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Oxidative Stress and the Metabolic Pathology of Autism

  • Chapter
Autism

Part of the book series: Current Clinical Neurology ((CCNEU))

Abstract

Chronic metabolic imbalance in the cellular microenvironment is often a primary factor in the development of complex disease. An integrated metabolic profile reflects the combined influence of genetic, epigenetic, and environmental factors that affect the candidate pathway of interest. In this way, the metabolic phenotype of an individual reflects the combined influence of both endogenous and exogenous factors on genotype and provides a window through which the cumulative impact of genes and environment may be viewed. Although both genetic and environmental factors appear to be necessary, in the majority of cases neither is independently sufficient for the autistic phenotype. A metabolic endophenotype provides an intermediate biomarker that is influenced by both genes and environment and can offer insights into relevant candidate genes and pathways.

Moreover, chronic or systemic metabolic imbalance can leave a metabolic footprint that can be followed analytically to gain mechanistic insights into the pathophysiology and pathogenesis of autism and thereby open new windows for therapeutic intervention. Escalating evidence suggests that many autistic children may be under chronic oxidative stress. The scientific question posed in this chapter is whether the autism phenotype reflects multiple and variable susceptibility alleles that converge to create a fragile, environmentally sensitive homeostasis with diminished ability to control and resolve pro-oxidant exposures.

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References

  1. Miller AL. The methionine-homocysteine cycle and its effects on cognitive diseases. Altern Med Rev 2003; 8(1):7–19.

    PubMed  Google Scholar 

  2. Serra JA, Dominguez RO, de Lustig ES, Guareschi EM, Famulari AL, Bartolome EL, et al. Parkinson's disease is associated with oxidative stress: Comparison of peripheral antioxidant profiles in living Parkinson's, Alzheimer's and vascular dementia patients. J Neural Transm 2001; 108(10):1135–1148.

    PubMed  CAS  Google Scholar 

  3. Schulz JB, Lindenau J, Seyfried J, Dichgans J. Glutathione, oxidative stress and neurodegeneration. Eur J Biochem 2000; 267(16):4904–4911.

    PubMed  CAS  Google Scholar 

  4. Muntjewerff JW, Van der Put N, Eskes T, Ellenbroek B, Steegers E, Blom H, et al. Homocysteine metabolism and B-vitamins in schizophrenic patients: Low plasma folate as a possible independent risk factor for schizophrenia. Psychiatry Res 2003; 121(1):1–9.

    PubMed  CAS  Google Scholar 

  5. Pogribna M, Melnyk S, Pogribny I, Chango A, Yi P, James SJ. Homocysteine metabolism in children with Down syndrome: In vitro modulation. Am J Hum Genet 2001; 69(1):88–95.

    PubMed  CAS  Google Scholar 

  6. James SJ, Cutler P, Melnyk S, Jernigan S, Janak L, Gaylor DW, et al. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr 2004; 80(6):1611–1617.

    PubMed  CAS  Google Scholar 

  7. James SJ, Melnyk S, Jernigan S, Cleves MA, Halsted CH, Wong DH, et al. Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism. Am J Med Genet B Neuropsychiatr Genet 2006; 141(8):947–956.

    Google Scholar 

  8. Banerjee RV, Matthews RG. Cobalamin-dependent methionine synthase. FASEB J 1990; 4(5):1450–1459.

    PubMed  CAS  Google Scholar 

  9. Vitvitsky V, Mosharov E, Tritt M, Ataullakhanov F, Banerjee R. Redox regulation of homocysteine-dependent glutathione synthesis. Redox Rep 2003; 8(1):57–63.

    PubMed  CAS  Google Scholar 

  10. McQuillen PS, Ferriero DM. Selective vulnerability in the developing central nervous system. Pediatr Neurol 2004; 30(4):227–235.

    PubMed  Google Scholar 

  11. Rougemont M, Do KQ, Castagne V. New model of glutathione deficit during development: Effect on lipid peroxidation in the rat brain. J Neurosci Res 2002; 70(6):774–783.

    PubMed  CAS  Google Scholar 

  12. Dringen R, Gutterer JM, Hirrlinger J. Glutathione metabolism in brain metabolic interaction between astrocytes and neurons in the defense against reactive oxygen species. Eur J Biochem 2000; 267(16):4912–4916.

    PubMed  CAS  Google Scholar 

  13. Dringen R, Gutterer JM, Hirrlinger J. Glutathione metabolism in brain metabolic interaction between astrocytes and neurons in the defense against reactive oxygen species. Eur J Biochem 2000; 267(16):4912–4916.

