Prenatal alcohol exposure triggers ceramide-induced apoptosis in neural crest-derived tissues concurrent with defective cranial development

Abstract

Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption during pregnancy. The reason why specific embryonic tissues are sensitive toward ethanol is not understood. We found that in neural crest-derived cell (NCC) cultures from the first branchial arch of E10 mouse embryos, incubation with ethanol increases the number of apoptotic cells by fivefold. Apoptotic cells stain intensely for ceramide, suggesting that ceramide-induced apoptosis mediates ethanol damage to NCCs. Apoptosis is reduced by incubation with CDP-choline (citicoline), a precursor for the conversion of ceramide to sphingomyelin. Consistent with NCC cultures, ethanol intubation of pregnant mice results in ceramide elevation and increased apoptosis of NCCs in vivo. Ethanol also increases the protein level of prostate apoptosis response 4 (PAR-4), a sensitizer to ceramide-induced apoptosis. Prenatal ethanol exposure is concurrent with malformation of parietal bones in 20% of embryos at day E18. Meninges, a tissue complex derived from NCCs, is disrupted and generates reduced levels of TGF-β1, a growth factor critical for bone and brain development. Ethanol-induced apoptosis of NCCs leading to defects in the meninges may explain the simultaneous presence of cranial bone malformation and cognitive retardation in FAS. In addition, our data suggest that treatment with CDP-choline may alleviate the tissue damage caused by alcohol.

Neural Crest Cells in Craniofacial Skeletal Development

“…Ethanol induces apoptosis in NCC in vitro and in vivo reduces Tgfbeta1 expression and disrupts formation of parietal bones [166]. Induction of endogenous antioxidants through activation of nuclear factor-erythroid 2-related factor 2 (Nrf2) prevents oxidative stress and apoptosis in ethanol-exposed mice, revealing interactions between EtOH-induced cell death and hypoxia [167].…”

It’s a Lipid’s World: Bioactive Lipid Metabolism and Signaling in Neural Stem Cell Differentiation

“…Phosphatidylcholine is then a precursor for the generation of sphingomyelin from ceramide, a reaction that is known to reduce inflammatory and pro-apoptotic cell signaling pathways [164]. Most recently, we have found that CDP-choline-driven detoxification of ceramide by its conversion to sphingomyelin can also protect neural crest stem cells and may be useful for treatment or prevention of fetal alcohol syndrome [165]. These studies and their implications for the metabolic compartmentalization of stem cell niches will be discussed in Conclusions.…”

Introduction to the Fractality Principle of Consciousness and the Sentyon Postulate

“…If the current input pattern on the dendritic tree of the client neuron is in phase with the recurrent signals from the router network, it connects with other peripheral networks to retrieve the actual memory trace. In his fascinating book “Proust was a neuroscientist” (50), Jonah Lehrer uses a neat example of how current input is almost immediately connected to a pertinent memory trace. The protagonist in Marcel Proust’s novel “In Search of Lost Time” suddenly experiences his entire childhood memory because he bites into a butter cookie that tastes exactly like the ones his grandmother served him when he was a child.…”