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Short-term transcriptomic changes in the mouse neural tube induced by an acute alcohol exposure

ABSTRACT: Alcohol exposure during the formation and closure of the neural tube, or neurulation (embryonic day [E] 8-10 in mice; ∼4th week of human pregnancy), perturbs development of midline brain structures and significantly disrupts gene expression in the rostroventral neural tube (RVNT). Previously, alcohol exposure during neurulation was found to alter gene pathways related to cell proliferation, p53 signaling, ribosome biogenesis, immune signaling, organogenesis, and cell migration 6 or 24 hours after administration. Our current study expands upon this work by investigating short-term gene expression changes in the RVNT following a single binge-like alcohol exposure during neurulation. Female C57BL/6J mice were administered a single dose of 2.9 g/kg alcohol or vehicle on E9.0 to target mid-neurulation. The RVNTs of stage-matched embryos were collected 2 or 4 hours after exposure and processed for RNA-seq. Functional profiling was performed with g:Profiler, as well as the CiliaCarta and DisGeNet databases. Two hours following E9.0 alcohol exposure, 650 genes in the RVNT were differentially expressed. Functional enrichment analysis revealed that pathways related to cellular metabolism, gene expression, cell cycle, organogenesis, and Hedgehog signaling were down-regulated and pathways related to cellular stress response, p53 signaling, and hypoxia were up-regulated by alcohol. Four hours after alcohol, 225 genes were differentially expressed. Biological processes related to metabolism, RNA binding, ribosome biogenesis, and methylation were down-regulated, while protein localization and binding, autophagy, and intracellular signaling pathways were up-regulated. Two hr after alcohol, the differentially expressed genes were associated with disease terms related to eye and craniofacial development and anoxia. These data provide further information regarding the biological functions targeted by alcohol exposure during neurulation in regions of the neural tube that give rise to alcohol-sensitive midline brain structures. Disruption of these gene pathways contributes to the craniofacial and brain malformations associated with prenatal alcohol exposure.

ORGANISM(S): Mus musculus

PROVIDER: GSE199646 | GEO | 2022/10/19

REPOSITORIES: GEO

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Project description:EXPERIMENT: Microarray expression profiles derived from the cranial neural folds (headfold) of neurulation-stage mouse embryos 3.0h after maternal alcohol exposure on 8 d.p.c. ANIMAL MODEL: Pregnancies from 2 substrains of C57BL/6 mice that differ in relative risk of Fetal Alcohol Syndrome (FAS): C57BL/6J (B6J) high-risk condition, and C57BL/6NCrl (B6N) low-risk condition. EXPOSURE: Dams dosed with ethanol (EtOH) by intraperitoneal injection at 2.9 g EtOH per kg body weight. Controls received vehicle (saline) alone. A third group of dams received EtOH + 4.0 mg/kg PK11195, a specific high-affinity ligand to the 18 KDa mitochondrial peripheral benzodiazepine receptor site. INTERVAL: High blood alcohol content must be sustained in dams for several hours to invoke FAS and is traditionally accomplished by a double injection of EtOH 4.0h apart. Since these embryos were harvested for genetic analysis 1h before dams would have gotten the second alcohol injection, the interval represents a snapshot of the critical response, prior to the second maternal injection that invokes greater risk. Counter-exposure to PK11195 significantly lowers the adverse response of B6J embryos to EtOH. PLATFORM: Two independent assays run. The first dataset (PE), run April 2002 – January 2003, used samples pooled from 2 litters (PE) and the platform was a two-channel MPS621 array (http://www.lifesciences.perkinelmer.com/). This platform has 4800 sequence-verified gene elements derived from over 50 different human cDNA libraries reflecting a variety of well-annotated cellular processes and disease pathways. The second dataset (AF), run between May 2005 – November 2005, used samples pooled from 1 litter and the platform was Affymetrix GeneChip® Mouse Genome 430A 2.0 Array (http://www.affymetrix.com/). The MG430A 2.0 platform has 45,102 oligonucleotide probe cells representing approximately 14,000 well-characterized genes in the draft mouse genome assembly. The corresponding GEO samples are GSM12218 - GSM12227 for the two-channel PE arrays, and GSM136067 - GSM136078 for the one-channel AF arrays. Keywords = fetal alcohol syndrome Keywords = alcohol-related birth defects Keywords = EtOH Keywords = PK11195 Keywords = embryo Keywords = strain differences Keywords: Ordered

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Short-term transcriptomic changes in the mouse neural tube induced by an acute alcohol exposure

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