Non-Smad, BMP-dependent signaling protects against the effects of acute ethanol toxicity

• Published in: Toxicology letters 2021-12, Vol.353, p.118-126
• Main Authors: Habeeb, Naila, Najafi, Sheyda, Perron, Jeanette C.
• Format: Article
• Language: English
• Subjects: Animals; BMPs; Bone Morphogenetic Protein 7 - pharmacology; Cell Line; DRG neurons; Ethanol - administration & dosage; Ethanol - toxicity; FASD; Ganglia, Spinal - cytology; Gene Expression Regulation - drug effects; Mice; Myoblasts; Neurons - drug effects; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction - drug effects; Smad Proteins - genetics; Smad Proteins - metabolism; STAT1 Transcription Factor
• ISSN: 0378-4274; 1879-3169
• DOI: 10.1016/j.toxlet.2021.10.009

[Display omitted] •BMPs stimulate canonical (Smad) and non-canonical (PI3K/Akt) signaling pathways.•Acute ethanol exposure selectively affects non-canonical BMP signaling.•Nuclear translocation of pSmads was unaffected by acute ethanol exposure.•Severe reductions in pAkt levels induced by ethanol were restored by BMPs.•BMPs protect against ethanol-induced changes to cellular and growth cone morphology. This study explores the effect of acute Ethanol (EtOH) exposure on Bone Morphogenetic Protein (BMP)-evoked intracellular signaling, and the concomitant morphological changes induced by EtOH in C2C12 cells and DRG (Dorsal root ganglion) neurons in an in vitro model related to Fetal Alcohol Syndrome Disorder (FASD). All assays were performed within 30 min of BMP stimulation to specifically investigate the earliest events occurring in BMP-evoked intracellular signaling pathways. We show that Smad phosphorylation and nuclear translocation stimulated by BMPs was not altered following acute exposure to EtOH. In contrast, acute EtOH exposure alone caused a striking concentration-dependent decrease in Akt phosphorylation, as well as a loss of adhesion in C2C12 cells. The addition of BMPs before exposure to EtOH was associated with maintenance of Akt phosphorylation, greater cell adhesion in C2C12 cells, and preservation of growth cone complexity in DRG neurons. Thus, for both C2C12 cells and DRG neurons, BMPs, acting through non-canonical BMP signaling pathways, appear to impart some protection against the profound effects of acute EtOH exposure on cellular adhesion and structure.