Journal of Autism and Developmental Disorders

, Volume 38, Issue 10, pp 1966–1975 | Cite as

Abnormal Transmethylation/transsulfuration Metabolism and DNA Hypomethylation Among Parents of Children with Autism

  • S. Jill James
  • Stepan Melnyk
  • Stefanie Jernigan
  • Amanda Hubanks
  • Shannon Rose
  • David W. Gaylor
Original Paper


An integrated metabolic profile reflects the combined influence of genetic, epigenetic, and environmental factors that affect the candidate pathway of interest. Recent evidence suggests that some autistic children may have reduced detoxification capacity and may be under chronic oxidative stress. Based on reports of abnormal methionine and glutathione metabolism in autistic children, it was of interest to examine the same metabolic profile in the parents. The results indicated that parents share similar metabolic deficits in methylation capacity and glutathione-dependent antioxidant/detoxification capacity observed in many autistic children. Studies are underway to determine whether the abnormal profile in parents reflects linked genetic polymorphisms in these pathways or whether it simply reflects the chronic stress of coping with an autistic child.


Autism Homocysteine Glutathione DNA methylation Parents 



The authors would like to express their gratitude to the participating families affected by autism in Arkansas without whom this study would not have been possible. This research was supported, in part, with funding from the National Institute of Child Health and Development (RO1 HD051873) to SJJ, and by grants from the University of Arkansas for Medical Sciences Children’s University Medical Group and the Arkansas Biosciences Institute (SJJ).


  1. Abdolmaleky, H. M., Cheng, K. H., Faraone, S. V., Wilcox, M., Glatt, S. J., Gao, F., et al. (2006). Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder. Human Molecular Genetics, 15, 3132–3145. doi: 10.1093/hmg/ddl253.PubMedCrossRefGoogle Scholar
  2. Abdolmaleky, H. M., Cheng, K. H., Russo, A., Smith, C. L., Faraone, S. V., Wilcox, M., et al. (2005). Hypermethylation of the reelin (RELN) promoter in the brain of schizophrenic patients: A preliminary report. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, 134, 60–66. doi: 10.1002/ajmg.b.30140.CrossRefGoogle Scholar
  3. Abdolmaleky, H. M., Smith, C. L., Faraone, S. V., Shafa, R., Stone, W., Glatt, S. J., et al. (2004). Methylomics in psychiatry: Modulation of gene-environment interactions may be through DNA methylation. American Journal of Medical Genetics, 127B, 51–59. doi: 10.1002/ajmg.b.20142.PubMedCrossRefGoogle Scholar
  4. Alonso-Aperte, E., Ubeda, N., Achon, M., Perez-Miguelsanz, J., & Varela-Moreiras, G. (1999). Impaired methionine synthesis and hypomethylation in rats exposed to valproate during gestation. Neurology, 52, 750–756.PubMedGoogle Scholar
  5. Badcock, C., & Crespi, B. (2006). Imbalanced genomic imprinting in brain development: An evolutionary basis for the aetiology of autism. Journal of Evolutionary Biology, 19, 1007–1032. doi: 10.1111/j.1420-9101.2006.01091.x.PubMedCrossRefGoogle Scholar
  6. Bains, J. S., & Shaw, C. A. (1997). Neurodegenerative disorders in humans: The role of glutathione in oxidative stress-mediated neuronal death. Brain Research. Brain Research Reviews, 25, 335–358. doi: 10.1016/S0165-0173(97)00045-3.PubMedCrossRefGoogle Scholar
  7. Beaudet, A. L. (2002). Is medical genetics neglecting epigenetics? Genetics in Medicine, 4, 399–402. doi: 10.1097/00125817-200209000-00013.PubMedCrossRefGoogle Scholar
  8. Bleich, S., Frieling, H., & Hillemacher, T. (2007). Elevated prenatal homocysteine levels and the risk of schizophrenia. Archives of General Psychiatry, 64, 980–981. doi: 10.1001/archpsyc.64.8.980.PubMedCrossRefGoogle Scholar