    PubMed  CAS  Google Scholar 

  14. Bains JS, Shaw CA. Neurodegenerative disorders n humans: The role of glutathione in oxidative atress-mediated neuronal death. Brain Res Rev 1997; 25:335–358.

    PubMed  CAS  Google Scholar 

  15. Chauhan A, Chauhan V. Oxidative stress in autism. Pathophysiology 2006; 13(3):171–181.

    PubMed  CAS  Google Scholar 

  16. Kern JK, Jones AM. Evidence of toxicity, oxidative stress, and neuronal insult in autism. J Toxicol Environ Health B Crit Rev 2006; 9(6):485–499.

    PubMed  CAS  Google Scholar 

  17. Zoroglu SS, Armutcu F, Ozen S, Gurel A, Sivasli E, Yetkin O, et al. Increased oxidative stress and altered activities of erythrocyte free radical scavenging enzymes in autism. Eur Arch Psychiatry Clin Neurosci 2004; 254(3):143–147.

    PubMed  Google Scholar 

  18. Zoroglu SS, Yurekli M, Meram I, Sogut S, Tutkun H, Yetkin O, et al. Pathophysiological role of nitric oxide and adrenomedullin in autism. Cell Biochem Funct 2003; 21(1):55–60.

    PubMed  CAS  Google Scholar 

  19. Yorbik O, Sayal A, Akay C, Akbiyik DI, Sohmen T. Investigation of antioxidant enzymes in children with autistic disorder. Prostaglandins Leukot Essent Fatty Acids 2002; 67(5):341–343.

    PubMed  CAS  Google Scholar 

  20. Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol 2005; 57(1):67–81.

    PubMed  CAS  Google Scholar 

  21. Pardo CA, Vargas DL, Zimmerman AW. Immunity, neuroglia and neuroinflammation in autism. Int Rev Psychiatry 2005; 17(6):485–495.

    PubMed  Google Scholar 

  22. Ming X, Stein TP, Brimacombe M, Johnson WG, Lambert GH, Wagner GC. Increased excretion of a lipid peroxidation biomarker in autism. Prostaglandins Leukot Essent Fatty Acids 2005; 73(5):379–384.

    PubMed  CAS  Google Scholar 

  23. Chauhan A, Chauhan V, Brown WT, Cohen I. Oxidative stress in autism: Increased lipid peroxidation and reduced serum levels of ceruloplasmin and transferrin – the antioxidant proteins. Life Sci 2004; 75(21):2539–2549.

    PubMed  CAS  Google Scholar 

  24. Schafer FQ, Buettner GR. Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. Free Radic Biol Med 2001; 30(11):1191–1212.

    PubMed  CAS  Google Scholar 

  25. Lu SC. Regulation of hepatic glutathione synthesis. Semin Liver Dis 1998; 18(4):331–343.

    PubMed  CAS  Google Scholar 

  26. Klatt P, Lamas S. Regulation of protein function by S-glutathiolation in response to oxidative and nitrosative stress. Eur J Biochem 2000; 267(16):4928–4944.

    PubMed  CAS  Google Scholar 

  27. Dickinson DA, Forman HJ. Cellular glutathione and thiols metabolism. Biochem Pharmacol 2002; 64(5–6):1019–1026.

    PubMed  CAS  Google Scholar 

  28. Paolicchi A, Dominici S, Pieri L, Maellaro E, Pompella A. Glutathione catabolism as a signaling mechanism. Biochem Pharmacol 2002; 64(5–6):1027–1035.

    PubMed  CAS  Google Scholar 

  29. Rahman I, Marwick J, Kirkham P. Redox modulation of chromatin remodeling: Impact on histone acetylation and deacetylation, NF-kappaB and pro-inflammatory gene expression. Biochem Pharmacol 2004; 68(6):1255–1267.

    PubMed  CAS  Google Scholar 

  30. Pastore A, Federici G, Bertini E, Piemonte F. Analysis of glutathione: Implication in redox and detoxification. Clin Chim Acta 2003; 333(1):19–39.

    PubMed  CAS  Google Scholar 

  31. Jonas CR, Ziegler TR, Gu LH, Jones DP. Extracellular thiol/disulfide redox state affects proliferation rate in a human colon carcinoma (Caco2) cell line. Free Radic Biol Med 2002; 33(11):1499–1506.

    PubMed  CAS  Google Scholar 

  32. Bains JS, Shaw CA. Neurodegenerative disorders in humans: The role of glutathione in oxidative stress-mediated neuronal death. Brain Res Brain Res Rev 1997; 25(3):335–358.

