Ethanol-induced neuronal death during a sensitive period of brain development is considered one of the significant causes of
fetal alcohol spectrum disorders (
FASD). In rodent models,
ethanol triggers robust apoptotic neurodegeneration during a period of active synaptogenesis that occurs around the first two postnatal weeks, equivalent to the third trimester in human fetuses. The
ethanol-induced apoptosis is mitochondria-dependent, involving Bax and
caspase-3 activation. Such apoptotic pathways are often mediated by
sphingolipids, a class of bioactive
lipids ubiquitously present in eukaryotic cellular membranes. While the central role of
lipids in
ethanol liver toxicity is well recognized, the involvement of
sphingolipids in
ethanol neurotoxicity is less explored despite mounting evidence of their importance in neuronal apoptosis. Nevertheless, recent studies indicate that
ethanol-induced neuronal apoptosis in animal models of
FASD is mediated or regulated by cellular
sphingolipids, including via the pro-apoptotic action of
ceramide and through the neuroprotective action of
GM1 ganglioside. Such
sphingolipid involvement in
ethanol neurotoxicity in the developing brain may provide unique targets for therapeutic applications against
FASD. Here we summarize findings describing the involvement of
sphingolipids in
ethanol-induced apoptosis and discuss the possibility that the combined action of various
sphingolipids in mitochondria may control neuronal cell fate.