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Impaired Redox Control in Autism Spectrum Disorders: Could It Be the X in GxE?

  • Complex Medical-Psychiatric Issues (M Riba, Section Editor)
  • Published:
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Abstract

Purpose of Review

This review aims to provide a brief description of the complex etiology of autism spectrum disorders (ASD), with special emphasis on the recent findings of impaired redox control in ASD, and to suggest a possible model of oxidative stress-specific gene-environment interaction in this group of disorders.

Recent Findings

Recent findings point out to the significance of environmental, prenatal, and perinatal factors in ASD but, at the same time, are in favor of the potentially significant oxidative stress-specific gene-environment interaction in ASD. Available evidence suggests an association between both the identified environmental factors and genetic susceptibility related to the increased risk of ASD and the oxidative stress pathway.

Summary

There might be a potentially significant specific gene-environment interaction in ASD, which is associated with oxidative stress. Revealing novel susceptibility genes (including those encoding for antioxidant enzymes), or environmental factors that might increase susceptibility to ASD in carriers of a specific genotype, might enable the stratification of individuals more prone to developing ASD and, eventually, the possibility of applying preventive therapeutic actions.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Washington DC: American Psychiatric Association; 2013.

    Book  Google Scholar 

  2. Christensen DL, Baio J, Van Naarden BK, Bilder D, Charles J, Constantino JN, et al. Prevalence and characteristics of autism spectrum disorder among children aged 8 years—autism and developmental disabilities monitoring network, 11 sites, United States, 2012. MMWR Surveill Summ. 2016;65(SS-3):1–23.

    Article  PubMed  Google Scholar 

  3. Lai MC, Lombardo MV, Auyeung B, Chakrabarti B, Baron-Cohen S. Sex/gender differences and autism: setting the scene for future research. J Am Acad Child Adolesc Psychiatry. 2015;54(1):11–24.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Jensen CM, Steinhausen HC, Lauritsen MB. Time trends over 16 years in incidence-rates of autism spectrum disorders across the lifespan based on nationwide Danish register data. J Autism Dev Disord. 2014;44(8):1808–18. doi:10.1007/s10803-014-2053-6.

    Article  PubMed  Google Scholar 

  5. Baron-Cohen S, Knickmeyer RC, Belmonte MK. Sex differences in the brain: implications for explaining autism. Science. 2005;310(5749):819–23.

    Article  CAS  PubMed  Google Scholar 

  6. Mandic-Maravic V, Pejovic-Milovancevic M, Mitkovic-Voncina M, Kostic M, Aleksic-Hil O, Radosavljev-Kircanski J, et al. Sex differences in autism spectrum disorders: does sex moderate the pathway from clinical symptoms to adaptive behavior? Sci Rep. 2015;5:10418.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Dworzynski K, Ronald A, Bolton P, Happé F. How different are girls and boys above and below the diagnostic threshold for autism spectrum disorders? J Am Acad Child Adolesc Psychiatry. 2012;51(8):788–97.

    Article  PubMed  Google Scholar 

  8. Burstyn I, Sithole F, Zwaigenbaum L. Autism spectrum disorders, maternal characteristics and obstetric complications among singletons born in Alberta, Canada. Chronic Dis Can. 2010;30(4):125–34.

    CAS  PubMed  Google Scholar 

  9. Hertz-Picciotto I, Delwiche L. The rise in autism and the role of age at diagnosis. Epidemiology. 2009;20(1):84–90. doi:10.1097/EDE.0b013e3181902d15.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Fisch GS. Autism and epistemology III: child development, behavioral stability, and reliability of measurement. Am J Med Genet A. 2012;158A(5):969–79. doi:10.1002/ajmg.a.35269.

    Article  PubMed  Google Scholar 

  11. Hansen SN, Schendel DE, Parner ET. Explaining the increase in the prevalence of autism spectrum disorders: the proportion attributable to changes in reporting practices. JAMA Pediatr. 2015;169(1):56–62.