    PubMed  CAS  Google Scholar 

  33. Horvath K, Perman JA. Autism and gastrointestinal symptoms. Curr Gastroenterol Rep 2002; 4(3):251–258.

    PubMed  Google Scholar 

  34. McFadden SA. Phenotypic variation in xenobiotic metabolism and adverse environmental response: Focus on sulfur-dependent detoxification pathways. Toxicology 1996; 111(1–3):43–65.

    PubMed  CAS  Google Scholar 

  35. Dringen R, Hirrlinger J. Glutathione pathways in the brain. Biol Chem 2003; 384(4):505–516.

    PubMed  CAS  Google Scholar 

  36. Droge W, Breitkreutz R. Glutathione and immune function. Proc Nutr Soc 2000; 59(4):595–600.

    PubMed  CAS  Google Scholar 

  37. Sen CK. Cellular thiols and redox-regulated signal transduction. Curr Top Cell Regul 2000; 36:1–30.

    PubMed  CAS  Google Scholar 

  38. Filomeni G, Rotilio G, Ciriolo MR. Cell signalling and the glutathione redox system. Biochem Pharmacol 2002; 64(5–6):1057–1064.

    PubMed  CAS  Google Scholar 

  39. Dickinson DA, Forman HJ. Cellular glutathione and thiols metabolism. Biochem Pharmacol 2002; 64(5–6):1019–1026.

    PubMed  CAS  Google Scholar 

  40. Janaky R, Ogita K, Pasqualotto BA, Bains JS, Oja SS, Yoneda Y, et al. Glutathione and signal transduction in the mammalian CNS. J Neurochem 1999; 73(3):889–902.

    PubMed  CAS  Google Scholar 

  41. Meister A. Glutathione metabolism. Methods Enzymol 1995; 251:3–7.

    PubMed  CAS  Google Scholar 

  42. Thomas JA, Mallis RJ. Aging and oxidation of reactive protein sulfhydryls. Exp Gerontol 2001; 36(9):1519–1526.

    PubMed  CAS  Google Scholar 

  43. Dargel R. Lipid peroxidation – a common pathogenetic mechanism? Exp Toxicol Pathol 1992; 44(4):169–181.

    PubMed  CAS  Google Scholar 

  44. Shih AY, Erb H, Sun X, Toda S, Kalivas PW, Murphy TH. Cystine/glutamate exchange modulates glutathione supply for neuroprotection from oxidative stress and cell proliferation. J Neurosci 2006; 26(41):10514–10523.

    PubMed  CAS  Google Scholar 

  45. Himi T, Ikeda M, Yasuhara T, Nishida M, Morita I. Role of neuronal glutamate transporter in the cysteine uptake and intracellular glutathione levels in cultured cortical neurons. J Neural Transm 2003; 110(12):1337–1348.

    PubMed  CAS  Google Scholar 

  46. Machlin LJ, Bendich A. Free radical tissue damage: Protective role of antioxidant nutrients. FASEB J 1987; 1:441–445.

    PubMed  CAS  Google Scholar 

  47. Yao JK, Leonard S, Reddy R. Altered glutathione redox state in schizophrenia. Dis Markers 2006; 22(1–2):83–93.

    PubMed  CAS  Google Scholar 

  48. Frey BN, Andreazza AC, Kunz M, Gomes FA, Quevedo J, Salvador M, et al. Increased oxidative stress and DNA damage in bipolar disorder: A twin-case report. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31(1):283–285.

    PubMed  CAS  Google Scholar 

  49. Tilleux S, Hermans E. Neuroinflammation and regulation of glial glutamate uptake in neurological disorders. J Neurosci Res 2007; 85(10):2059–2070.

    PubMed  CAS  Google Scholar 

  50. Yao JK, Reddy RD, van Kammen DP. Oxidative damage and schizophrenia: An overview of the evidence and its therapeutic implications. CNS Drugs 2001; 15(4):287–310.

    PubMed  CAS  Google Scholar 

  51. Yamamoto BK, Bankson MG. Amphetamine neurotoxicity: Cause and consequence of oxidative stress. Crit Rev Neurobiol 2005; 17(2):87–117.

    PubMed  CAS  Google Scholar 

  52. Loeken MR. Free radicals and birth defects. J Matern Fetal Neonatal Med 2004; 15(1):6–14.

    PubMed  CAS  Google Scholar 

  53. Dringen R. Glutathione metabolism and oxidative stress in neurodegeneration. Eur J Biochem 2000; 267(16):4903.

    PubMed  CAS  Google Scholar 

  54. Kovacic P, Jacintho JD. Systemic lupus erythematosus and other autoimmune diseases from endogenous and exogenous agents: Unifying theme of oxidative stress. Mini Rev Med Chem 2003; 3(6):568–575.

