Abstract
Introduction: Prenatal alcohol exposure is a risk factor for congenital heart defects, but it is unclear how alcohol exposure in utero leads to disruption of normal cardiovascular development. To gain insight into the transcriptomic pathways involved, we performed RNA-sequencing (RNA-seq) of embryonic mouse hearts 24h (E10.5) and 48h (E11.5) after a single dose of maternal alcohol. Hypothesis: Maternal binge alcohol consumption at E9.5 disrupts expression of specific embryonic genes important for heart development. Methods: Alcohol treatment (2.5g/Kg ethanol in saline) or control solution (0.9% saline) was administered to pregnant C57Bl/6 mice via single oral gavage at E9.5. Embryonic hearts were collected 24h and 48h later for RNA isolation and analysis by RNA-Seq and quantitative PCR (qPCR) methods. Reactome® pathway analysis was performed to determine which were most affected. Results: Of the nearly 20,000 genes expressed in the embryonic heart, we found remarkably few (less than 0.1%) showing significant alterations in expression. Most of the gene expression changes induced by alcohol occurred within 24h and were largely genes involved in transcriptional regulation or signaling pathways. In particular, Wnt7a showed significant ( p=0.013 ) and substantial change (nearly 5-fold decrease relative to control expression, n=11 per group) in response to maternal binge alcohol 24h post-gavage. Similar results were observed for Wnt7a at 48h post-binge (p=0.043, n=8/group). Further analyses showed that Wnt -related genes, Dkk2, Rtl1,Wnt3, Wnt6, and Wnt10a showed significantly decreased expression and Wnt11 showed significantly increased expression in the embryonic heart 24h post-binge alcohol. Conclusions: These results suggest that Wnt7a and related signaling pathway genes are disrupted by alcohol action in the embryonic heart, thereby opening new avenues for investigation into molecular underpinnings of alcohol-induced congenital heart defects.
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