    Article  PubMed  Google Scholar 

  12. Volk HE, Lurmann F, Penfold B, Hertz-Picciotto I, McConnell R. Traffic-related air pollution, particulate matter, and autism. JAMA Psychiatry. 2013;70(1):71–7.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Perera FP, Whyatt R, Hoepner L, Wang S, Camann D, Rauh V. Prenatal airborne polycyclic aromatic hydrocarbon exposure and child IQ at age 5 years. Pediatrics. 2009;124(2):e195–202. doi:10.1542/peds.2008-3506 94.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Kong A, Frigge ML, Masson G, Besenbacher S, Sulem P, Magnusson G, et al. Rate of de novo mutations and the importance of father’s age to disease risk. Nature. 2012;488:471–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sandin S, Schendel D, Magnusson P, Hultman C, Surén P, Susser E, et al. Autism risk associated with parental age and with increasing difference in age between the parents. Mol Psychiatry. 2016;21(5):693–700.

  16. Chauhan A, Chauhan V. Oxidative stress in autism. Pathophysiology. 2006;13(3):171–81.

    Article  CAS  PubMed  Google Scholar 

  17. Menezo YJ, Elder K, Dale B. Link between increased prevalence of autism spectrum disorder syndromes and oxidative stress, DNA methylation, and imprinting: the impact of the environment. JAMA Pediatr. 2015;169(11):1066–7. doi:10.1001/jamapediatrics.2015.2125.

    Article  PubMed  Google Scholar 

  18. Ghanizadeh A, Akhondzadeh S, Hormozi M, Makarem A, Abotorabi-Zarchi M, Firoozabadi A. Glutathione-related factors and oxidative stress in autism, a review. Curr Med Chem. 2012;19(23):4000–5.

    Article  CAS  PubMed  Google Scholar 

  19. Frustaci A, Neri M, Cesario A, Adams JB, Domenici E, Dalla Bernardina B, et al. Oxidative stress-related biomarkers in autism: systematic review and meta-analyses. Free Radic Biol Med. 2012;52(10):2128–41. doi:10.1016/j.freeradbiomed.2012.03.011.

    Article  CAS  PubMed  Google Scholar 

  20. Tordjman S, Somogyi E, Coulon N, Kermarrec S, Cohen D, Bronsard G. Gene×environment interactions in autism spectrum disorders: role of epigenetic mechanisms. Front Psychiatry. 2014;5:53. doi:10.3389/fpsyt.2014.00053.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Constantino JN, Zhang Y, Frazier T, Abbacchi AM, Law P. Sibling recurrence and the genetic epidemiology of autism. Am J Psychiatry. 2010;167:1349–56.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Yin J, Schaaf CP. Autism genetics—an overview. Prenat Diagn. 2017;37(1):14–30. doi:10.1002/pd.4942.

    Article  PubMed  Google Scholar 

  23. Devlin B, Scherer SW. Genetic architecture in autism spectrum disorder. Curr Opin Genet Dev. 2012;22(3):229–37. doi:10.1016/j.gde.2012.03.002.

    Article  CAS  PubMed  Google Scholar 

  24. Milovančević MP, Vešić M, Jelisavčić M, Nikšić S, Pilić GR, Maravić VM. Family paracentric inversion of the short arm of chromosome X (Xp21.2p11.23) and connection with autism spectrum disorders. Srp Arh Celok Lek. 2012;140(11–12):760–4.

    PubMed  Google Scholar 

  25. Klei L, Sanders SJ, Murtha MT, Hus V, Lowe JK, Willsey AJ, et al. Common genetic variants, acting additively, are a major source of risk for autism. Mol Autism. 2012;3(1):9. doi:10.1186/2040-2392-3-9.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Tammimies K, Marshall CR, Walker S, Kaur G, Thiruvahindrapuram B, Lionel AC, et al. Molecular diagnostic yield of chromosomal microarray analysis and whole-exome sequencing in children with autism spectrum disorder. JAMA. 2015;314(9):895–903. doi:10.1001/jama.2015.10078.

