title: Alteration of gene expression by alcohol exposure at early neurulation.
abstract: BACKGROUND
  We 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.
  
  
  RESULTS
  Alcohol 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.
  
  
  CONCLUSIONS
  This study revealed a set of genes vulnerable to alcohol exposure and genes that were associated with neural tube defects during early neurulation.
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USA. imce100@iupui.edu
authors.forename: Feng C
authors.initials: FC
authors.lastname: Zhou
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Zhao
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Liu
authors.forename: Charles R
authors.initials: CR
authors.lastname: Goodlett
authors.forename: Tiebing
authors.initials: T
authors.lastname: Liang
authors.forename: Jeanette N
authors.initials: JN
authors.lastname: McClintick
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Edenberg
authors.forename: Lang
authors.initials: L
authors.lastname: Li
mesh_terms: D000818:Animals; D016000:Cluster Analysis; D046149:Embryo Culture Techniques; D004622:Embryo, Mammalian / Q000187:drug effects* / Q000378:metabolism; D000431:Ethanol / Q000009:adverse effects*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009436:Neural Tube Defects / Q000196:embryology / Q000235:genetics; D054261:Neurulation; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D013723:Teratogens
chemical_list: D013723:Teratogens; D000431:Ethanol