J Immunol 125: 1665–1670PubMedGoogle Scholar
  61. Tan YH, Tischfield J, Ruddle FH (1973) The linkage of genes for the human interferon induced antiviral protein and indophenol oxidase-B traits to chromosome G-21. J Exp Med 137: 317–330PubMedCrossRefGoogle Scholar
  62. Wadhera S, Millar WT (1994) Second trimester abortions: trends and medical complications. Health Reports 6: 441–454PubMedGoogle Scholar
  63. White BA, Bancoft FC (1982) Cytoplasmic dot hybridization. Simple analysis of relative mRNA levels in multiple small cell or tissue samples. J Biol Chem 257: 8569–8572Google Scholar
  64. Wisniewski KE, Wisniewski HM, Wen GY (1985) Occurrence of neuropathological changes and dementia of Alzheimer’s disease in Down’s Syndrome. Ann Neurol 17: 278–282PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • J. B. de Haan
    • 1
    • 2
  • B. Susil
    • 3
  • M. Pritchard
    • 1
  • I. Kola
    • 4
  1. 1.Monash Institute of Reproduction and Development, Centre for Functional Genomics and Human DiseaseMonash UniversityClayton VictoriaAustralia
  2. 2.Baker Heart Research InstituteDiabetic Complications GroupPrahranAustralia
  3. 3.Department of PathologyMonash Medical CentreClayton VictoriaAustralia
  4. 4.Merck Research LaboratoriesMerck & Co., IncRahwayUSA

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