    Article  CAS  PubMed  Google Scholar 

  27. Koufaris C, Sismani C. Modulation of the genome and epigenome of individuals susceptible to autism by environmental risk factors. Int J Mol Sci. 2015;16(4):8699–718.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lyall K, Schmidt RJ, Hertz-Picciotto I. Maternal lifestyle and environmental risk factors for autism spectrum disorders. Int J Epidemiol. 2014;43(2):443–64. doi:10.1093/ije/dyt282.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Kalkbrenner AE, Schmidt RJ, Penlesky AC. Environmental chemical exposures and autism spectrum disorders: a review of the epidemiological evidence. Curr Probl Pediatr Adolesc Health Care. 2014;44(10):277–318.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Christensen J, Gronborg TK, Sorensen MJ, Schendel D, Parner ET, Pedersen LH, et al. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA. 2013;309:1696–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ornoy A, Weinstein-Fudim L, Ergaz Z. Prenatal factors associated with autism spectrum disorder (ASD). Reprod Toxicol. 2015;56:155–69. doi:10.1016/j.reprotox.2015.05.007.

    Article  CAS  PubMed  Google Scholar 

  32. Stromland K, Nordin V, Miller M, Akerstrom B, Gillberg C. Autism in thalidomide embryopathy: a population study. Dev Med Child Neurol. 1994;36:351–6.

    Article  CAS  PubMed  Google Scholar 

  33. • Kubota T, Mochizuki K, et al. Int J Environ Res Public Health. 2016;13:504. doi:10.3390/ijerph13050504. This review emphasizes the gene-environment interplay, introduces the term epigenetic inheritance, and points out to therapeutic possibilities which can reverse the epigenetic changes

    Article  PubMed Central  Google Scholar 

  34. De Felice A, Greco A, Calamandrei G, Minghetti L. Prenatal exposure to the organophosphate insecticide chlorpyrifos enhances brain oxidative stress and prostaglandin E2 synthesis in a mouse model of idiopathic autism. J Neuroinflammation. 2016;13(1):149. doi:10.1186/s12974-016-0617-4.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Volk HE, Hertz-Picciotto I, Delwiche L, Lurmann F, McConnell R. Residential proximity to freeways and autism in the CHARGE study. Environ Health Perspect. 2011;119(6):873–7.

    Article  PubMed  Google Scholar 

  36. Costa LG, Cole TB, Coburn J, Chang YC, Dao K, Roqué PJ. Neurotoxicity of traffic-related air pollution. Neurotoxicology. 2015;S0161-813X(15):30024–3. doi:10.1016/j.neuro.2015.11.008.

    Google Scholar 

  37. Volk HE, Kerin T, Lurmann F, Hertz-Picciotto I, McConnell R, Campbell DB. Autism spectrum disorder: interaction of air pollution with the MET receptor tyrosine kinase gene. Epidemiology. 2014;25(1):44–7.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Sealey LA, Hughes BW, Sriskanda AN, Guest JR, Gibson AD, Johnson-Williams L, et al. Environmental factors in the development of autism spectrum disorders. Environ Int. 2016;88:288–98. doi:10.1016/j.envint.2015.12.021.

    Article  CAS  PubMed  Google Scholar 

  39. Ornoy A, Weinstein- Fudim L, Ergaz Z. Genetic syndromes, maternal diseases and antenatal factors associated with autism spectrum disorders (ASD). Front Neurosci. 2016;10:316. doi:10.3389/fnins.2016.00316.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Roberts AL, Lyall K, Hart JE, Laden F, Just AC, Bobb JF, et al. Perinatal air pollutant exposures and autism spectrum disorder in the children of Nurses’ Health Study II participants. Environ Health Perspect. 2013;121:978–84.

    PubMed  PubMed Central  Google Scholar 

  41. Dickerson AS, Rahbar MH, Bakian AV, Bilder DA, Harrington RA, Pettygrove S, et al. Autism spectrum disorder prevalence and associations with air concentrations of lead, mercury, and arsenic. Environ Monit Assess. 2016;188(7):407. doi:10.1007/s10661-016-5405-1.

    Article  PubMed  Google Scholar 

  42. Yau VM, Green PG, Alaimo CP, Yoshida CK, Lutsky M, Windham GC, et al. Prenatal and neonatal peripheral blood mercury levels and autism spectrum disorders. Environ Res. 2014;133:294–303.

    Article  CAS  PubMed  Google Scholar 

  43. van Wijngaarden E, Davidson PW, Smith TH, Evans K, Yost K, Love T, et al. Autism spectrum disorder phenotypes and prenatal exposure to methylmercury. Epidemiology. 2013;24(5):651–9. doi:10.1097/EDE.0b013e31829d2651.