    PubMed  CAS  Google Scholar 

  55. Muhle R, Trentacoste SV, Rapin I. The genetics of autism. Pediatrics 2004; 113(5):e472–e486.

    PubMed  Google Scholar 

  56. Risch N, Spiker D, Lotspeich L, Nouri N, Hinds D, Hallmayer J, et al. A genomic screen of autism: Evidence for a multilocus etiology. Am J Hum Genet 1999; 65(2):493–507.

    PubMed  CAS  Google Scholar 

  57. Wiznitzer M. Autism and tuberous sclerosis. J Child Neurol 2004; 19(9):675–679.

    PubMed  Google Scholar 

  58. Humphrey A, Higgins JN, Yates JR, Bolton PF. Monozygotic twins with tuberous sclerosis discordant for the severity of developmental deficits. Neurology 2004; 62(5):795–798.

    PubMed  Google Scholar 

  59. Gomez MR, Kuntz NL, Westmoreland BF. Tuberous sclerosis, early onset of seizures, and mental subnormality: Study of discordant homozygous twins. Neurology 1982; 32(6):604–611.

    PubMed  CAS  Google Scholar 

  60. Mueller SG, Trabesinger AH, Boesiger P, Wieser HG. Brain glutathione levels in patients with epilepsy measured by in vivo (1)H-MRS. Neurology 2001; 57(8):1422–1427.

    PubMed  CAS  Google Scholar 

  61. Bellissimo MI, Amado D, Abdalla DS, Ferreira EC, Cavalheiro EA, Naffah-Mazzacoratti MG. Superoxide dismutase, glutathione peroxidase activities and the hydroperoxide concentration are modified in the hippocampus of epileptic rats. Epilepsy Res 2001; 46(2):121–128.

    PubMed  CAS  Google Scholar 

  62. Sudha K, Rao AV, Rao A. Oxidative stress and antioxidants in epilepsy. Clin Chim Acta 2001; 303(1–2):19–24.

    PubMed  CAS  Google Scholar 

  63. Bolton PF, Park RJ, Higgins JN, Griffiths PD, Pickles A. Neuro-epileptic determinants of autism spectrum disorders in tuberous sclerosis complex. Brain 2002; 125(Pt 6):1247–1255.

    PubMed  Google Scholar 

  64. Hrdlicka M, Komarek V, Propper L, Kulisek R, Zumrova A, Faladova L, et al. Not EEG abnormalities but epilepsy is associated with autistic regression and mental functioning in childhood autism. Eur Child Adolesc Psychiatry 2004; 13(4):209–213.

    PubMed  Google Scholar 

  65. Sierra C, Vilaseca MA, Brandi N, Artuch R, Mira A, Nieto M, et al. Oxidative stress in Rett syndrome. Brain Dev 2001; 23(Suppl 1):S236–S239.

    PubMed  Google Scholar 

  66. Piven J, Gayle J, Landa R, Wzorek M, Folstein S. The prevalence of fragile X in a sample of autistic individuals diagnosed using a standardized interview. J Am Acad Child Adolesc Psychiatry 1991; 30(5):825–830.

    PubMed  CAS  Google Scholar 

  67. Valinluck V, Tsai HH, Rogstad DK, Burdzy A, Bird A, Sowers LC. Oxidative damage to methyl-CpG sequences inhibits the binding of the methyl-CpG binding domain (MBD) of methyl-CpG binding protein 2 (MeCP2). Nucleic Acids Res 2004; 32(14):4100–4108.

    PubMed  CAS  Google Scholar 

  68. Berry-Kravis E. Epilepsy in fragile X syndrome. Dev Med Child Neurol 2002; 44(11):724–728.

    PubMed  Google Scholar 

  69. Moretti P, Zoghbi HY. MeCP2 dysfunction in Rett syndrome and related disorders. Curr Opin Genet Dev 2006; 16(3):276–281.

    PubMed  Google Scholar 

  70. Sandberg G, Schalling M. Effect of in vitro promoter methylation and CGG repeat expansion on FMR-1 expression. Nucleic Acids Res 1997; 25(14):2883–2887.

    PubMed  CAS  Google Scholar 

  71. Amir RE, Van dV I, Wan M, Tran CQ, Francke U, Zoghbi HY. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 1999; 23(2):185–188.

