Alteration of gene expression by alcohol exposure at early neurulation

Abstract

BackgroundWe have previously demonstrated that alcohol exposure at early neurulation induces growth retardation, neural tube abnormalities, and alteration of DNA methylation. To explore the global gene expression changes which may underline these developmental defects, microarray analyses were performed in a whole embryo mouse culture model that allows control over alcohol and embryonic variables.ResultAlcohol caused teratogenesis in brain, heart, forelimb, and optic vesicle; a subset of the embryos also showed cranial neural tube defects. In microarray analysis (accession number GSM9545), adopting hypothesis-driven Gene Set Enrichment Analysis (GSEA) informatics and intersection analysis of two independent experiments, we found that there was a collective reduction in expression of neural specification genes (neurogenin, Sox5, Bhlhe22), neural growth factor genes [Igf1, Efemp1, Klf10 (Tieg), and Edil3], and alteration of genes involved in cell growth, apoptosis, histone variants, eye and heart development. There was also a reduction of retinol binding protein 1 (Rbp1), and de novo expression of aldehyde dehydrogenase 1B1 (Aldh1B1). Remarkably, four key hematopoiesis genes (glycophorin A, adducin 2, beta-2 microglobulin, and ceruloplasmin) were absent after alcohol treatment, and histone variant genes were reduced. The down-regulation of the neurospecification and the neurotrophic genes were further confirmed by quantitative RT-PCR. Furthermore, the gene expression profile demonstrated distinct subgroups which corresponded with two distinct alcohol-related neural tube phenotypes: an open (ALC-NTO) and a closed neural tube (ALC-NTC). Further, the epidermal growth factor signaling pathway and histone variants were specifically altered in ALC-NTO, and a greater number of neurotrophic/growth factor genes were down-regulated in the ALC-NTO than in the ALC-NTC embryos.ConclusionThis study revealed a set of genes vulnerable to alcohol exposure and genes that were associated with neural tube defects during early neurulation.

Proteomic analysis of ethanol-induced embryotoxicity in cultured post-implantation rat embryos

“…Deformed organs included branchial arch, heart, neural tube, optic vesicle, otic vesicle, somite, and tail ( Fig. 1), which is in agreement with previous reports (Giavini et al, 1992;Zhou et al, 2011).…”

Alcohol-Induced Morphological Deficits in the Development of Octavolateral Organs of the Zebrafish (Danio rerio)

“…28,52 In addition, experimental evidence has shown that embryonic alcohol exposure altered expression of genes that are specifically involved in the induction and development of the otic vesicle in zebrafish. For example, acute embryonic alcohol exposure reduces expression of the raldh2 gene that is required to activate retinoic acid signalling at the beginning of gastrulation.…”

Ethanol Alters the Balance of Sox2, Oct4, and Nanog Expression in Distinct Subpopulations During Differentiation of Embryonic Stem Cells

“…Alcohol consumption in early pregnancy, and especially around gastrulation (third week) when pregnancy may be unknown, has been shown to lead to a high FAS incidence [6,13,14]. Inhibition of neural stem cell differentiation by ethanol in mouse has been proposed as the mechanism of developmental delay and deficits of the nervous system underlying FAS phenotypes [15,16]. An earlier ethanol perturbation of embryonic development at the stage of cell lineage specification [17] would impact formation of the ectoderm lineage and derived progenitors.…”