  44. Guinchat V, Thorsen P, Laurent C, Cans C, Bodeau N, Cohen D. Pre-, peri- and neonatal risk factors for autism. Acta Obstet Gynecol Scand. 2012;91(3):287–300.

    Article  PubMed  Google Scholar 

  45. Duan G, Yao M, Ma Y, Zhang W. Perinatal and background risk factors for childhood autism in central China. Psychiatry Res. 2014;220(1–2):410–7.

    Article  PubMed  Google Scholar 

  46. Maramara LA, He W, Ming X. Pre- and perinatal risk factors for autism spectrum disorder in a New Jersey cohort. J Child Neurol. 2014;29(12):1645–51.

    Article  PubMed  Google Scholar 

  47. Mamidala MP, Polinedi A, PK PTV, Rajesh N, Vallamkonda OR, Udani V, et al. Prenatal, perinatal and neonatal risk factors of autism spectrum disorder: a comprehensive epidemiological assessment from India. Res Dev Disabil. 2013;34(9):3004–13.

    Article  PubMed  Google Scholar 

  48. Krakowiak P, Walker CK, Bremer AA, Baker AS, Ozonoff S, Hansen RL, et al. Maternal metabolic conditions and risk for autism and other neurodevelopmental disorders. Pediatrics. 2012;129(5):e1121–8.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Guy A, Seaton SE, Boyle EM, Draper ES, Field DJ, Manktelow BN, et al. Infants born late/moderately preterm are at increased risk for a positive autism screen at 2 years of age. J Pediatr. 2015;166:269–275, e263. doi:10.1016/j.jpeds.2014.10.053.

  50. Hultman CM, Sandin S, Levine SZ, Lichtenstein P, Reichenberg A. Advancing paternal age and risk of autism: new evidence from a population-based study and a meta-analysis of epidemiological studies. Mol Psychiatry. 2011;16(12):1203–12. doi:10.1038/mp.2010.121.

    Article  CAS  PubMed  Google Scholar 

  51. Back SA, Miller SP. Brain injury in premature neonates: a primary cerebral dysmaturation disorder? Ann Neurol. 2014;75:469–86.

    Article  PubMed  Google Scholar 

  52. •• van Tilborg E, Heijnen CJ, Benders MJ, van Bel F, Fleiss B, Gressens P, et al. Impaired oligodendrocyte maturation in preterm infants: potential therapeutic targets. Prog Neurobiol. 2016;136:28–49. doi:10.1016/j.pneurobio.2015.11.002. The study emphasizes the connection between preterm birth as a perinatal complication, diffuse white matter brain injury, oxidative stress, and sequent cognitive and behavioral problems in preterm children.

  53. Maimburg RD, Vaeth M, Schendel DE, Bech BH, Olsen J, Thorsen P. Neonatal jaundice: a risk factor for infantile autism? Paediatr Perinat Emidemiol. 2008;22(6):562–8.

    Article  Google Scholar 

  54. Maimburg RD, Bech BH, Vaeth M, Moller-Madsen B, Olsen J. Neonatal jaundice, autism, and other disorders of psychological development. Pediatrics. 2010;126(5):872–8.

    Article  PubMed  Google Scholar 

  55. Zhang X, Lv CC, Tian J, Miao RJ, Xi W, Hertz-Picciotto I, et al. Prenatal and perinatal risk factors for autism in China. J Autism Dev Disord. 2010;40(11):1311–21.

  56. Basu S, De D, Dev Khanna H, Kumar A. Lipid peroxidation, DNA damage and total antioxidant status in neonatal hyperbilirubinemia. J Perinatol. 2014;34(7):519–23. doi:10.1038/jp.2014.45.

    Article  CAS  PubMed  Google Scholar 

  57. • Altuner Torun Y, Ertural U, Ergul AB, Karakukcu C, Akin MA. Reduction in serum paraoxonase level in newborns with hyperbilirubinemia as a marker of oxidative stress. J Matern Fetal Neonatal Med. 2016;1–4. doi:10.1080/14767058.2016.1247154. The study shows markers of oxidative stress: decreased level of serum paraoxonase and increased level of malondialdehyde in newborns with hyperbilirubinaemia, a known perinatal factor increasing the risk of ASD.

