Chronic Binge Alcohol Exposure During Pregnancy Alters mTOR System in Rat Fetal Hippocampus.
Animals
Binge Drinking
Central Nervous System Depressants
/ pharmacology
Crown-Rump Length
Ethanol
/ pharmacology
Fetal Development
/ drug effects
Fetal Weight
/ drug effects
Fetus
/ drug effects
Hippocampus
/ drug effects
Intracellular Signaling Peptides and Proteins
/ drug effects
Mechanistic Target of Rapamycin Complex 1
/ drug effects
Rapamycin-Insensitive Companion of mTOR Protein
/ drug effects
Rats
Regulatory-Associated Protein of mTOR
/ drug effects
Ribosomal Protein S6 Kinases, 70-kDa
/ drug effects
Signal Transduction
TOR Serine-Threonine Kinases
/ drug effects
Alcohol
FASD
Fetal
Pregnancy
Teratogen
Journal
Alcoholism, clinical and experimental research
ISSN: 1530-0277
Titre abrégé: Alcohol Clin Exp Res
Pays: England
ID NLM: 7707242
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
04
10
2019
revised:
10
04
2020
accepted:
19
04
2020
pubmed:
26
4
2020
medline:
15
12
2021
entrez:
26
4
2020
Statut:
ppublish
Résumé
Gestational alcohol exposure can contribute to fetal alcohol spectrum disorders (FASD), an array of cognitive, behavioral, and physical developmental impairments. Mammalian target of rapamycin (mTOR) plays a key role in regulating protein synthesis in response to neuronal activity, thereby modulating synaptic plasticity and long-term memory formation in the brain. Based on our previous quantitative mass spectrometry proteomic studies, we hypothesized that gestational chronic binge alcohol exposure alters mTOR signaling and downstream pathways in the fetal hippocampus. Pregnant Sprague-Dawley rats were assigned to either a pair-fed control (PF-Cont) or a binge alcohol (Alcohol) treatment group. Alcohol dams were acclimatized via a once-daily orogastric gavage of 4.5 g/kg alcohol (peak BAC, 216 mg/dl) from GD 5-10 and progressed to 6 g/kg alcohol (peak BAC, 289 mg/dl) from GD 11-21. Pair-fed dams similarly received isocaloric maltose dextrin. In the Alcohol group, following this exposure paradigm, fetal body weight and crown-rump length were decreased. The phosphorylation level of mTOR (P-mTOR) in the fetal hippocampus was decreased in the Alcohol group compared with controls. Alcohol exposure resulted in dysregulation of fetal hippocampal mTORC1 signaling, as evidenced by an increase in total 4E-BP1 expression. Phosphorylation levels of 4E-BP1 and p70 S6K were also increased following alcohol exposure. P-mTOR and P-4E-BP1 were exclusively detected in the dentate gyrus and oriens layer of the fetal hippocampus, respectively. DEPTOR and RICTOR expression levels in the fetal hippocampus were increased; however, RAPTOR was not altered by chronic binge alcohol exposure. We conclude that chronic binge alcohol exposure during pregnancy alters mTORC1 signaling pathway in the fetal hippocampus. We conjecture that this dysregulation of mTOR protein expression, its activity, and downstream proteins may play a critical role in FASD neurobiological phenotypes.
Sections du résumé
BACKGROUND
Gestational alcohol exposure can contribute to fetal alcohol spectrum disorders (FASD), an array of cognitive, behavioral, and physical developmental impairments. Mammalian target of rapamycin (mTOR) plays a key role in regulating protein synthesis in response to neuronal activity, thereby modulating synaptic plasticity and long-term memory formation in the brain. Based on our previous quantitative mass spectrometry proteomic studies, we hypothesized that gestational chronic binge alcohol exposure alters mTOR signaling and downstream pathways in the fetal hippocampus.
METHODS
Pregnant Sprague-Dawley rats were assigned to either a pair-fed control (PF-Cont) or a binge alcohol (Alcohol) treatment group. Alcohol dams were acclimatized via a once-daily orogastric gavage of 4.5 g/kg alcohol (peak BAC, 216 mg/dl) from GD 5-10 and progressed to 6 g/kg alcohol (peak BAC, 289 mg/dl) from GD 11-21. Pair-fed dams similarly received isocaloric maltose dextrin.
RESULTS
In the Alcohol group, following this exposure paradigm, fetal body weight and crown-rump length were decreased. The phosphorylation level of mTOR (P-mTOR) in the fetal hippocampus was decreased in the Alcohol group compared with controls. Alcohol exposure resulted in dysregulation of fetal hippocampal mTORC1 signaling, as evidenced by an increase in total 4E-BP1 expression. Phosphorylation levels of 4E-BP1 and p70 S6K were also increased following alcohol exposure. P-mTOR and P-4E-BP1 were exclusively detected in the dentate gyrus and oriens layer of the fetal hippocampus, respectively. DEPTOR and RICTOR expression levels in the fetal hippocampus were increased; however, RAPTOR was not altered by chronic binge alcohol exposure.
CONCLUSION
We conclude that chronic binge alcohol exposure during pregnancy alters mTORC1 signaling pathway in the fetal hippocampus. We conjecture that this dysregulation of mTOR protein expression, its activity, and downstream proteins may play a critical role in FASD neurobiological phenotypes.
Identifiants
pubmed: 32333810
doi: 10.1111/acer.14348
pmc: PMC7328280
mid: NIHMS1599071
doi:
Substances chimiques
Central Nervous System Depressants
0
DEPTOR protein, rat
0
Intracellular Signaling Peptides and Proteins
0
Rapamycin-Insensitive Companion of mTOR Protein
0
Regulatory-Associated Protein of mTOR
0
Rptor protein, rat
0
rictor protein, rat
0
Ethanol
3K9958V90M
mTOR protein, rat
EC 2.7.1.1
Mechanistic Target of Rapamycin Complex 1
EC 2.7.11.1
Ribosomal Protein S6 Kinases, 70-kDa
EC 2.7.11.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1329-1336Subventions
Organisme : NIAAA NIH HHS
ID : K99 AA019446
Pays : United States
Organisme : NIAAA NIH HHS
ID : R00 AA019446
Pays : United States
Organisme : NIAAA NIH HHS
ID : R01 AA023520
Pays : United States
Organisme : NIAAA NIH HHS
ID : R21 AA023035
Pays : United States
Informations de copyright
© 2020 by the Research Society on Alcoholism.
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