  9. Brattström, L., Landgren, F., Israelsson, B., Lindgren, A., Hultberg, B., Andersson, A., et al. (1998). Lowering blood homocysteine with folic acid based supplements: Meta-analysis of randomised trials. BMJ (Clinical Research Ed), 316, 894–898.Google Scholar
  10. Castro, R., Rivera, I., Struys, E. A., Jansen, E. E. W., Ravasco, P., Camilo, M. E., et al. (2003). Increased, homocysteine and S-adenosylhomocysteine concentrations and DNA hypomethylation in vascular disease. Clinical Chemistry, 49, 1292–1296. doi: 10.1373/49.8.1292.PubMedCrossRefGoogle Scholar
  11. Caudill, M. A., Wang, J. C., Melnyk, S., Pogribny, I. P., Jernigan, S., Collins, M. D., et al. (2001). Intracellular S-adenosylhomocysteine concentrations predict global DNA hypomethylation in tissues of methyl deficient cystathionine β-synthase heterozygous mice. The Journal of Nutrition, 131, 2811–2818.PubMedGoogle Scholar
  12. Chakraborti, A., Gulati, K., Banerjee, B. D., & Ray, A. (2007). Possible involvement of free radicals in the differential neurobehavioral responses to stress in male and female rats. Behavioural Brain Research, 179, 321–325. doi: 10.1016/j.bbr.2007.02.018.PubMedCrossRefGoogle Scholar
  13. Chauhan, A., Chauhan, V., Brown, W. T., & Cohen, I. (2004). Oxidative stress in autism: Increased lipid peroxidation and reduced serum levels of ceruloplasmin and transferrin–the antioxidant proteins. Life Sciences, 75, 2539–2549. doi: 10.1016/j.lfs.2004.04.038.PubMedCrossRefGoogle Scholar
  14. Corrales, F., Ochoa, P., Rivas, C., Martin-Lomas, M., Mato, J. M., & Pajares, M. A. (1991). Inhibition of glutathione synthesis in the liver leads to S-adenosyl-L-methionine synthetase reduction. Hepatology (Baltimore, Md.), 14, 528–533.Google Scholar
  15. Cuco, G., Fernandez-Ballart, J., Sala, J., Viladrich, C., Iranzo, R., Vila, J., et al. (2006). Dietary patterns and associated lifestyles in preconception, pregnancy and postpartum. European Journal of Clinical Nutrition, 60, 364–371. doi: 10.1038/sj.ejcn.1602324.PubMedCrossRefGoogle Scholar
  16. De Bree, A., Verschuren, W. M., Kromhout, D., Kluijtmans, L. A., & Blom, H. J. (2002). Homocysteine determinants and the evidence to what extent homocysteine determines the risk of coronary heart disease. Pharmacological Reviews, 54, 599–618. doi: 10.1124/pr.54.4.599.PubMedCrossRefGoogle Scholar
  17. Dreosti, I. E. (1998). Nutrition, cancer, and aging. Annals of the New York Academy of Sciences, 854, 371–377. doi: 10.1111/j.1749-6632.1998.tb09917.x.PubMedCrossRefGoogle Scholar
  18. Eskiocak, S., Gozen, A. S., Yapar, S. B., Tavas, F., Kilic, A. S., & Eskiocak, M. (2005). Glutathione and free sulphydryl content of seminal plasma in healthy medical students during and after exam stress. Human Reproduction (Oxford, England), 20, 2595–2600. doi: 10.1093/humrep/dei062.CrossRefGoogle Scholar
  19. Feil, R. (2006a). Environmental and nutritional effects on the epigenetic regulation of genes. Mutation Research, 600, 46–57. doi: 10.1016/j.mrfmmm.2006.05.029.PubMedGoogle Scholar
  20. Fidelus, R. K., & Tsan, M. F. (1987). Glutathione and lymphocyte activation: A function of ageing and auto-immune disease. Immunology, 61, 503–508.PubMedGoogle Scholar
  21. Filomeni, G., Rotilio, G., & Ciriolo, M. R. (2002). Cell signalling and the glutathione redox system. Biochemical Pharmacology, 64, 1057–1064. doi: 10.1016/S0006-2952(02)01176-0.PubMedCrossRefGoogle Scholar
  22. Frey, B. N., Andreazza, A. C., Kunz, M., Gomes, F. A., Quevedo, J., Salvador, M., et al. (2007). Increased oxidative stress and DNA damage in bipolar disorder: A twin-case report. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 31, 283–285. doi: 10.1016/j.pnpbp.2006.06.011.PubMedCrossRefGoogle Scholar
