Abstract
Although genetic factors occupy an important place in the development of autism spectrum disorder (ASD), oxidative stress and exposure to environmental toxicants have also been linked to the condition. The aim of this study was to examine dynamic thiol/disulfide homeostasis in children diagnosed with ASD. Forty-eight children aged 3–12 years diagnosed with ASD and 40 age- and sex-matched healthy children were included in the study. A sociodemographic data form was completed for all the cases, and the Childhood Autism Rating Scale (CARS) was applied to the patients. Thiol/disulfide parameters in serum were measured in all cases and compared between the two groups. Mean native thiol, total thiol concentrations (μmol/L), and median reduced thiol ratios were significantly lower in the ASD group than in the control group (p = 0.001 for all). Median disulfide concentrations (μmol/L), redox potential, and median oxidized thiol ratios were significantly higher in the ASD group than in the control group (p = 0.001, p = 0.001, and p = 0.001, respectively). ROC analysis revealed that area under the curve (AUC) values with “excellent discriminatory potential,” for native thiol, total thiol, the reduced thiol ration, the oxidized thiol ratio, and redox potential and with “acceptable discriminatory potential” for disulfide were significantly capable of differentiating individuals with ASD from healthy individuals. No correlation was determined between the severity of autism and laboratory parameters. Impaired dynamic thiol/disulfide homeostasis was observed in children with ASD, suggesting that dynamic thiol/disulfide homeostasis in serum may be of diagnostic value in autism.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Adams JB, Baral M, Geis E, Mitchell J, Ingram J, Hensley A, Zappia I, Newmark S, Gehn E, Rubin RA, Mitchell K, Bradstreet J, El-Dahr JM (2009) The severity of autism is associated with toxic metal body burden and red blood cell glutathione levels. J Toxicol 2009:532640. https://doi.org/10.1155/2009/532640
Altun H, Şahin N, Kurutaş EB, Karaaslan U, Sevgen FH, Fındıklı E (2018) Assessment of malondialdehyde levels, superoxide dismutase, and catalase activity in children with autism spectrum disorders. Klinik Psikofarmakol Bülteni 28:408–415. https://doi.org/10.1080/24750573.2018.1470360
American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders (DSM-5®), 5th edn. American Psychiatric Pub, Arlington, VA
Anderson GM (2015) Autism biomarkers: challenges, pitfalls and possibilities. J Autism Dev Disord 45:1103–1113. https://doi.org/10.1007/s10803-014-2225-4
Asoğlu M, Kılıçaslan F, Beginoğlu Ö, Fedai l, Akıl Ö, Çelik H, Büyükaslan H (2017) Thiol/disulphide homeostasis as a new oxidative stress marker in untreated patients with generalized anxiety disorder. Anadolu Psikiyatri Derg 19:143–149. https://doi.org/10.5455/apd.261956
Autism Developmental Disabilities, Principal Monitoring Network Surveillance Year, I, (2014) Prevalence of Autism Spectrum Disorder Among Children Aged 8 Years — Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2010. MMWR Morb Mortal Wkly Rep 63:1–21
Avcil S, Uysal P, Avcil M, Alisik M, Bicer C (2017) Dynamic thiol/disulfide homeostasis in children with attention deficit hyperactivity disorder and its relation with disease subtypes. Compr Psychiatry 73:53–60. https://doi.org/10.1016/j.comppsych.2016.11.003
Chauhan A, Audhya T, Chauhan V (2012) Brain region-specific glutathione redox imbalance in autism. Neurochem Res 37:1681–1689. https://doi.org/10.1007/s11064-012-0775-4
Chen AF, Chen DD, Daiber A, Faraci FM, Li H, Rembold CM, Laher I (2012) Free radical biology of the cardiovascular system. Clin Sci (Lond) 123:73–91. https://doi.org/10.1042/cs20110562
Dichter GS, Felder JN, Green SR, Rittenberg AM, Sasson NJ, Bodfish JW (2012) Reward circuitry function in autism spectrum disorders. Soc Cogn Affect Neurosci 7:160–172. https://doi.org/10.1093/scan/nsq095
Efe A, Neşelioğlu S, Soykan A (2020) An Investigation of the Dynamic Thiol/Disulfide Homeostasis, As a Novel Oxidative Stress Plasma Biomarker, in Children With Autism Spectrum Disorders. Autism Res https://doi.org/10.1002/aur.2436
Erel O, Neselioglu S (2014) A novel and automated assay for thiol/disulphide homeostasis. Clin Biochem 47:326–332. https://doi.org/10.1016/j.clinbiochem.2014.09.026
