Oxidative Stress Impact on the Transcriptome of Differentiating Neuroblastoma Cells: Implication for Psychiatric Disorders.

Behnaz Khavari,Ebrahim Mahmoudi,Michael P. Geaghan,Murray J. Cairns

doi:10.3390/ijms21239182

Abstract

Prenatal environmental exposures that have been shown to induce oxidative stress (OS) during pregnancy, such as smoking and alcohol consumption, are risk factors for the onset of schizophrenia and other neurodevelopmental disorders (NDDs). While the OS role in the etiology of neurodegenerative diseases is well known, its contribution to the genomic dysregulation associated with psychiatric disorders is less well defined. In this study we used the SH-SY5Y cell line and applied RNA-sequencing to explore transcriptomic changes in response to OS before or during neural differentiation. We observed differential expression of many genes, most of which localised to the synapse and were involved in neuronal differentiation. These genes were enriched in schizophrenia-associated signalling pathways, including PI3K/Akt, axon guidance, and signalling by retinoic acid. Interestingly, circulatory system development was affected by both treatments, which is concordant with observations of increased prevalence of cardiovascular disease in patients with NDDs. We also observed a very significant increase in the expression of immunity-related genes, supporting current hypotheses of immune system involvement in psychiatric disorders. While further investigation of this influence in other cell and animal models is warranted, our data suggest that early life exposure to OS has a disruptive influence on neuronal gene expression that may perturb normal differentiation and neurodevelopment, thereby contributing towards overall risk for developing psychiatric diseases.

Highlights

Psychiatric disorders such as schizophrenia (SZ), autism spectrum disorder (ASD), bipolar disorder (BD), and major depressive disorder (MDD), are characterised by impairments in cognition, communication, behaviour and motor skills that are thought to arise from abnormal brain development, a process that initiates with the differentiation of the neural progenitor cells [1]
In our co-treatment experiment, SH-SY5Y cells were differentiated to neuron-like cells in the presence of 10μM H2O2 for seven days and compared to controls treated only with ATRA, whereas in the pre-treatment experiment, cells were exposed to 10 μM H2O2 for 72 h prior to the addition of ATRA
Retinoid compounds play a vital role in embryonic development, human brain neurogenesis, and several layers of evidence have implicated the involvement of retinoid signalling dysregulation in the etiology of various psychiatric disorders, such as intellectual disability (ID), ASD, and especially SZ [38]

Summary

Introduction

Psychiatric disorders such as schizophrenia (SZ), autism spectrum disorder (ASD), bipolar disorder (BD), and major depressive disorder (MDD), are characterised by impairments in cognition, communication, behaviour and motor skills that are thought to arise from abnormal brain development, a process that initiates with the differentiation of the neural progenitor cells [1]. While this process extends through late adolescence, and arguably throughout the lifespan of an individual [2], any disturbance can result in the malfunction and maladaption associated with neurodevelopmental disease. The brain is vulnerable to oxidative stress, due to its high energy requirements combined with high lipid and metal content and relatively low expression of endogenous antioxidant mechanisms [9]

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Conclusion