  23. Friso, S., & Choi, S. W. (2002). Gene-nutrient interactions and DNA methylation. The Journal of Nutrition, 132, 2382S–2387S.PubMedGoogle Scholar
  24. Friso, S., Choi, S. W., Dolnikowski, G. G., & Selhub, J. (2002a). A method to assess genomic DNA methylation using high-performance liquid chromatography/electrospray ionization mass spectrometry. Analytical Chemistry, 74, 4526–4531. doi: 10.1021/ac020050h.PubMedCrossRefGoogle Scholar
  25. Friso, S., Choi, S. W., Girelli, D., Mason, J. B., Dolnikowski, G. G., Bagley, P. J., et al. (2002b). A common mutation in the 5, 10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status. Proceedings of the National Academy of Sciences of the United States of America, 99, 5606–5611. doi: 10.1073/pnas.062066299.PubMedCrossRefGoogle Scholar
  26. Fuso, A., Seminara, L., Cavallaro, R. A., D’Anselmi, F., & Scarpa, S. (2005). S-adenosylmethionine/homocysteine cycle alterations modify DNA methylation status with consequent deregulation of PS1 and BACE and beta-amyloid production. Molecular and Cellular Neurosciences, 28, 195–204. doi: 10.1016/j.mcn.2004.09.007.PubMedCrossRefGoogle Scholar
  27. Giordano, V., Peluso, G., Iannuccelli, M., Benatti, P., Nicolai, R., & Calvani, M. (2007). Systemic and brain metabolic dysfunction as a new paradigm for approaching Alzheimer’s dementia. Neurochemical Research, 32, 555–567. doi: 10.1007/s11064-006-9125-8.PubMedCrossRefGoogle Scholar
  28. Greene, L. S. (1995). Asthma and oxidant stress: Nutritional, environmental, and genetic risk factors. Journal of the American College of Nutrition, 14, 317–324.PubMedGoogle Scholar
  29. Guerra-Shinohara, E. M., Paiva, A. A., Rondo, P. H., Yamasaki, K., Terzi, C. A., & D’Almeida, V. (2002). Relationship between total homocysteine and folate levels in pregnant women and their newborn babies according to maternal serum levels of vitamin B12. BJOG, 109, 784–791. doi: 10.1111/j.1471-0528.2002.01307.x.PubMedCrossRefGoogle Scholar
  30. Hayes, J. D., & Strange, R. C. (2000). Glutathione S-transferase polymorphisms and their biological consequences. Pharmacology, 61, 154–166. doi: 10.1159/000028396.PubMedCrossRefGoogle Scholar
  31. Hermann, A., Gowher, H., & Jeltsch, A. (2004). Biochemistry and biology of mammalian DNA methyltransferases. Cellular and Molecular Life Sciences, 61, 2571–2587. doi: 10.1007/s00018-004-4201-1.PubMedCrossRefGoogle Scholar
  32. Hobbs, C. A., Cleves, M. A., Melnyk, S., Zhao, W., & James, S. J. (2005a). Congenital heart defects and abnormal maternal biomarkers of methionine and homocysteine metabolism. The American Journal of Clinical Nutrition, 81, 147–153.PubMedGoogle Scholar
  33. Hobbs, C. A., Cleves, M. A., Zhao, W., Melnyk, S., & James, S. J. (2005b). Congenital heart defects and maternal biomarkers of oxidative stress. The American Journal of Clinical Nutrition, 82, 598–604.PubMedGoogle Scholar
  34. Hogart, A., Nagarajan, R. P., Patzel, K. A., Yasui, D. H., & LaSalle, J. M. (2007). 15q11–13 GABAA receptor genes are normally biallelically expressed in brain yet are subject to epigenetic dysregulation in autism-spectrum disorders. Human Molecular Genetics, 16, 691–703. doi: 10.1093/hmg/ddm014.PubMedCrossRefGoogle Scholar
  35. Ingrosso, D., D’angelo, S., di Carlo, E., Perna, A. F., Zappia, V., & Galletti, P. (2000). Increased methyl esterification of altered aspartyl residues in erythrocyte membrane proteins in response to oxidative stress. European Journal of Biochemistry, 267, 4397–4405. doi: 10.1046/j.1432-1327.2000.01485.x.PubMedCrossRefGoogle Scholar