    PubMed  CAS  Google Scholar 

  72. Kent L, Evans J, Paul M, Sharp M. Comorbidity of autistic spectrum disorders in children with Down syndrome. Dev Med Child Neurol 1999; 41(3):153–158.

    PubMed  CAS  Google Scholar 

  73. Zitnanova I, Korytar P, Sobotova H, Horakova L, Sustrova M, Pueschel S, et al. Markers of oxidative stress in children with Down syndrome. Clin Chem Lab Med 2006; 44(3):306–310.

    PubMed  CAS  Google Scholar 

  74. Zana M, Janka Z, Kalman J. Oxidative stress: A bridge between Down's syndrome and Alzheimer's disease. Neurobiol Aging 2007; 28(5):648–676.

    Google Scholar 

  75. Pastore A, Tozzi G, Gaeta LM, Giannotti A, Bertini E, Federici G, et al. Glutathione metabolism and antioxidant enzymes in children with Down syndrome. J Pediatr 2003; 142(5):583–585.

    PubMed  CAS  Google Scholar 

  76. Chango A, Abdennebi-Najar L, Tessier F, Ferre S, Do S, Gueant JL, et al. Quantitative methylation-sensitive arbitrarily primed PCR method to determine differential genomic DNA methylation in Down Syndrome. Biochem Biophys Res Commun 2006; 349(2):492–496.

    PubMed  CAS  Google Scholar 

  77. Baieli S, Pavone L, Meli C, Fiumara A, Coleman M. Autism and phenylketonuria. J Autism Dev Disord 2003; 33(2):201–204.

    PubMed  Google Scholar 

  78. Kienzle Hagen ME, Pederzolli CD, Sgaravatti AM, Bridi R, Wajner M, Wannmacher CM, et al. Experimental hyperphenylalaninemia provokes oxidative stress in rat brain. Biochim Biophys Acta 2002; 1586(3):344–352.

    PubMed  CAS  Google Scholar 

  79. Sierra C, Vilaseca MA, Moyano D, Brandi N, Campistol J, Lambruschini N, et al. Antioxidant status in hyperphenylalaninemia. Clin Chim Acta 1998; 276(1):1–9.

    PubMed  CAS  Google Scholar 

  80. Martinez-Cruz F, Pozo D, Osuna C, Espinar A, Marchante C, Guerrero JM. Oxidative stress induced by phenylketonuria in the rat: Prevention by melatonin, vitamin E, and vitamin C. J Neurosci Res 2002; 69(4):550–558.

    PubMed  CAS  Google Scholar 

  81. Tchantchou F, Graves M, Ortiz D, Chan A, Rogers E, Shea TB. S-adenosyl methionine: A connection between nutritional and genetic risk factors for neurodegeneration in Alzheimer's disease. J Nutr Health Aging 2006; 10(6):541–544.

    PubMed  CAS  Google Scholar 

  82. Purohit V, Abdelmalek MF, Barve S, Benevenga NJ, Halsted CH, Kaplowitz N, et al. Role of S-adenosylmethionine, folate, and betaine in the treatment of alcoholic liver disease: Summary of a symposium. Am J Clin Nutr 2007; 86(1):14–24.

    PubMed  CAS  Google Scholar 

  83. Williams G, King J, Cunningham M, Stephan M, Kerr B, Hersh JH. Fetal valproate syndrome and autism: Additional evidence of an association. Dev Med Child Neurol 2001; 43(3):202–206.

    PubMed  CAS  Google Scholar 

  84. Stromland K, Philipson E, Andersson GM. Offspring of male and female parents with thalidomide embryopathy: Birth defects and functional anomalies. Teratology 2002; 66(3):115–121.

    PubMed  CAS  Google Scholar 

  85. Holmes AS, Blaxill MF, Haley BE. Reduced levels of mercury in first baby haircuts of autistic children. Int J Toxicol 2003; 22(4):277–285.

    PubMed  CAS  Google Scholar 

  86. Blaxill MF, Redwood L, Bernard S. Thimerosal and autism? A plausible hypothesis that should not be dismissed. Med Hypotheses 2004; 62(5):788–794.

    PubMed  CAS  Google Scholar 

  87. Alonso-Aperte E, Ubeda N, Achon M, Perez-Miguelsanz J, Varela-Moreiras G. Impaired methionine synthesis and hypomethylation in rats exposed to valproate during gestation. Neurology 1999; 52(4):750–756.

    PubMed  CAS  Google Scholar 

  88. Hishida R, Nau H. VPA-induced neural tube defects in mice. I. Altered metabolism of sulfur amino acids and glutathione. Teratog Carcinog Mutagen 1998; 18(2): 49–61.