  58. Schmidt RJ, Hansen RL, Hartiala J, Allayee H, Schmidt LC, Tancredi DJ, et al. Prenatal vitamins, one-carbon metabolism gene variants, and risk for autism. Epidemiology. 2011;22(4):476–85.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Schmidt RJ, Tancredi DJ, Ozonoff S, Hansen RL, Hartiala J, Allayee H, et al. Maternalpericonceptional folic acid intake and risk of autism spectrum disorders and developmental delay in the CHARGE (Childhood Autism Risks from Genetics and Environment) case-control study. Am J Clin Nutr. 2012;96(1):80–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Sun C, Zou M, Zhao D, Xia W, Wu L. Efficacy of folic acid supplementation in autistic children participating in structured teaching: an open-label trial. Nutrients. 2016;8(6). doi:10.3390/nu8060337.

  61. Glasson EJ, Bower C, Petterson B, de Klerk N, Chaney G, Hallmayer JF. Perinatal factors and the development of autism: a population study. Arch Gen Psychiatry. 2004;61(6):618–27.

    Article  PubMed  Google Scholar 

  62. Rossignol DA, Frye RE. Evidence linking oxidative stress, mitochondrial dysfunction, and inflammation in the brain of individuals with autism. Front Physiol. 2014;22:5–150. doi:10.3389/fphys.2014.00150.

    Google Scholar 

  63. Castejon AM, Spaw JA. Autism and oxidative stress interventions: impact on autistic behavior. Austin J Pharmacol Ther. 2014;2(2):1015.

    Google Scholar 

  64. Jones DP. Redefining oxidative stress. Antioxid Redox Signal. 2006;8(9–20):1865–79.

    Article  CAS  PubMed  Google Scholar 

  65. Ali FT, Abd El-Azeem EM, Hamed MA, Ali MA, Abd Al-Kader NM, Hassan EA. Redox dysregulation, immuno-inflammatory alterations and genetic variants of BDNF and MMP-9 in schizophrenia: pathophysiological and phenotypic implications. Schizophr Res. 2017. doi:10.1016/j.schres.2017.01.016.

  66. Kim HK, Andreazza AC, Elmi N, Chen W, Young LT. Nod-like receptor pyrin containing 3 (NLRP3) in the post-mortem frontal cortex from patients with bipolar disorder: a potential mediator between mitochondria and immune-activation. J Psychiatr Res. 2016;72:43–50. doi:10.1016/j.jpsychires.2015.10.015.

  67. Black CN, Bot M, Scheffer PG, Cuijpers P, Penninx BW. Is depression associated with increased oxidative stress? A system review and meta-analysis. Psychoneuroendocrinology. 2015;51:164–75.

    Article  CAS  PubMed  Google Scholar 

  68. Pejovic-Milovancevic MM, Mandic-Maravic VD, Coric VM, Mitkovic-Voncina MM, Kostic MV, Savic-Radojevic AR, et al. Glutathione S-transferase deletion polymorphisms in early-onset psychotic and bipolar disorders: a case-control study. Lab Med. 2016;47(3):195–204.

    Article  PubMed  Google Scholar 

  69. Parellada M, Moreno C, Mac-Dowell K, Leza JC, Giraldez M, Bailón C, et al. Plasma antioxidant capacity is reduced in Asperger syndrome. J Psychiatr Res. 2012;46:394–401.

    Article  PubMed  Google Scholar 

  70. Linseman AD. Targeting oxidative stress for neuroprotection. Antioxid Redox Signal. 2009;11:421–3.

    Article  CAS  PubMed  Google Scholar 

  71. Davies KJA. Protein damage and degradation by oxygen free radicals. II modification of amino acids. J Biol Chem. 1987;262:9902–7.

    CAS  PubMed  Google Scholar 

  72. Feng C, Chen Y, Pan J, Yang A, Niu L, Min J, et al. Redox proteomic identification of carbonylated proteins in autism plasma: insight into oxidative stress and its related biomarkers in autism. Clin Proteom. 2017;14:2. doi:10.1186/s12014-017-9138-0.

    Article  Google Scholar 

  73. Finkel T, Holbrook NJ. Oxidants, oxidative stress and the biology of ageing. Nature. 2000;408:239–47.

    Article  CAS  PubMed  Google Scholar 

  74. Juurlink BH, Thorburne SK, Hertz L. Peroxide-scavenging deficit underlies oligodendrocyte susceptibility to oxidative stress. Glia. 1998;22(4):371–8.