Ernst M, Zametkin AJ, Matochik JA, Pascualvaca D, Cohen RM (1997) Low medial prefrontal dopaminergic activity in autistic children. Lancet 350:638. https://doi.org/10.1016/s0140-6736(05)63326-0
Frustaci A, Neri M, Cesario A, Adams JB, Domenici E, Dalla Bernardina B, Bonassi S (2012) Oxidative stress-related biomarkers in autism: systematic review and meta-analyses. Free Radic Biol Med 52:2128–2141. https://doi.org/10.1016/j.freeradbiomed.2012.03.011
Ghanizadeh A, Akhondzadeh S, Hormozi M, Makarem A, Abotorabi-Zarchi M, Firoozabadi A (2012) Glutathione-related factors and oxidative stress in autism, a review. Curr Med Chem 19:4000–4005. https://doi.org/10.2174/092986712802002572
Goldani AA, Downs SR, Widjaja F, Lawton B, Hendren RL (2014) Biomarkers in autism. Front. Psychiatry 5:1–13. https://doi.org/10.3389/fpsyt.2014.00100
Gormez V, Orengul AC, Ozer OF, Uzuner S, Selek S (2016) Thiol/Disulphide Homeostasis and Oxidative Stress Parameters in Children and Adolescents with Attention Deficit/ Hyperactivity Disorder. Anatol Clin 21. https://doi.org/10.21673/anadoluklin.2016.254221
Grossberg S, Kishnan D (2018) Neural Dynamics of Autistic Repetitive Behaviors and Fragile X Syndrome: Basal Ganglia Movement Gating and mGluR-Modulated Adaptively Timed Learning. Front Psychol 9:269. https://doi.org/10.3389/fpsyg.2018.00269
Gu F, Chauhan V, Chauhan A (2013) Impaired synthesis and antioxidant defense of glutathione in the cerebellum of autistic subjects: alterations in the activities and protein expression of glutathione-related enzymes. Free Radic Biol Med 65:488–496. https://doi.org/10.1016/j.freeradbiomed.2013.07.021
Guney E, Cetin FH, Alisik M, Tunca H, Tas Torun Y, Iseri E, Isik Taner Y, Cayci B, Erel O (2015) Attention Deficit Hyperactivity Disorder and oxidative stress: A short term follow up study. Psychiatry Res 229:310–317. https://doi.org/10.1016/j.psychres.2015.07.003
Heo JH, Han SW, Lee SK (2005) Free radicals as triggers of brain edema formation after stroke. Free Radic Biol Med 39:51–70. https://doi.org/10.1016/j.freeradbiomed.2005.03.035
Hosmer DW, Lemeshow S, Sturdivant RX (2013) Applied Logistic Regression. 3rd ed edn. John Wiley & Sons, New Jersey
Incekas Gassaloglu S, Baykara B, Avcil S, Demiral Y (2016) Validity and Reliability Analysis of Turkish Version of Childhood Autism Rating Scale. Turk Psikiyatri Derg 27:266–274
Iuga C, Alvarez-Idaboy JR, Vivier-Bunge A (2011) ROS initiated oxidation of dopamine under oxidative stress conditions in aqueous and lipidic environments. J Phys Chem B 115:12234–12246. https://doi.org/10.1021/jp206347u
Khramova TV, Kaysheva AL, Ivanov YD, Pleshakova TO, Iourov IY, Vorsanova SG, Yurov YB, Schetkin AA, Archakov AI (2017) Serologic Markers of Autism Spectrum Disorder. J Mol Neurosci 62:420–429. https://doi.org/10.1007/s12031-017-0950-9
Kulaksizoglu B, Kulaksizoglu S (2017) Thiol-Disulfide Homeostasis in Patients with Panic Disorder. Int J Clin Exp Med 08:34–41. https://doi.org/10.4236/ijcm.2017.81004
Lewis M, Kim SJ (2009) The pathophysiology of restricted repetitive behavior. J Neurodev Disord 1:114–132. https://doi.org/10.1007/s11689-009-9019-6
Lewis MH, Bodfish JW (1998) Repetitive behavior disorders in autism. Ment Retard Dev Disabil Res Rev 4:80–89
Main PA, Angley MT, O’Doherty CE, Thomas P, Fenech M (2012) The potential role of the antioxidant and detoxification properties of glutathione in autism spectrum disorders: a systematic review and meta-analysis. Nutr Metab (Lond) 9:35. https://doi.org/10.1186/1743-7075-9-35
Margis R, Dunand C, Teixeira FK, Margis-Pinheiro M (2008) Glutathione peroxidase family - an evolutionary overview. Febs j 275:3959–3970. https://doi.org/10.1111/j.1742-4658.2008.06542.x
Masi A, Glozier N, Dale R, Guastella AJ (2017) The Immune System, Cytokines, and Biomarkers in Autism Spectrum Disorder. Neurosci Bull 33:194–204. https://doi.org/10.1007/s12264-017-0103-8
Ming X, Stein TP, Brimacombe M, Johnson WG, Lambert GH, Wagner GC (2005) Increased excretion of a lipid peroxidation biomarker in autism. Prostaglandins Leukot Essent Fatty Acids 73:379–384. https://doi.org/10.1016/j.plefa.2005.06.002
Momeni N, Bergquist J, Brudin L, Behnia F, Sivberg B, Joghataei MT, Persson BL (2012) A novel blood-based biomarker for detection of autism spectrum disorders. Transl Psychiatry 2:e91. https://doi.org/10.1038/tp.2012.19
