| Fetal Alcohol Syndrome (FAS) is the leading known cause of mental retardation in the Western world. However, high levels of maternal alcohol consumption do not always produce the typical FAS phenotype of craniofacial abnormalities, central nervous system dysfunction, and growth deficits. This is, in part, due to genetic variation in the mother and the fetus. Our studies in a chicken embryo model indicate that one effect of ethanol exposure early in development is increased apoptosis in neural crest cells, which contribute largely to the formation of the face. We also find alterations in craniofacial structure after ethanol exposure. Furthermore, both of these endpoints are affected by genetic background of the embryo, although the association between the two is complex. Our investigation into the basis of this genetic modulation focused on the cell signaling pathways mediating ethanol's effects. We found that an increase in intracellular calcium ([Ca2+]i ) occurs shortly after ethanol exposure in a region of the embryo known to contain neural crest cell precursors. Chelation of [Ca2+] i during ethanol exposure attenuates excess neural crest apoptosis, without affecting endogenous apoptosis. Furthermore, this [Ca2+] i increase and subsequent apoptosis are blocked by pharmacological inhibition of phospholipase C (PLC), indicating that an initial target of ethanol in the early embryo is a PLC-dependent signaling pathway. Importantly, this ethanol-induced [Ca2+]i increase is seen in chicken strains that are both sensitive and resistant to ethanol-induced neural crest apoptosis. Thus, genetic modulation of the apoptotic response likely lies downstream of an ethanol-induced calcium signal. |