    PubMed  CAS  Google Scholar 

  89. Tong V, Teng XW, Chang TK, Abbott FS. Valproic acid I: Time course of lipid peroxidation biomarkers, liver toxicity, and valproic acid metabolite levels in rats. Toxicol Sci 2005; 86(2):427–435.

    PubMed  CAS  Google Scholar 

  90. Sinn DI, Kim SJ, Chu K, Jung KH, Lee ST, Song EC, et al. Valproic acid-mediated neuroprotection in intracerebral hemorrhage via histone deacetylase inhibition and transcriptional activation. Neurobiol Dis 2007; 26(2):464–472.

    PubMed  CAS  Google Scholar 

  91. Schulpis KH, Lazaropoulou C, Regoutas S, Karikas GA, Margeli A, Tsakiris S, et al. Valproic acid monotherapy induces DNA oxidative damage. Toxicology 2006; 217(2–3):228–232.

    PubMed  CAS  Google Scholar 

  92. Marchion DC, Bicaku E, Daud AI, Sullivan DM, Munster PN. Valproic acid alters chromatin structure by regulation of chromatin modulation proteins. Cancer Res 2005; 65(9):3815–3822.

    PubMed  CAS  Google Scholar 

  93. Hansen JM, Harris KK, Philbert MA, Harris C. Thalidomide modulates nuclear redox status and preferentially depletes glutathione in rabbit limb versus rat limb. J Pharmacol Exp Ther 2002; 300(3):768–776.

    PubMed  CAS  Google Scholar 

  94. Parman T, Wiley MJ, Wells PG. Free radical-mediated oxidative DNA damage in the mechanism of thalidomide teratogenicity. Nat Med 1999; 5(5):582–585.

    PubMed  CAS  Google Scholar 

  95. James SJ, Slikker W III, Melnyk S, New E, Pogribna M, Jernigan S. Thimerosal neurotoxicity is associated with glutathione depletion: protection with glutathione precursors. Neurotoxicology 2005; 26(1):1–8.

    PubMed  CAS  Google Scholar 

  96. Baskin DS, Ngo H, Didenko VV. Thimerosal induces DNA breaks, caspase-3 activation, membrane damage, and cell death in cultured human neurons and fibroblasts. Toxicol Sci 2003; 74(2):361–368.

    PubMed  CAS  Google Scholar 

  97. Makani S, Gollapudi S, Yel L, Chiplunkar S, Gupta S. Biochemical and molecular basis of thimerosal-induced apoptosis in T cells: A major role of mitochondrial pathway. Genes Immun 2002; 3(5):270–278.

    PubMed  CAS  Google Scholar 

  98. Kenchappa RS, Diwakar L, Annepu J, Ravindranath V. Estrogen and neuroprotection: Higher constitutive expression of glutaredoxin in female mice offers protection against MPTP-mediated neurodegeneration. FASEB J 2004; 18(10):1102–1104.

    PubMed  Google Scholar 

  99. Green PS, Simpkins JW. Neuroprotective effects of estrogens: Potential mechanisms of action. Int J Dev Neurosci 2000; 18(4–5):347–358.

    PubMed  CAS  Google Scholar 

  100. Behl C, Skutella T, Lezoualc'h F, Post A, Widmann M, Newton CJ, et al. Neuroprotection against oxidative stress by estrogens: structure-activity relationship. Mol Pharmacol 1997; 51(4):535–541.

    PubMed  CAS  Google Scholar 

  101. Roof RL, Hall ED. Gender differences in acute CNS trauma and stroke: Neuroprotective effects of estrogen and progesterone. J Neurotrauma 2000; 17(5):367–388.

    PubMed  CAS  Google Scholar 

  102. Behl C. Estrogen can protect neurons: Modes of action. J Steroid Biochem Mol Biol 2002; 83(1–5):195–197.

    PubMed  CAS  Google Scholar 

  103. Vina J, Sastre J, Pallardo F, Borras C. Mitochondrial theory of aging: importance to explain why females live longer than males. Antioxid Redox Signal 2003; 5(5):549–556.

    PubMed  CAS  Google Scholar 

  104. Wu GY, Fang YZ, Yang S, Lupton JR, Turner ND. Glutathione metabolism and its implications for health. J Nutr 2004; 134(3):489–492.

    PubMed  CAS  Google Scholar 

  105. Ibim S, Randall R, Han P. Modulation of hepatic glucose-6-phosphate dehydrogenase activity in male and female rats by estrogen. Life Sci 1994; 45:1559–1565.