  36. Jacob, R. A., Gretz, D. M., Taylor, P. C., James, S. J., Pogribny, I. P., Miller, B. J., et al. (1998). Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women. The Journal of Nutrition, 128, 1204–1212.PubMedGoogle Scholar
  37. James, S. J., Cutler, P., Melnyk, S., Jernigan, S., Janak, L., Gaylor, D. W., et al. (2004). Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. The American Journal of Clinical Nutrition, 80, 1611–1617.PubMedGoogle Scholar
  38. James, S. J., Melnyk, S., Jernigan, S., Cleves, M. A., Halsted, C. H., Wong, D. H., et al. (2006). Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, 141, 947–956. doi: 10.1002/ajmg.b.30366.CrossRefGoogle Scholar
  39. James, S. J., Melnyk, S., Pogribna, M., Pogribny, I. P., & Caudill, M. A. (2002). Elevation in S-adenosylhomocysteine and DNA hypomethylation: Potential epigenetic mechanism for homocysteine-related pathology. The Journal of Nutrition, 132, 2361S–2366S.PubMedGoogle Scholar
  40. Kates, W. R., Burnette, C. P., Eliez, S., Strunge, L. A., Kaplan, D., Landa, R., et al. (2004). Neuroanatomic variation in monozygotic twin pairs discordant for the narrow phenotype for autism. The American Journal of Psychiatry, 161, 539–546. doi: 10.1176/appi.ajp.161.3.539.PubMedCrossRefGoogle Scholar
  41. Kilbourne, A. M., Brar, J. S., Drayer, R. A., Xu, X., & Post, E. P. (2007). Cardiovascular disease and metabolic risk factors in male patients with schizophrenia, schizoaffective disorder, and bipolar disorder. Psychosomatics, 48, 412–417. doi: 10.1176/appi.psy.48.5.412.PubMedCrossRefGoogle Scholar
  42. Kuratomi, G., Iwamoto, K., Bundo, M., Kusumi, I., Kato, N., Iwata, N., et al. (2007). Aberrant DNA methylation associated with bipolar disorder identified from discordant monozygotic twins. Molecular Psychiatry, 13(4), 429–441.Google Scholar
  43. Li, Z., Dong, T., Proschel, C., & Noble, M. (2007). Chemically diverse toxicants converge on Fyn and c-Cbl to disrupt precursor cell function. PLoS Biology, 5, e35. doi: 10.1371/journal.pbio.0050035.PubMedCrossRefGoogle Scholar
  44. Lopez-Rangel, E., & Lewis, M. E. (2006). Loud and clear evidence for gene silencing by epigenetic mechanisms in autism and related neurodevelopmental disorders. Clinical Genetics, 69, 21–22. doi: 10.1111/j.1399-0004.2006.00543a.x.PubMedCrossRefGoogle Scholar
  45. Lyons, J., Rauh-Pfeiffer, A., Yu, Y. M., Lu, X. M., Zurakowski, D., Tompkins, R. G., et al. (2000). Blood glutathione synthesis rates in healthy adults receiving a sulfur amino acid-free diet. Proceedings of the National Academy of Sciences of the United States of America, 97, 5071–5076. doi: 10.1073/pnas.090083297.PubMedCrossRefGoogle Scholar
  46. Mattson, M. P. (2003). Methylation and acetylation in nervous system development and neurodegenerative disorders. Ageing Research Reviews, 2, 329–342. doi: 10.1016/S1568-1637(03)00013-8.PubMedCrossRefGoogle Scholar
  47. Mattson, M. P., & Shea, T. B. (2003). Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders. Trends in Neurosciences, 26, 137–146. doi: 10.1016/S0166-2236(03)00032-8.PubMedCrossRefGoogle Scholar
  48. McKeever, M., Molloy, A., Weir, D. G., Young, P. B., Kennedy, D. G., Kennedy, S., et al. (1995). An abnormal methylation ratio induces hypomethylation in vitro in the brain of pig and man, but not in rat. Clinical Science, 88, 73–79.PubMedGoogle Scholar
  49. Melnyk, S., Pogribna, M., Pogribny, I., Hine, R. J., & James, S. J. (1999). A new HPLC method for the simultaneous determination of oxidized and reduced plasma aminothiols using coulometric electrochemical detection. The Journal of Nutritional Biochemistry, 10, 490–497. doi: 10.1016/S0955-2863(99)00033-9.PubMedCrossRefGoogle Scholar
