Mapping Peripheral Molecular Mechanisms Associated With Long-Lasting Effects of Early Life Stress: A Transcriptomic Set-Based Approach

Background Exposure to adversities in early life may leave long-lasting neurobiological alterations, increasing the risk of developing mental disorders in later life. Emerging evidence has suggested that stress in early life can interfere with neuroendocrine signalling and immunological cascades through genetic and epigenetic modifications determining long-term consequences on brain morphology, functioning and behaviour. These changes may lead to dysfunctions of hypothalamus-pituitary-adrenal (HPA) axis, an increase of peripheral inflammation and alterations in the neurotransmitter signalling and expression of several molecules, such as brain-derived neurotrophic factor (BDNF) and oxytocin. However, how these biological modifications can lead to mental disorders in adolescence and in adulthood is not fully understood. In this context, investigation of transcriptomic profiles may take advantage of the identification of biological pathways altered by early stressors that in turn may cause enhanced vulnerability for mental disorders later in life. Aims & Objectives Due to the inaccessibility and lack of brain tissues from living patients, peripheral biomarkers may be of particular relevance for the study of psychiatric disorders. By using a transcriptomic approach, the aim of this study is to identify potential peripheral biological signatures associated with the early life stress and the risk of developing mental disorders in a cohort of children and adolescents. Method Through a whole-transcriptome approach, we analyse blood mRNA expression of a cohort of Brazilian children and adolescents screened for high-risk for mental disorders. RNA-Sequencing libraries were prepared using the Illumina Stranded mRNA Prep kit (Illumina). Quality and quantity checks were assessed by the Agilent 4200 TapeStation system, Qubit 2.0 Fluorometer and KAPA Library Quantification kit. Once quality and quantity assessments were completed, libraries were sequenced on a NextSeq2000 platform (Illumina). Raw reads were counted by using Salmon and differential expression analysis by using DESeq2. Lastly, pathways analyses were conducted by the interpretation of the results by using the Ingenuity Pathways Analysis (IPA). Results Gene expression analysis showed significant differences in transcriptomic profiles in children who reported exposure to childhood adversities, as compared to those who had not such stressful experiences (q-value < 0.1, FC ± |1.2|). Significant peripheral biological pathways were found in association with stress in early life (p <0.05, z-score > |2|). Discussion & Conclusions Results of this study revealed a different transcriptomic profile in children and adolescents exposed to adverse childhood experiences compared to controls, suggesting thus that different molecular signatures are associated with an increased risk of developing psychopathology later in life. Furthermore, our data reinforce the idea that the use of omic-technologies is becoming an essential strategy to map peripheral molecular mechanisms associated with long-lasting effects of early life stress, with the final goal of developing effective preventive and treatment options for individuals with a high risk for developing mental disorders.