    Google Scholar 

  106. Lavoie JC, Rouleau T, Truttmann AC, Chessex P. Postnatal gender-dependent maturation of cellular cysteine uptake. Free Radic Res 2002; 36(8):811–817.

    PubMed  CAS  Google Scholar 

  107. Lavoie JC, Chessex P. Gender and maturation affect glutathione status in human neonatal tissues. Free Radic Biol Med 1997; 23(4):648–657.

    PubMed  CAS  Google Scholar 

  108. Du L, Bayir H, Lai Y, Zhang X, Kochanek PM, Watkins SC, et al. Innate gender-based proclivity in response to cytotoxicity and programmed cell death pathway. J Biol Chem 2004; 279(37):38563–38570.

    PubMed  CAS  Google Scholar 

  109. Dimitrova KR, DeGroot K, Myers AK, Kim YD. Estrogen and homocysteine. Cardiovasc Res 2002; 53:577–588.

    PubMed  CAS  Google Scholar 

  110. Dimitrova KR, DeGroot KW, Suyderhoud JP, Pirovic EA, Munro TJ, Wieneke J, et al. 17-beta estradiol preserves endothelial cell viability in an in vitro model of homocysteine-induced oxidative stress. J Cardiovasc Pharmacol 2002; 39(3):347–353.

    PubMed  CAS  Google Scholar 

  111. White JF. Intestinal Pathology in Autism. Exp Biol Med 2003; 228:639–649.

    CAS  Google Scholar 

  112. White JF. Intestinal pathophysiology in autism. Exp Biol Med (Maywood) 2003; 228(6):639–649.

    CAS  Google Scholar 

  113. Jefferies H, Bot J, Coster J, Khalil A, Hall JC, McCauley RD. The role of glutathione in intestinal dysfunction. J Invest Surg 2003; 16(6):315–323.

    PubMed  Google Scholar 

  114. Martensson J, Jain A, Meister A. Glutathione is required for intestinal function. Proc Natl Acad Sci USA 1990; 87(5):1715–1719.

    PubMed  CAS  Google Scholar 

  115. Deykin EY, MacMahon B. Viral exposure and autism. Am J Epidemiol 1979; 109(6):628–638.

    PubMed  CAS  Google Scholar 

  116. Nicolson GL, Gan R, Nicolson NL, Haier J. Evidence for Mycoplasma ssp., Chlamydia pneunomiae, and human herpes virus-6 coinfections in the blood of patients with autistic spectrum disorders. J Neurosci Res 2007; 85(5):1143–1148.

    PubMed  CAS  Google Scholar 

  117. Cai J, Chen Y, Seth S, Furukawa S, Compans RW, Jones DP. Inhibition of influenza infection by glutathione. Free Radic Biol Med 2003; 34(7):928–936.

    PubMed  CAS  Google Scholar 

  118. Kalebic T, Kinter A, Poli G, Anderson ME, Meister A, Fauci AS. Suppression of human immunodeficiency virus expression in chronically infected monocytic cells by glutathione, glutathione ester, and N-acetylcysteine. Proc Natl Acad Sci USA 1991; 88(3):986–990.

    PubMed  CAS  Google Scholar 

  119. Bailey A, Le Couteur A, Gottesman I, Bolton P, Simonoff E, Yuzda E, et al. Autism as a strongly genetic disorder: Evidence from a British twin study. Psychol Med 1995; 25(1):63–77.

    PubMed  CAS  Google Scholar 

  120. Kates WR, Burnette CP, Eliez S, Strunge LA, Kaplan D, Landa R, et al. Neuroanatomic variation in monozygotic twin pairs discordant for the narrow phenotype for autism. Am J Psychiatry 2004; 161(3):539–546.

    PubMed  Google Scholar 

  121. Grandjean P, Landrigan PJ. Developmental neurotoxicity of industrial chemicals. Lancet 2006; 368(9553):2167–2178.

    PubMed  CAS  Google Scholar 

  122. Zaibo L, Dong T, Proschel C, Noble M. Chemically diverse toxicants converge on Fyn and c-Clb to disrupt precursor cell function. PLoS Biol 2007; 5:212–231.

    Google Scholar 

  123. Zhao X, Leotta A, Kustanovich V, Lajonchere C, Geschwind DH, Law K, et al. A unified genetic theory for sporadic and inherited autism. Proc Natl Acad Sci USA 2007; 104(31):12831–12836.

