Dataset Information

Gestational binge alcohol-induced alterations in maternal uterine artery transcriptome.

ABSTRACT: Binge alcohol exposure during pregnancy results in diminished vessel function and altered proteome in the maternal uterine artery. We aimed to utilize high throughput RNA-seq deep-sequencing to characterize specific effects of binge alcohol exposure during pregnancy on the uterine artery transcriptome, and gain insight into mechanisms underlying alcohol-mediated uterine artery dysfunction. Pregnant Sprague-Dawley rats assigned to Pair-Fed Control or Alcohol groups, received a once-daily orogastric gavage in a binge paradigm. RNA-sequencing using Illumina NextSeq 500, identified 13,941 genes; 40 significantly altered genes were altered by log2(fold change) > 2; 27 genes were upregulated and 13 were downregulated in the Alcohol group. Transcripts altered included those which encode for aldehyde dehydrogenases, matrix metalloproteases, and molecules vital for vasodilation and vascular remodeling. Biological pathways that were disproportionally altered by alcohol were proline and citrulline biosynthesis/metabolism. Disruption of these pathways suggests candidate mechanism(s) for alcohol-mediated impairments to the proteome and vascular function.

SUBMITTER: Orzabal MR

PROVIDER: S-EPMC6628922 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Gestational binge alcohol-induced alterations in maternal uterine artery transcriptome.

Orzabal Marcus R MR Lunde-Young Emilie R ER Ramirez Josue I JI Naik Vishal D VD Hillhouse Andrew A Konganti Kranti K Threadgill David W DW Ramadoss Jayanth J

Reproductive toxicology (Elmsford, N.Y.) 20190509

Binge alcohol exposure during pregnancy results in diminished vessel function and altered proteome in the maternal uterine artery. We aimed to utilize high throughput RNA-seq deep-sequencing to characterize specific effects of binge alcohol exposure during pregnancy on the uterine artery transcriptome, and gain insight into mechanisms underlying alcohol-mediated uterine artery dysfunction. Pregnant Sprague-Dawley rats assigned to Pair-Fed Control or Alcohol groups, received a once-daily orogastr ...[more]

PMID: 31078653

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Project description:Genomic studies on fetal alcohol spectrum disorders (FASD) have utilized either genome-wide microarrays/bioinformatics or targeted real-time PCR (RT-PCR). We utilized herein for the first time a novel digital approach with high throughput as well as the capability to focus on one physiological system. The aim of the present study was to investigate alcohol-induced alterations in uterine angiogenesis-related mRNA abundance using digital mRNA technology. Four biological and three technical replicates of uterine arterial endothelial cells from third-trimester ewes were fluorescence-activated cell sorted, validated, and treated without or with binge-like alcohol. A capture probe covalently bound to an oligonucleotide containing biotin and a color-coded reporter probe were designed for 85 angiogenesis-related genes and analyzed with the Nanostring nCounter system. Twenty genes were downregulated (↓) and two upregulated (↑), including angiogenic growth factors/receptors (↓placental growth factor), adhesion molecules (↓angiopoietin-like-3; ↓collagen-18A1; ↓endoglin), proteases/matrix proteins/inhibitors (↓alanyl aminopeptidase; ↓collagen-4A3; ↓heparanase; ↓plasminogen, ↑plasminogen activator urokinase; ↓platelet factor-4; ↓plexin domain containing-1; ↓tissue inhibitor of metalloproteinases-3), transcription/signaling molecules (↓heart and neural crest derivatives-2; ↓DNA-binding protein inhibitor; ↓NOTCH-4; ↓ribosomal protein-L13a1; ↓ribosomal protein large-P1), cytokines/chemokines (↓interleukin-1B), and miscellaneous growth factors (↓leptin; ↓platelet-derived growth factor-α); ↓transforming growth factor (TGF-α; ↑TGF-β receptor-1). These novel data show significant detrimental alcohol effects on genes controlling angiogenesis supporting a mechanistic role for abnormal uteroplacental vascular development in FASD. The tripartite digital gene expression system is therefore a valuable tool to answer many additional questions about FASD from both mechanistic as well as ameliorative perspectives.

Project description:Ethanol-inducible cytochrome P450 2E1 (CYP2E1) contributes to increased oxidative stress and steatosis in chronic alcohol-exposure models. However, its role in binge ethanol-induced gut leakiness and hepatic injury is unclear. This study was aimed at investigating the role of CYP2E1 in binge alcohol-induced gut leakiness and the mechanisms of steatohepatitis. Female wild-type (WT) and Cyp2e1-null mice were treated with three doses of binge ethanol (WT-EtOH or Cyp2e1-null-EtOH) (6g/kg oral gavage at 12-h intervals) or dextrose (negative control). Intestinal histology of only WT-EtOH exhibited epithelial alteration and blebbing of lamina propria, and liver histology obtained at 6h after the last ethanol dose showed elevated steatosis with scattered inflammatory foci. These were accompanied by increased levels of serum endotoxin, hepatic enterobacteria, and triglycerides. All these changes, including the intestinal histology and hepatic apoptosis, determined by TUNEL assay, were significantly reversed when WT-EtOH mice were treated with the specific inhibitor of CYP2E1 chlormethiazole and the antioxidant N-acetylcysteine, both of which suppressed oxidative markers including intestinal CYP2E1. WT-EtOH also exhibited elevated amounts of serum TNF-α, hepatic cytokines, CYP2E1, and lipid peroxidation, with decreased levels of mitochondrial superoxide dismutase and suppressed aldehyde dehydrogenase 2 activity. Increased hepatocyte apoptosis with elevated levels of proapoptotic proteins and decreased levels of active (phosphorylated) p-AKT, p-AMPK, and peroxisome proliferator-activated receptor-α, all of which are involved in fat metabolism and inflammation, were observed in WT-EtOH. These changes were significantly attenuated in the corresponding Cyp2e1-null-EtOH mice. These data indicate that both intestinal and hepatic CYP2E1 induced by binge alcohol seems critical in binge alcohol-mediated increased nitroxidative stress, gut leakage, and endotoxemia; altered fat metabolism; and inflammation contributing to hepatic apoptosis and steatohepatitis.

Dataset Information

Gestational binge alcohol-induced alterations in maternal uterine artery transcriptome.

Publications

Gestational binge alcohol-induced alterations in maternal uterine artery transcriptome.

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