Autism Spectrum Disorders and Perinatal Complications-Is Oxidative Stress the Connection?

Vanja Mandic-Maravic; Marija Mitkovic-Voncina; Marija Pljesa-Ercegovac; Ana Savic-Radojevic; Miroslav Djordjevic; Tatjana Pekmezovic; Roberto Grujicic; Marko Ercegovac; Tatjana Simic; Dusica Lecic-Tosevski; Milica Pejovic-Milovancevic

doi:10.3389/fpsyt.2019.00675

Autism Spectrum Disorders and Perinatal Complications-Is Oxidative Stress the Connection?

Front Psychiatry. 2019 Sep 25:10:675. doi: 10.3389/fpsyt.2019.00675. eCollection 2019.

Authors

Vanja Mandic-Maravic^{1

2}, Marija Mitkovic-Voncina^{1

2}, Marija Pljesa-Ercegovac^{2

3}, Ana Savic-Radojevic^{2

3}, Miroslav Djordjevic^{2

4}, Tatjana Pekmezovic^{2

5}, Roberto Grujicic¹, Marko Ercegovac², Tatjana Simic^{2

3

6}, Dusica Lecic-Tosevski^{1

6}, Milica Pejovic-Milovancevic^{1

2}

Affiliations

¹ Institute of Mental Health, Belgrade, Serbia.
² Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
³ Institute of Medical and Clinical Biochemistry, Belgrade, Serbia.
⁴ University Children's Hospital, Belgrade, Serbia.
⁵ Institute of Epidemiology, Belgrade, Serbia.
⁶ Serbian Academy of Sciences and Arts, Belgrade, Serbia.

Abstract

Background: Autism spectrum disorders (ASD) are complex psychiatric disorders, with gene environment interaction being in the basis of their etiology. The association of perinatal complications and ASD is well established. Recent findings suggested that oxidative stress and polymorphism in genes encoding antioxidant enzymes might be involved in the development of ASD. Glutathione transferases (GSTs) have an important role in the antioxidant defense system. We aimed to establish whether the predictive effects of prenatal and perinatal complications (as possible oxidative stress inducers) on ASD risk are dependent on GST polymorphisms. Methods: The study included 113 ASD cases and 114 age- and sex group-matched healthy controls. All participants were genotyped for GSTA1, GSTM1, GSTT1, and GSTP1 polymorphisms. The questionnaire regarding prenatal and perinatal risk factors and complications was administered for all the subjects in the study. Results: The evaluated perinatal complications as a group significantly increased the risk of ASD [odds ratio (OR) = 9.415; p = 0.000], as well as individual perinatal complications, such as prematurity (OR = 11.42; p = 0.001), neonatal jaundice (OR = 8.774; p = 0.000), respiratory distress syndrome (OR = 4.835; p = 0.047), and the use of any medication during pregnancy (OR = 2.413; p = 0.03). In logistic regression model, adding GST genotypes did not modify the significant effects found for prematurity and neonatal jaundice as risk factors in ASD. However, there was a significant interaction of GST genotype with medication use during pregnancy and the use of tocolytics during pregnancy, which was predictive of ASD risk only in carriers of GSTM1-null, as opposed to carriers of GSTM1-active genotype. Conclusion: Specific perinatal complications may be significant risk factors for ASD. GSTM1 genotype may serve as a moderator of the effect of some prenatal factors on the risk of ASD such as using medication during pregnancy. It may be speculated that different oxidative stress-related genetic and environmental factors could lead to development of ASD. Apart from etiological mechanisms, possible therapeutic implications in ASD are also discussed.

Keywords: autism; glutathione transferase; oxidative stress; perinatal complications; prematurity.