Napoli E, Wong S, Giulivi C (2013) Evidence of reactive oxygen species-mediated damage to mitochondrial DNA in children with typical autism. Mol Autism 4:2. https://doi.org/10.1186/2040-2392-4-2
Pop-Jordanova N, Plasevska-Karanfilska D (2014) Autism–genetics, electrophysiology and clinical syndromes. Pril (Makedon Akad Nauk Umet Odd Med Nauki) 35:133–146
Popa-Wagner A, Mitran S, Sivanesan S, Chang E, Buga AM (2013) ROS and brain diseases: the good, the bad, and the ugly. Oxid Med Cell Longev 2013:963520. https://doi.org/10.1155/2013/963520
Prakash M, Upadhya S, Prabhu R (2004) Protein thiol oxidation and lipid peroxidation in patients with uraemia. Scand J Clin Lab Invest 64:599–604. https://doi.org/10.1080/00365510410002869
Rose S, Melnyk S, Pavliv O, Bai S, Nick TG, Frye RE, James SJ (2012) Evidence of oxidative damage and inflammation associated with low glutathione redox status in the autism brain. Transl Psychiatry 2:e134. https://doi.org/10.1038/tp.2012.61
Rose S, Melnyk S, Trusty TA, Pavliv O, Seidel L, Li J, Nick T, James SJ (2012) Intracellular and extracellular redox status and free radical generation in primary immune cells from children with autism. Autism Res Treat 2012:986519. https://doi.org/10.1155/2012/986519
Sajdel-Sulkowska EM, Xu M, McGinnis W, Koibuchi N (2011) Brain region-specific changes in oxidative stress and neurotrophin levels in autism spectrum disorders (ASD). Cerebellum 10:43–48. https://doi.org/10.1007/s12311-010-0223-4
Schopler E, Reichler RJ, DeVellis RF, Daly K (1980) Toward objective classification of childhood autism: Childhood Autism Rating Scale (CARS). J Autism Dev Disord 10:91–103. https://doi.org/10.1007/bf02408436
Scott-Van Zeeland AA, Dapretto M, Ghahremani DG, Poldrack RA, Bookheimer SY (2010) Reward processing in autism. Autism Res 3:53–67. https://doi.org/10.1002/aur.122
Taurines R, Segura M, Schecklmann M, Albantakis L, Grunblatt E, Walitza S, Jans T, Lyttwin B, Haberhausen M, Theisen FM, Martin B, Briegel W, Thome J, Schwenck C, Romanos M, Gerlach M (2014) Altered peripheral BDNF mRNA expression and BDNF protein concentrations in blood of children and adolescents with autism spectrum disorder. J Neural Transm (Vienna) 121:1117–1128. https://doi.org/10.1007/s00702-014-1162-x
Teke H (2018) Dynamic thiol/disulphide homeostasis and oxidative stress parameters in children with autism spectrum disorder. Mersin University
Topcuoglu C, Bakirhan A, Yilmaz FM, Neselioglu S, Erel O, Sahiner SY (2017) Thiol/disulfide homeostasis in untreated schizophrenia patients. Psychiatry Res 251:212–216. https://doi.org/10.1016/j.psychres.2017.02.016
Zoroglu SS, Armutcu F, Ozen S, Gurel A, Sivasli E, Yetkin O, Meram I (2004) Increased oxidative stress and altered activities of erythrocyte free radical scavenging enzymes in autism. Eur Arch Psychiatry Clin Neurosci 254:143–147. https://doi.org/10.1007/s00406-004-0456-7
Acknowledgments
We would like to thank the patient and the patient’s family for allowing us to publish this article and Harran University Scientific Research Coordination Office.
Funding
This research was supported by the Harran University Scientific Research Coordination Office (protocol no. 17187 dated 08/12/2017).
Author information
Authors and Affiliations
Contributions
Concept: H.A., İ.K.; design: H.A., İ.K., H.Ç.; supervision: H.A., M.Ç., İ.K; materials: H.A., F.K., A.K., A.G.; data collection and/or processing: H.A., F.K., A.K., A.G.,; analysis and/or interpretation: H.A., İ.K., H.Ç., A.G.; literature review: H.A., F.K., A.K.; writing: H.A., F.K.; critical review: H.A., M.Ç., H.Ç.
Corresponding author
Ethics declarations
Competing Interests
The authors declare that they have no conflict of interest.
Ethics Approval and Consent to Participate
The study protocol was approved by the Harran University Medical Faculty Clinical Research Ethical Committee (session 04, decision 13, dated 6 April 2017). All subjects’ mothers and/or fathers read a volunteer information form and signed informed consent forms prior to participation.
Consent for Publication
Allowed for publication.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Ayaydın, H., Kılıçaslan, F., Koyuncu, İ. et al. Impaired Thiol/Disulfide Homeostasis in Children Diagnosed with Autism: A Case–Control Study. J Mol Neurosci 71, 1394–1402 (2021). https://doi.org/10.1007/s12031-021-01790-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-021-01790-1