PMID- 31140755 OWN - NLM STAT- MEDLINE DCOM- 20200319 LR - 20240214 IS - 2162-3279 (Electronic) VI - 9 IP - 7 DP - 2019 Jul TI - Hippocampal transcriptome reveals novel targets of FASD pathogenesis. PG - e01334 LID - 10.1002/brb3.1334 [doi] LID - e01334 AB - 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( degrees ) 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. CI - (c) 2019 The Authors. Brain and Behavior published by Wiley Periodicals, Inc. FAU - Lunde-Young, Raine AU - Lunde-Young R AUID- ORCID: 0000-0002-5098-9991 AD - Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas. FAU - Ramirez, Josue AU - Ramirez J AD - Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas. FAU - Naik, Vishal AU - Naik V AD - Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas. FAU - Orzabal, Marcus AU - Orzabal M AD - Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas. FAU - Lee, Jehoon AU - Lee J AD - Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas. FAU - Konganti, Kranti AU - Konganti K AD - Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas. FAU - Hillhouse, Andrew AU - Hillhouse A AD - Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas. FAU - Threadgill, David AU - Threadgill D AD - Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas. FAU - Ramadoss, Jayanth AU - Ramadoss J AUID- ORCID: 0000-0002-9778-5224 AD - Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas. LA - eng GR - K99 AA019446/AA/NIAAA NIH HHS/United States GR - R00 AA019446/AA/NIAAA NIH HHS/United States GR - R01 AA023520/AA/NIAAA NIH HHS/United States GR - R21 AA023035/AA/NIAAA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20190529 PL - United States TA - Brain Behav JT - Brain and behavior JID - 101570837 RN - 3K9958V90M (Ethanol) SB - IM MH - Animals MH - Disease Models, Animal MH - Ethanol/administration & dosage MH - Female MH - Fetal Alcohol Spectrum Disorders/*pathology MH - High-Throughput Nucleotide Sequencing/methods MH - Hippocampus/*pathology MH - Male MH - Pregnancy MH - Prenatal Exposure Delayed Effects/chemically induced MH - Rats MH - Rats, Sprague-Dawley MH - Transcriptome/*drug effects PMC - PMC6625466 OTO - NOTNLM OT - brain OT - hippocampus OT - nitric oxide OT - pregnancy OT - teratology COIS- None. EDAT- 2019/05/30 06:00 MHDA- 2020/03/20 06:00 PMCR- 2019/05/29 CRDT- 2019/05/30 06:00 PHST- 2019/04/11 00:00 [received] PHST- 2019/05/01 00:00 [revised] PHST- 2019/05/06 00:00 [accepted] PHST- 2019/05/30 06:00 [pubmed] PHST- 2020/03/20 06:00 [medline] PHST- 2019/05/30 06:00 [entrez] PHST- 2019/05/29 00:00 [pmc-release] AID - BRB31334 [pii] AID - 10.1002/brb3.1334 [doi] PST - ppublish SO - Brain Behav. 2019 Jul;9(7):e01334. doi: 10.1002/brb3.1334. Epub 2019 May 29.