Novel Targets of FASD Pathogenesis in the Developing Hippocampus
Abstract
Prenatal alcohol exposure can contribute to fetal alcohol spectrum disorders (FASD), characterized by a myriad of developmental impairments affecting behavior and cognition. Studies show many of these functional impairments are associated with the hippocampus, a structure exhibiting exquisite vulnerability to developmental alcohol exposure and critically implicated in learning and memory, however mechanisms underlying alcohol-induced hippocampal deficits remain poorly understood. Utilizing a high-throughput RNA-Seq approach to address the neurobiological and molecular basis of prenatal alcohol-induced hippocampal functional deficits, we hypothesized that chronic binge prenatal alcohol exposure alters gene expression and global molecular pathways in the fetal hippocampus. Timed-pregnant Sprague Dawley rats were randomly assigned to a pair-fed control (PF) or binge-alcohol treatment (ALC) group on gestational day (GD) 4. ALC dams acclimatized from GD 5-10 with a daily treatment of 4.5 g/kg alcohol and subsequently received 6 g/kg on GDs 11-20. PF dams received a once-daily maltose dextrin gavage on GDs 5-20, isocalorically matching ALC counterparts.
On GD 21, bilateral hippocampi were dissected, flash frozen, and stored at -80°C. Total RNA was then isolated from homogenized tissues. Samples were normalized to ~4nM and pooled equally. Sequencing was performed by Illumina NextSeq 500 on a 75 cycle, single end sequencing run. RNA-Seq identified 13,388 genes, of these, 76 genes showed a significant difference (P < 0.05, log2 fold change> 2) in expression between the PF and ALC groups. 49 genes showed sex-dependent dysregulation, of which, 23 were significantly altered in ALC-exposed females, 26 were altered in ALC-exposed males, and 2 were altered in both ALC-exposed males and females compared with PF offspring. We conclude that chronic binge alcohol exposure during pregnancy dysregulates fetal hippocampal gene expression in a sex-specific manner. Identification of subtle, transcriptome-level dysregulation in hippocampal molecular pathways offers potential mechanistic insights underlying FASD pathogenesis.
Citation
Ramirez, Josue Israel (2019). Novel Targets of FASD Pathogenesis in the Developing Hippocampus. Master's thesis, Texas A&M University. Available electronically from https : / /hdl .handle .net /1969 .1 /189165.