A major component of the pathogenesis of alcohol-induced major malformations, as observed in animal models of alcohol related birth defects, is associated with cell death. We propose to examine the selective sensitivity of various cell populations in early mouse embryos to ethanol-induced cell death. This will involve in vivo as well as in vitro (whole embryo culture) studies of control and ethanol-exposed gestational day 7-9 1/2 mouse embryos. Morphological analyses utilizing a vital dye, Nile blue sulphate which comprehensively reveals patterns of cell death, as well as light, scanning and transmission electron microscopy will be performed. The patterns of ethanol-induced cell death will be compared to those of normal programmed cell death as well as to sites of intense mitotic activity, cell migration, etc. in control embryos and will be related to subsequent patterns of malformation. Dose-response and time- response studies utilizing the whole embryo culture system will be conducted using excessive cell death and other morphological abnormalities as the developmental end point. Electron microscopic analysis of these embryos to determine whether ethanol-induced cell death is apoptotic or necrotic will be carried out. The objective of this investigation is to generate data which will provide us with a better understanding of the mechanism of ethanol-induced cellular damage as well as the basis for the vulnerability of selected cell populations to this teratogenic agent.
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