Hippocampal transcriptome reveals novel targets of FASD pathogenesis
Introduction Prenatal alcohol exposure can contribute to fetal alcohol spectrum disorders (FASD), characterized by a myriad of developmental impairments affecting behavior and cognition. Studies show that many of these functional impairments are associated with the hippocampus, a structure exhibitin...
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Published in | Brain and behavior Vol. 9; no. 7; pp. e01334 - n/a |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
John Wiley & Sons, Inc
01.07.2019
John Wiley and Sons Inc Wiley |
Subjects | |
Online Access | Get full text |
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Summary: | Introduction
Prenatal alcohol exposure can contribute to fetal alcohol spectrum disorders (FASD), characterized by a myriad of developmental impairments affecting behavior and cognition. Studies show that many of these functional impairments are associated with the hippocampus, a structure exhibiting exquisite vulnerability to developmental alcohol exposure and critically implicated in learning and memory; however, mechanisms underlying alcohol‐induced hippocampal deficits remain poorly understood. By utilizing a high‐throughput RNA‐sequencing (RNA‐seq) approach to address the neurobiological and molecular basis of prenatal alcohol‐induced hippocampal functional deficits, we hypothesized that chronic binge prenatal alcohol exposure alters gene expression and global molecular pathways in the fetal hippocampus.
Methods
Timed‐pregnant Sprague–Dawley rats were randomly assigned to a pair‐fed control (PF) or binge alcohol (ALC) treatment group on gestational day (GD) 4. ALC dams acclimatized from GDs 5–10 with a daily treatment of 4.5 g/kg alcohol and subsequently received 6 g/kg on GDs 11–20. PF dams received a once daily maltose dextrin gavage on GDs 5–20, isocalorically matching ALC counterparts. On GD 21, bilateral hippocampi were dissected, flash frozen, and stored at −80°C. Total RNA was then isolated from homogenized tissues. Samples were normalized to ~4nM and pooled equally. Sequencing was performed by Illumina NextSeq 500 on a 75 cycle, single‐end sequencing run.
Results
RNA‐seq identified 13,388 genes, of these, 76 genes showed a significant difference (p < 0.05, log2 fold change ≥2) in expression between the PF and ALC groups. Forty‐nine genes showed sex‐dependent dysregulation; IPA analysis showed among female offspring, dysregulated pathways included proline and citrulline biosynthesis, whereas in males, xenobiotic metabolism signaling and alaninine biosynthesis etc. were altered.
Conclusion
We conclude that chronic binge alcohol exposure during pregnancy dysregulates fetal hippocampal gene expression in a sex‐specific manner. Identification of subtle, transcriptome‐level dysregulation in hippocampal molecular pathways offers potential mechanistic insights underlying FASD pathogenesis.
Chronic binge alcohol exposure during pregnancy dysregulates fetal hippocampal gene expression in a sex‐specific manner. Identification of subtle, transcriptome‐level dysregulation in hippocampal molecular pathways offers potential mechanistic insights underlying FASD pathogenesis. |
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Bibliography: | 2019 Data Availability Statement The data that support the findings will be available in U.S. National Library of Medicine, NCBI Sequence Read Archive (SRA) following an embargo that ends on 14 February 2020 (Ramadoss . ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Data Availability Statement: The data that support the findings will be available in U.S. National Library of Medicine, NCBI Sequence Read Archive (SRA) following an embargo that ends on 14 February 2020 (Ramadoss, 2019). Raine Lunde‐Younga and Josue Ramireza contributed equally. |
ISSN: | 2162-3279 2162-3279 |
DOI: | 10.1002/brb3.1334 |