  50. Melnyk, S., Pogribna, M., Pogribny, I. P., Yi, P., & James, S. J. (2000). Measurement of plasma and intracellular S-adenosylmethionine and S-adenosylhomocysteine utilizing coulometric electrochemical detection: Alterations with plasma homocysteine and pyridoxal 5’-phosphate concentrations. Clinical Chemistry, 46, 265–272.PubMedGoogle Scholar
  51. Ming, X., Stein, T. P., Brimacombe, M., Johnson, W. G., Lambert, G. H., & Wagner, G. C. (2005). Increased excretion of a lipid peroxidation biomarker in autism. Prostaglandins Leukotrienes and Essential Fatty Acids, 73, 379–384. doi: 10.1016/j.plefa.2005.06.002.CrossRefGoogle Scholar
  52. Morrison, J. A., Jacobsen, D. W., Sprecher, D. L., Robinson, K., Khoury, P., & Daniels, S. R. (1999). Serum glutathione in adolescent males predicts parental coronary heart disease. Circulation, 100, 2244–2247.PubMedGoogle Scholar
  53. Murphy, M. M., Fernandez-Ballart, J. D., Arija, V., Scott, J. M., Molloy, A. M., & Canals, J. (2007). Maternal homocysteine at preconception is negatively correlated with cognitive achievement in children at 4 months and 6 years of age. Conference Proceedings, 6th International Conference on Homocysteine Metabolism. Clinical Chemistry and Laboratory Medicine, 45(5), A23.Google Scholar
  54. Murphy, M. M., Scott, J. M., Arija, V., Molloy, A. M., & Fernandez-Ballart, J. D. (2004). Maternal homocysteine before conception and throughout pregnancy predicts fetal homocysteine and birth weight. Clinical Chemistry, 50, 1406–1412. doi: 10.1373/clinchem.2004.032904.PubMedCrossRefGoogle Scholar
  55. Nakayama, A., Masaki, S., & Aoki, E. (2006). Nihon Shinkei Seishin Yakurigaku Zasshi, 26, 209–212. (Genetics and epigenetics in autism).Google Scholar
  56. Niculescu, M. D., & Zeisel, S. H. (2002). Diet, methyl donors and DNA methylation: Interactions between dietary folate, methionine and choline. The Journal of Nutrition, 132, 2333S–2335S.PubMedGoogle Scholar
  57. Ono, H., Sakamoto, A., & Sakura, N. (2001). Plasma total glutathione concentrations in healthy pediatric and adult subjects. Clinica Chimica Acta, 312, 227–229. doi: 10.1016/S0009-8981(01)00596-4.CrossRefGoogle Scholar
  58. Pastore, A., Federici, G., Bertini, E., & Piemonte, F. (2003). Analysis of glutathione: Implication in redox and detoxification. Clinica Chimica Acta, 333, 19–39. doi: 10.1016/S0009-8981(03)00200-6.CrossRefGoogle Scholar
  59. Pennington, K., Beasley, C. L., Dicker, P., Fagan, A., English, J., Pariante, C. M., et al. (2007). Prominent synaptic and metabolic abnormalities revealed by proteomic analysis of the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder. Molecular Psychiatry [Epub ahead of print].Google Scholar
  60. Perna, A. F., Ingrosso, D., Lombardi, C., Acanfora, F., Satta, E., Cesare, C. M., et al. (2003). Possible mechanisms of homocysteine toxicity. Kidney International, 63, S137–S140. doi: 10.1046/j.1523-1755.63.s84.33.x.CrossRefGoogle Scholar
  61. Razin, A. (1998). CpG methylation, chromatin structure and gene silencing - a three-way connection. The EMBO Journal, 17, 4905–4908. doi: 10.1093/emboj/17.17.4905.PubMedCrossRefGoogle Scholar
  62. Regland, B., Johansson, B. V., & Gottfries, C.-G. (1994). Homocysteinemia and schizophrenia as a case of methylation deficiency. Journal of Neural Transmission, 98, 143–152. doi: 10.1007/BF01277017.PubMedCrossRefGoogle Scholar
  63. Reik, W., & Dean, W. (2001). DNA methylation and mammalian epigenetics. Electrophoresis, 22, 2838–2843. doi:10.1002/1522-2683(200108)22:14≤2838::AID-ELPS2838≥3.0.CO;2-M.PubMedCrossRefGoogle Scholar
  64. Richardson, B. (2003). DNA methylation and autoimmune disease. Clinical Immunology (Orlando, Fla.), 109, 72–79. doi: 10.1016/S1521-6616(03)00206-7.CrossRefGoogle Scholar