    Article  CAS  PubMed  Google Scholar 

  75. Devi PU, Manocha A, Vohora D. Seizures, antiepileptics, antioxidants and oxidative stress: an insight for researchers. Expert Opin Pharmacother. 2008;9:3169–77.

    Article  CAS  PubMed  Google Scholar 

  76. Ono H, Sakamoto A, Sakura N. Plasma total glutathione concentrations in healthy pediatric and adult subjects. Clin Chim Acta. 2001;312(1–2):227–9.

    Article  CAS  PubMed  Google Scholar 

  77. Erden-Inal M, Sunal E, Kanbak G. Age-related changes in the glutathione redox system. Cell Biochem Funct. 2002;20(1):61–6.

    Article  CAS  PubMed  Google Scholar 

  78. Jain SK. The accumulation of malonyldialdehyde, a product of fatty acid peroxidation, can disturb aminophospholipid organization in the membrane bilayer of human erythrocytes. J Biol Chem. 1984;25:3391–4.

    Google Scholar 

  79. Chauhan A, Chauhan V, Brown WT, Cohen IL. Oxidative stress in autism: increased lipid peroxidation and reduced serum levels of ceruloplasmin and transferrin—the antioxidant proteins. Life Sci. 2004;75:2539–49.

    Article  CAS  PubMed  Google Scholar 

  80. Zorŏglu 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;254:143–7.

  81. 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;73:379–84.

    Article  CAS  PubMed  Google Scholar 

  82. Sogut S, Zoroglu SS, Ozyurt H, Yilmaz HR, Ozugurlu F, et al. Changes in nitric oxide levels and antioxidant enzyme activities may have a role in the pathophysiological mechanisms involved in autism. Clin Chim Acta. 2003;331:111–7.

    Article  CAS  PubMed  Google Scholar 

  83. Al-Gadani Y, El-Ansary A, Attas O, Al-Ayadhi L. Metabolic biomarkers related to oxidative stress and antioxidant status in Saudi autistic children. Clin Biochem. 2009;42:1032–40.

    Article  CAS  PubMed  Google Scholar 

  84. Yaki K. Lipid peroxides and related radicals in clinical medicine. In: Armstrong D, editor. Free radicals in diagnostic medicine. New York: Plenum; 1999. p. 1–14.

    Google Scholar 

  85. Sajdel-Sulkowska EM, Xu M, Koibuchi N. Increase in cerebellar neurotrophin-3 and oxidative stress markers in autism. Cerebellum. 2009;8(3):366–72.

    Article  CAS  PubMed  Google Scholar 

  86. Napoli E, Wong S, Giulivi C. Evidence of reactive oxygen species-mediated damage to mitochondrial DNA in children with typical autism. Mol Autism. 2013;4:2. doi:10.1186/2040-2392-4-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Shpyleva S, Ivanovsky S, de Conti A, Melnyk S, Tryndyak V, Beland FA, et al. Cerebellar oxidative DNA damage and altered DNA methylation in the BTBR T+tf/J mouse model of autism and similarities with human post mortem cerebellum. PLoS One. 2014;9(11):e113712. doi:10.1371/journal.pone.0113712.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Markkanen E, Meyer U, Dianov G. DNA damage and repair in schizophrenia and autism: implications for cancer comorbidity and beyond. Int J Mol Sci. 2016;17(6):856.

    Article  PubMed Central  Google Scholar 

  89. • Dasdemir S, Guven M, Pekkoc KC, Ulucan H, Dogangun B, Kirtas E, et al. DNA repair gene XPD Asp312Asn and XRCC4 G-1394T polymorphisms and the risk of autism spectrum disorder. Cell Mol Biol. 2016;62(3):46–50. The study shows an association of specific DNA repair gene polymorphism and ASD (XRCC4-1394 T/G+G/G genotypes, implicating the genetic basis of impaired redox imbalance in ASD.

    CAS  PubMed  Google Scholar 

  90. Uchida K, Kawakishi S. Identification of oxidized histidine generated at the active site of Cu, Zn-superoxide dismutase exposed to H2O2. Selective generation of 2-oxo-histidine at the histidine 118. J Biol Chem. 1994;269:2405–10.

