Objectives: To determine whether methylation and antioxidant metabolic profile differs between case children, unaffected siblings, and age-matched control children and to determine whether the metabolic imbalance is accompanied by DNA hypomethylation and protein/DNA oxidative damage.
Methods: Subjects included 162 children, ages 3-10, who were participants in the autism IMAGE study (Integrated Metabolic And Genomic Endeavor) at Arkansas Children’s Hospital Research Institute. The IMAGE cohort is comprised of 162 children including of 68 case children, 54 age-matched controls and 40 unaffected siblings. Children with autistic disorder were diagnosed using DSM-IV (299.0), ADOS and/or CARS >30. Fasting plasma samples were analyzed for folate-dependent transmethylation and transsulfuration metabolites and 3-nitrotyrosine (oxidized protein derivative) using HPLC with electrochemical detection. Genome-wide DNA methylation (as %5-methylcytosine) and the oxidized DNA adduct 8-oxo-deoxyguanine were quantified with Dionex HPLC-UV system coupled to an electrospray ionization (ESI) tandem mass spectrometer.
Results: In a pair-wise comparison, the overall metabolic profile of the unaffected siblings differed significantly from their autistic siblings but was not different from unrelated control children. In addition, we report new evidence of genome-wide DNA hypomethylation (epigenetic dysregulation) and oxidative protein/DNA damage in children with autism that was not present in their paired siblings or in unaffected control children.
Conclusions: These data indicate that the deficit in antioxidant and methylation capacity is autism-specific and is associated with DNA hypomethylation (epigenetic dysregulation) and oxidative damage. Further, these results suggest a plausible mechanism by which environmental stressors might modulate the genetic predisposition to autism.
Acknowledgement: This research was supported with funding from the National Institute of Child Health and Development (RO1 HD051873; SJJ) and Department of Defense (AS073218P1; SJJ)
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