Fetal alcohol spectrum disorders (FASD) are caused by prenatal alcohol exposure (PAE) and affect 1‑5% of the North American population. Children born with FASD often face maternal separation throughout childhood. How this early life stress (ELS) affects the severity of FASD-related deficits is poorly understood. Using a mouse model, this dissertation establishes that behavioural deficits accumulate following prenatal alcohol exposure and early life stress, assessed using tests for activity, anxiety-like behaviour as well as learning and memory. Hippocampal gene expression was evaluated using RNA-seq followed by clustering of expression profiles through weighted gene co-expression network analysis (WGCNA). A set of transcripts are associated with anxiety-like behaviour (r = 0.79, p = 0.002) and treatment (r = 0.68, p = 0.015). Genes in this module are overrepresented by transcriptional regulation and neurodevelopment genes. One member of this module, Polr2a, is downregulated by the combination of treatments. Hippocampal promoter DNA methylation was assessed using methylated DNA immunoprecipitation sequencing (MeDIP-Seq). Methylation at different genes is affected by each treatment independently, and a unique set of genes are affected by the combination of treatments. PAE leads to altered promoter DNA methylation at genes important for transcriptional regulation and ELS leads to changes at genes important for histone methylation and immune response. The combination of treatments results in DNA methylation changes at genes important for neuronal migration and immune response. The results from the same samples show that genes with altered expression and promoter methylation are critical in brain development and function. Also, there is minimal complementarity between changes in promoter DNA methylation and gene expression. Mechanisms beyond promoter DNA methylation are likely involved in lasting gene expression changes leading to behavioural deficits seen in FASD. Although further research is required to elucidate the mechanism, the results included may be valuable towards early and reliable diagnosis, together with the development of novel strategies for the amelioration of FASD-related deficits