    CAS  PubMed  Google Scholar 

  91. • Wang L, Jia J, Zhang J, Li K. Serum levels of SOD and risk of autism spectrum disorder: a case-control study. Int J Dev Neurosci. 2016;5:12–6. A case-control study showing the levels of serum superoxide-dismutase were significantly lower in ASD subject compared to healthy controls, and inversely correlated with severity of clinical manifestations.

    Article  Google Scholar 

  92. Vergani L, Lanza C, Rivaro P, Abelmoschi ML, Genti S, Veneselli E, et al. Metals, metallothioneins and oxidative stress in blood of autistic children. Res Autism Spectrum Disord. 2011;5:286–93.

    Article  Google Scholar 

  93. Meguid NA, Dardir AA, Abdel-Raouf ER, Hashish A. Evaluation of oxidative stress in autism: defective antioxidant enzymes and increased lipid peroxidation. Biol Trace Elem Res. 2011;143:58–65.

    Article  CAS  PubMed  Google Scholar 

  94. Takakhashi K, Avissar N, Whitin J, Cohen H. Purification and characterization of human plasma glutathione peroxidase: a selenoglycoprotein distinct from the known cellular enzyme. Arch Biochem Biophys. 1987;256:677–86.

    Article  Google Scholar 

  95. Whitin JC, Bhamre S, Tham DM, Cohen HJ. Extracellular glutathione peroxidaseis secreted basolateraly by human renal proximal tubule cells. Am J Physiol Renal Physiol. 2002;283:F20–8.

    Article  CAS  PubMed  Google Scholar 

  96. Dringen R. Metabolism and function of glutathione in brain. Prog Neurobiol. 2000;62:649–71.

    Article  CAS  PubMed  Google Scholar 

  97. Schulz JB, Lindenau J, Seyfried J, Dichgans J. Glutathione, oxidative stress and neurodegeneration. Eur J Biochem. 2000;267:4904–11.

    Article  CAS  PubMed  Google Scholar 

  98. Mostafa GA, El-Hadidi ES, Hewedi DH, Abdou MM. Oxidative stress in Egyptian children with autism: relation to autoimmunity. J Neuroimmunol. 2010;219:114–8.

    Article  CAS  PubMed  Google Scholar 

  99. Hayes JD, Flanaquan JU, Jowsey IR. Glutathione S-transferases. Annu Rev Pharmacol Toxicol. 2005;45:51–8.

    Article  CAS  PubMed  Google Scholar 

  100. Ercegovac M, Jovic N, Sokic D, Savic-Radojevic A, Coric V, Radic T, et al. GSTA1, GSTM1, GSTP1 and GSTT1 polymorphisms in progressive myoclonus epilepsy: a Serbian case-control study. Seizure. 2015;32:30–6.

  101. •• Rahbar MH, Samms-Vaughan M, Ma J, Bressler J, Dickerson AS, Hessabi M, et al. Synergic effect of GSTP1 and blood manganese concentrations in autism spectrum disorder. Res Autism Spectr Disord. 2015;18:73–82. Study demonstrating a role of gene-environment interaction regarding the system of oxidative stress in ASD. The authors have shown a possible synergistic effect of blood manganese concentration and GSTP1 polymorphism in ASD.

  102. Weikang C, Jie L, Likang L, Weiwen Q, Liping L. A meta-analysis of association between glutathione S-transferase M1 gene polymorphism and Parkinson’s disease susceptibility. Open Med. 2016;11:578–83. doi:10.1515/med-2016-0094.

  103. Landi S. Mammalian class theta GST and differential susceptibility to carcinogens: areview. Mutat Res. 2000;463:247–83.

    Article  CAS  PubMed  Google Scholar 

  104. Williams TA, Mars AE, Buyske SG, et al. Risk of autistic disorder in affected offspringof mothers with a glutathione S-transferase P1 haplotype. Arch Pediatr Adolesc Med. 2007;161(4):356–61.

    PubMed  Google Scholar 

  105. •• Rahbar MH, Samms-Vaughan M, Pitcher MR, Bressler J, Hessabi M, Loveland KA, et al. Role of metabolic genes in blood aluminum concentrations of Jamaican children with and without autism spectrum disorder. Int J Environ Res Public Health. 2016;13(11). doi:10.3390/ijerph13111095. The study showed a possible modifying effect of ASD status on the association between GSTP1 rs1695 and blood aluminum concentrations in Jamaican children.

