Abstract
BackgroundFetal alcohol spectrum disorders (FASD) are common, seen in 1–5% of the population in the USA and Canada. Children diagnosed with FASD are not likely to remain with their biological parents, facing early maternal separation and foster placements throughout childhood.MethodsWe model FASD in mice via prenatal alcohol exposure and further induce early life stress through maternal separation. We use RNA-seq followed by clustering of expression profiles through weighted gene co-expression network analysis (WGCNA) to analyze transcriptomic changes that result from the treatments. We use reverse transcription qPCR to validate these changes in the mouse hippocampus.ResultsWe report an association between adult hippocampal gene expression and prenatal ethanol exposure followed by postnatal separation stress that is related to behavioral changes. Expression profile clustering using WGCNA identifies a set of transcripts, module 19, associated with anxiety-like behavior (r = 0.79, p = 0.002) as well as treatment group (r = 0.68, p = 0.015). Genes in this module are overrepresented by genes involved in transcriptional regulation and other pathways related to neurodevelopment. Interestingly, one member of this module, Polr2a, polymerase (RNA) II (DNA directed) polypeptide A, is downregulated by the combination of prenatal ethanol and postnatal stress in an RNA-Seq experiment and qPCR validation (q = 2e−12, p = 0.004, respectively).ConclusionsTogether, transcriptional control in the hippocampus is implicated as a potential underlying mechanism leading to anxiety-like behavior via environmental insults. Further research is required to elucidate the mechanism involved and use this insight towards early diagnosis and amelioration strategies involving children born with FASD.
Highlights
Fetal alcohol spectrum disorders (FASD) are common, seen in 1–5% of the population in the USA and Canada
RNA-Seq was performed on hippocampal RNA samples from three individuals for each of four groups of mice representing a control group with no experimental interventions, an ethanol group of mice prenatally exposed to ethanol, a stress group with mice subjected to postnatal maternal separation stress, and an ethanol + stress group with mice prenatally exposed to ethanol followed by postnatal maternal separation stress
weighted gene coexpression network analysis (WGCNA) was used to cluster transcripts into modules based on correlated expression across samples that can be assessed in relation to other known traits
Summary
Fetal alcohol spectrum disorders (FASD) are common, seen in 1–5% of the population in the USA and Canada. Fetal alcohol spectrum disorder (FASD) is a direct result of gestational alcohol use, characterized by prenatal and postnatal growth restrictions, facial abnormalities, structural brain abnormalities, microcephaly, developmental delays, intellectual impairment, and behavioral difficulties [5]. In Canada, an estimated 10% of pregnant women consume alcohol [6], and the prevalence of FASD in Canadian 7–9-year-olds is estimated between 2–3% [7]. In a cross-sectional study of four communities in the USA, the estimated prevalence of FASD ranged from 1.1 to 5% [8]. The annual cost of FASD in Canada is estimated at approximately $1.8 billion, including costs due to productivity losses, the correctional system, and health care [9]. FASD remains a common and costly societal burden throughout an affected individual’s lifetime
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