Metabolic Imbalance Associated with Methylation Dysregulation and Oxidative Damage in Children with Autism
- 1.3k Downloads
Oxidative stress and abnormal DNA methylation have been implicated in the pathophysiology of autism. We investigated the dynamics of an integrated metabolic pathway essential for cellular antioxidant and methylation capacity in 68 children with autism, 54 age-matched control children and 40 unaffected siblings. The metabolic profile of unaffected siblings differed significantly from case siblings but not from controls. Oxidative protein/DNA damage and DNA hypomethylation (epigenetic alteration) were found in autistic children but not paired siblings or controls. These data indicate that the deficit in antioxidant and methylation capacity is specific for autism and may promote cellular damage and altered epigenetic gene expression. Further, these results suggest a plausible mechanism by which pro-oxidant environmental stressors may modulate genetic predisposition to autism.
KeywordsAutism Oxidative stress Metabolic Epigenetics Glutathione DNA methylation
The authors would like to express their gratitude to the families in Arkansas affected by autism whose participation made this study possible. We also acknowledge the invaluable help of the nurses and clinicians at the Dennis Developmental Center for referral and evaluation. This research was supported, in part, with funding from the National Institute of Child Health and Development (RO1 HD051873; SJJ), the Department of Defense (AS073218P1; SJJ) and by grants from the Arkansas Children’s Hospital and Arkansas Biosciences Institute (SJJ).
- Andreazza, A. C., Kapczinski, F., Kauer-Sant’Anna, M., Walz, J. C., Bond, D. J., Goncalves, C. A., et al. (2009). 3-Nitrotyrosine and glutathione antioxidant system in patients in the early and late stages of bipolar disorder. Journal of Psychiatry & Neuroscience, 34, 263–271.Google Scholar
- Chan, A., Tchantchou, F., Graves, V., Rozen, R., & Shea, T. B. (2008). Dietary and genetic compromise in folate availability reduces acetylcholine, cognitive performance and increases aggression: Critical role of S-adenosyl methionine. The Journal of Nutrition, Health & Aging, 12, 252–261.CrossRefGoogle Scholar
- Dean, O. M., van den Buuse, M., Bush, A. I., Copolov, D. L., Ng, F., Dodd, S., et al. (2009). A role for glutathione in the pathophysiology of bipolar disorder and schizophrenia? Animal models and relevance to clinical practice. Current Medicinal Chemistry, 16, 2965–2976.PubMedCrossRefGoogle Scholar
- Gauthier, J., Spiegelman, D., Piton, A., Lafreniere, R. G., Laurent, S., St-Onge, J., et al. (2009). Novel de novo SHANK3 mutation in autistic patients. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics: The Official Publication of the International Society of Psychiatric Genetics, 150B, 421–424.Google Scholar
- 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.CrossRefGoogle Scholar
- Li, Y., Liu, Y., Strickland, F. M., & Richardson, B. (2010). Age-dependent decreases in DNA methyltransferase levels and low transmethylation micronutrient levels synergize to promote overexpression of genes implicated in autoimmunity and acute coronary syndromes. Experimental Gerontology, 45, 312–322.PubMedCrossRefGoogle Scholar
- Melnyk, S., Pogribna, M., Pogribny, I. P., & James, S. J. (2000). Measurement of plasma and intracellular S-adenosylmethionine and S-adenosylhomocysteine utilizing coulemetric electrochemical detection: Alteration with plasma homocysteine and pyridoxal 5’-phosphate concentrations. Clinical Chemistry, 46, 265–272.PubMedGoogle Scholar
- Schanen, N. C. (2006). Epigenetics of autism spectrum disorders. Human Molecular Genetics 15(Spec No 2), R138–R150.Google Scholar
- Shigenaga, M. K., Park, J. W., Cundy, K. C., Gimeno, C. J., & Ames, B. N. (1990). In vivo oxidative DNA damage: measurement of 8-hydroxy-2’-deoxyguanosine in DNA and urine by high-performance liquid chromatography with electrochemical detection. Methods in Enzymology, 186, 521–530.PubMedCrossRefGoogle Scholar
- Strous, R. D., Ritsner, M. S., Adler, S., Ratner, Y., Maayan, R., Kotler, M., et al. (2009). Improvement of aggressive behavior and quality of life impairment following S-adenosyl-methionine (SAM-e) augmentation in schizophrenia. European Neuropsychopharmacology, 19, 14–22.PubMedCrossRefGoogle Scholar