    PubMed  CAS  Google Scholar 

  124. Adinolfi M. The development of the human blood-CSF-brain barrier. Dev Med Child Neurol 1985; 27(4):532–537.

    PubMed  CAS  Google Scholar 

  125. Ghersi-Egea JF, Strazielle N, Murat A, Jouvet A, Buenerd A, Belin MF. Brain protection at the blood-cerebrospinal fluid interface involves a glutathione-dependent metabolic barrier mechanism. J Cereb Blood Flow Metab 2006; 26(9):1165–1175.

    PubMed  CAS  Google Scholar 

  126. Sakamoto M, Kubota M, Liu XJ, Murata K, Nakai K, Satoh H. Maternal and fetal mercury and n-3 polyunsaturated fatty acids as a risk and benefit of fish consumption to fetus. Environ Sci Technol 2004; 38(14):3860–3863.

    PubMed  CAS  Google Scholar 

  127. Cai J, Chen Y, Seth S, Furukawa S, Compans RW, Jones DP. Inhibition of influenza infection by glutathione. Free Radic Biol Med 2003; 34(7):928–936.

    PubMed  CAS  Google Scholar 

  128. Lante F, Meunier J, Guiramand J, Maurice T, Cavalier M, Jesus Ferreira MC, et al. Neurodevelopmental damage after prenatal infection: role of oxidative stress in the fetal brain. Free Radic Biol Med 2007; 42(8):1231–1245.

    PubMed  CAS  Google Scholar 

  129. Thorburne SK, Juurlink BH. Low glutathione and high iron govern the susceptibility of oligodendroglial precursors to oxidative stress. J Neurochem 1996; 67(3):1014–1022.

    PubMed  CAS  Google Scholar 

  130. Herbert MR. Autism: A brain disorder or a disorder that affects the brain. Clin Neuropsych 2005; 2:2354–2379.

    Google Scholar 

  131. Horvath K, Perman JA. Autistic disorder and gastrointestinal disease. Curr Opin Pediatr 2002; 14(5):583–587.

    PubMed  Google Scholar 

  132. Jyonouchi H, Sun SN, Itokazu N. Innate immunity associated with inflammatory responses and cytokine production against common dietary proteins in patients with autism spectrum disorder. Neuropsychobiology 2002; 46(2):76–84.

    PubMed  CAS  Google Scholar 

  133. Ashwood P, Murch SH, Anthony A, Pellicer AA, Torrente F, Thomson MA, et al. Intestinal lymphocyte populations in children with regressive autism: Evidence for extensive mucosal immunopathology. J Clin Immunol 2003; 23(6):504–517.

    PubMed  Google Scholar 

  134. Wakefield AJ, Ashwood P, Limb K, Anthony A. The significance of ileo-colonic lymphoid nodular hyperplasia in children with autistic spectrum disorder. Eur J Gastroenterol Hepatol 2005; 17(8):827–836.

    PubMed  Google Scholar 

  135. Shaw CA, Bains JS. Synergistic versus antagonistic actions of glutamate and glutathione: The role of excitotoxicity and oxidative stress in neuronal disease. Cell Mol Biol 2002; 48(2):127–136.

    PubMed  CAS  Google Scholar 

  136. Bains JS, Shaw CA. Neurodegenerative disorders in humans: The role of glutathione in oxidative stress-mediated neuronal death. Brain Res Brain Res Rev 1997; 25(3):335–358.

    PubMed  CAS  Google Scholar 

  137. Risher JF, Murray HE, Prince GR. Organic mercury compounds: Human exposure and its relevance to public health. Toxicol Ind Health 2002; 18(3):109–160.

    PubMed  CAS  Google Scholar 

  138. Finkelstein JD. Methionine metabolism in mammals. J Nutr Biochem 1990; 1:228–237.

    PubMed  CAS  Google Scholar 

  139. Mato JM, Corrales FJ, Lu SC, Avila MA. S-adenosylmethionine: A control switch that regulates liver function. FASEB J 2002; 16(1):15–26.

    PubMed  CAS  Google Scholar 

  140. Finkelstein JD. The metabolism of homocysteine: Pathways and regulation. Eur J Pediatr 1998; 157:S40–S44.

    PubMed  CAS  Google Scholar 

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  1. Arkansas Children’s Hospital Research Institute, 1120 Marshall St., Slot 512-40B, Little Rock, AR 72202, USA

    S. Jill James

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James, S.J. (2008). Oxidative Stress and the Metabolic Pathology of Autism. In: Autism. Current Clinical Neurology. Humana Press. https://doi.org/10.1007/978-1-60327-489-0_11

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