Third Trimester-Equivalent Ethanol Exposure Is Characterized by an Acute Cellular Stress Response and an Ontogenetic Disruption of Genes Critical for Synaptic Establishment and Function in Mice

Abstract

The developing brain is remarkably sensitive to alcohol exposure, resulting in the wide range of cognitive and neurobehavioral characteristics categorized under the term fetal alcohol spectrum disorders (FASD). The brain is particularly susceptible to alcohol during synaptogenesis, a process that occurs heavily during the third trimester and is characterized by the establishment and pruning of neural circuitry; however, the molecular response of the brain to ethanol during synaptogenesis has not been documented. To model a binge-like exposure during the third-trimester neurodevelopmental equivalent, neonate mice were given a high (5 g/kg over 2 h) dose of ethanol at postnatal day 7. Acute transcript changes within the brain were assessed using expression arrays and analyzed for associations with gene ontology functional categories, canonical pathways, and gene network interactions. The short-term effect of ethanol was characterized by an acute stress response and a downregulation of energetically costly cellular processes. Further, alterations to a number of genes with roles in synaptic transmission and hormonal signaling, particularly those associated with the neuroendocrine development and function, were evident. Ethanol exposure during synaptogenesis was also associated with altered histone deacetylase and microRNA transcript levels, suggesting that abnormal epigenetic patterning may maintain some of the persistent molecular consequences of developmental ethanol exposure. The results shed insight into the sensitivity of the brain to ethanol during the third-trimester equivalent and outline how ethanol-induced alterations to genes associated with neural connectivity may contribute to FASD phenotypes.

Epigenetics Studies of Fetal Alcohol Spectrum Disorder: Where are We Now?

“…Given the close relationship between gene expression and epigenetic patterns, it is not surprising that initial evidence of the programming effects of alcohol on the genome were identified through changes in transcription. A number of key studies have demonstrated that alcohol exposure during gestation leads to persistent genome-wide alterations to the transcriptome [ 30–34 ]. Indeed, PAE causes widespread changes to gene expression levels in the brain of fetal, neonatal and adult rodents [ 18 , 31–33 , 35 , 36 ].…”

Chromatin Switches during Neural Cell Differentiation and Their Dysregulation by Prenatal Alcohol Exposure

“…The expression of Hdac1 mRNA decreases four hours following alcohol exposure at P7 [199], while Hdac2 expression increases in adulthood in the hypothalamus [169]. Prenatal alcohol exposure reduces histone acetylation and Crebbp mRNA levels in the hypothalamus in adulthood, while neonatal exposure (from P2–12) reduces histone acetylation and CREBBP protein in the cerebellum within 1 h after the final exposure on P2–10 but no change relative to the control was seen at P12 [169,185].…”

Influence of sex and stress exposure across the lifespan on endophenotypes of depression: focus on behavior, glucocorticoids, and hippocampus

“…Despite the fact that clinical research points to strong associations between prenatal stress and likelihood to develop depression, preclinical research has yielded mixed results. However, it should be noted that the third trimester equivalent in rodents is the first week postnatal and thus one reason why there may be differences between human and animal studies is timing of “trimester” in different species (Kleiber et al, 2014 ). Timing of stress onset plays a critical role in how it affects offspring depressive-like behavior.…”