  106. Alabdali A, Al-Ayadhi L, El-Ansary A. A key role for an impaired detoxification mechanism in the etiology and severity of autism spectrum disorders. Behav Brain Funct. 2014;10:14. doi:10.1186/1744-9081-10-14.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Walker CK, Anderson KW, Milano KM, Ye S, Tancredi DJ, Pessah IN, et al. Trophoblast inclusions are significantly increased in the placentas of children in families at risk for autism. Biol Psychiatry. 2013;74(3):204–11.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Schroeder DI, Schmidt RJ, Crary-Dooley FK, Walker CK, Ozonoff S, Tancredi DJ, et al. Placental methylome analysis from a prospective autism study. Mol Autism. 2016;7:51.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Matelski L, Van de Water J. Risk factors in autism: thinking outside the brain. J Autoimmun. 2016;67:1–7.

    Article  PubMed  Google Scholar 

  110. Ishii S, Hashimoto-Torii K. Impact of prenatal environmental stress on cortical development. Front Cell Neurosci. 2015;9:207.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Wu H, Wang X, Gao J, Liang S, Hao Y, Sun C, et al. Fingolimod (FTY720) attenuates social deficits, learning and memory impairments, neuronal loss and neuroinflammation in the rat model of autism. Life Sci. 2017;S0024-3205(17):30036-X. doi:10.1016/j.lfs.2017.01.012.

    Google Scholar 

  112. Bhandari R, Kuhad A. Resveratrol suppresses neuroinflammation in the experimental paradigm of autism spectrum disorders. Neurochem Int. 2017;103:8–23.

    Article  CAS  PubMed  Google Scholar 

  113. Dean OM, Gray KM, Villagonzalo KA, Dodd S, Mohebbi M, Vick T, et al. A randomised, double blind, placebo-controlled trial of a fixed dose of N-acetyl cysteine in children with autistic disorder. Aust N Z J Psychiatry 2016.

  114. Wink LK, Adams R, Wang Z, Klaunig JE, Plawecki MH, Posey DJ, et al. A randomized placebo-controlled pilot study of N-acetylcysteine in youth with autism spectrum disorder. Mol Autism. 2016;7:26. doi:10.1186/s13229-016-0088-6.

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Institute of Mental Health, Palmotićeva 37, 11000 Belgrade, Serbia

    Vanja Mandic-Maravic, Marija Mitkovic-Voncina, Dusica Lecic-Tosevski & Milica Pejovic-Milovancevic

  2. Institute for Medical and Clinical Biochemistry, Belgrade, Serbia

    Marija Pljesa-Ercegovac, Ana Savic-Radojevic & Tatjana Simic

  3. Faculty of Medicine, University of Belgrade, Belgrade, Serbia

    Marija Pljesa-Ercegovac, Marija Mitkovic-Voncina, Ana Savic-Radojevic, Dusica Lecic-Tosevski, Tatjana Simic & Milica Pejovic-Milovancevic

  4. Serbian Academy of Sciences and Arts, Belgrade, Serbia

    Dusica Lecic-Tosevski

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  1. Vanja Mandic-Maravic
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  2. Marija Pljesa-Ercegovac
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  7. Milica Pejovic-Milovancevic
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Correspondence to Milica Pejovic-Milovancevic.

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Vanja Mandic-Maravic, Marija Pljesa-Ercegovac, Marija Mitkovic-Voncina, Ana Savic-Radojevic, Dusica Lecic-Tosevski, Tatjana Simic, and Milica Pejovic-Milovancevic each declare no potential conflicts of interest.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is part of the Topical Collection on Complex Medical-Psychiatric Issues

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Mandic-Maravic, V., Pljesa-Ercegovac, M., Mitkovic-Voncina, M. et al. Impaired Redox Control in Autism Spectrum Disorders: Could It Be the X in GxE?. Curr Psychiatry Rep 19, 52 (2017). https://doi.org/10.1007/s11920-017-0799-1

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  • DOI: https://doi.org/10.1007/s11920-017-0799-1

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