  65. Robertson, K. D., & Jones, P. A. (2000). DNA methylation: Past, present and future directions. Carcinogenesis, 21, 461–467. doi: 10.1093/carcin/21.3.461.PubMedCrossRefGoogle Scholar
  66. Samaco, R. C., Hogart, A., & LaSalle, J. M. (2005). Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3. Human Molecular Genetics, 14, 483–492. doi: 10.1093/hmg/ddi045.PubMedCrossRefGoogle Scholar
  67. Schanen, N. C. (2006). Epigenetics of autism spectrum disorders. Human Molecular Genetics, 15(Spec No 2), R138–R150.Google Scholar
  68. Sogut, S., Zoroglu, S. S., Ozyurt, H., Ramazan, Y. H., Ozugurlu, F., Sivasli, E., et al. (2003). Changes in nitric oxide levels and antioxidant enzyme activities may have a role in the pathophysiological mechanisms involved in autism. Clinica Chimica Acta, 331, 111–117. doi: 10.1016/S0009-8981(03)00119-0.CrossRefGoogle Scholar
  69. Ullegaddi, R., Powers, H. J., & Gariballa, S. E. (2006). Antioxidant supplementation with or without B-group vitamins after acute ischemic stroke: A randomized controlled trial. Journal of Parenteral and Enteral Nutrition, 30, 108–114.PubMedCrossRefGoogle Scholar
  70. Walker, M. C., Smith, G. N., Perkins, S. L., Keely, E. J., & Garner, P. R. (1999). Changes in homocysteine levels during normal pregnancy. American Journal of Obstetrics and Gynecology, 180, 660–664. doi: 10.1016/S0002-9378(99)70269-3.PubMedCrossRefGoogle Scholar
  71. Weaver, I. C., D’Alessio, A. C., Brown, S. E., Hellstrom, I. C., Dymov, S., Sharma, S., et al. (2007). The transcription factor nerve growth factor-inducible protein a mediates epigenetic programming: Altering epigenetic marks by immediate-early genes. The Journal of Neuroscience, 27, 1756–1768. doi: 10.1523/JNEUROSCI.4164-06.2007.PubMedCrossRefGoogle Scholar
  72. Wu, G., Fang, Y. Z., Yang, S., Lupton, J. R., & Turner, N. D. (2004). Glutathione metabolism and its implications for health. The Journal of Nutrition, 134, 489–492.PubMedGoogle Scholar
  73. Yao, J. K., Leonard, S., & Reddy, R. (2006a). Altered glutathione redox state in schizophrenia. Disease Markers, 22, 83–93.PubMedGoogle Scholar
  74. Yao, Y., Walsh, W. J., McGinnis, W. R., & Pratico, D. (2006b). Altered vascular phenotype in autism: Correlation with oxidative stress. Archives of Neurology, 63, 1161–1164. doi: 10.1001/archneur.63.8.1161.PubMedCrossRefGoogle Scholar
  75. Yi, P., Melnyk, S., Pogribna, M., Pogribny, I. P., Hines, R. J., & James, S. J. (2000). Increase in plasma homocysteine associated with parallel increases in plasma S-adenosylhomocysteine and lymphocyte DNA hypomethylation. The Journal of Biological Chemistry, 275, 29318–29323. doi: 10.1074/jbc.M002725200.PubMedCrossRefGoogle Scholar
  76. Zaidi, S. M., Al Qirim, T. M., & Banu, N. (2005). Effects of antioxidant vitamins on glutathione depletion and lipid peroxidation induced by restraint stress in the rat liver. Drugs in R&D, 6, 157–165. doi: 10.2165/00126839-200506030-00004.CrossRefGoogle Scholar
  77. Zoroglu, S. S., Armutcu, F., Ozen, S., Gurel, A., Sivasli, E., Yetkin, O., et al. (2004). Increased oxidative stress and altered activities of erythrocyte free radical scavenging enzymes in autism. European Archives of Psychiatry and Clinical Neuroscience, 254, 143–147. doi: 10.1007/s00406-004-0456-7.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • S. Jill James
    • 1
    • 2
  • Stepan Melnyk
    • 1
  • Stefanie Jernigan
    • 1
  • Amanda Hubanks
    • 1
  • Shannon Rose
    • 1
  • David W. Gaylor
    • 3
  1. 1.Department of PediatricsUniversity of Arkansas for Medical SciencesLittle RockUSA
  2. 2.Arkansas Children’s Hospital Research InstituteLittle RockUSA
  3. 3.Department of BiostatisticsUniversity of Arkansas for Medical SciencesLittle RockUSA

Personalised recommendations