MOLECULAR CHARACTERIZATION OF FETAL ALCOHOL SYNDROME PATHOGENESIS

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Fetal alcohol syndrome (FAS) is one of the leading causes of mental retardation in the world. We have undertaken a molecular and biochemical approach towards understanding the pathogenesis of FAS. The technique of differential mRNA display was used to detect changes in gene expression in developing mouse embryos caused by ethanol exposure. Mouse embryos were also treated with another known teratogen, 3- methylcholanthrene (3-MC), in order to identify mRNAs which are specifically regulated by ethanol. Northern blot analyses were performed to confirm the differential display findings. We have identified two known and one unknown cDNA whose corresponding mRNA levels are altered by exposure to ethanol. A brain specific isoform of alpha-tropomyosin is up-regulated by ethanol but not by 3-MC in 11-day old embryos. Immunoblot analyses indicate that the level of the alpha-tropomyosin protein is also elevated by ethanol exposure. The brain specific isoform of alpha-tropomyosin has been shown to be important for central nervous system development and its ectopic expression during a critical period of development may disrupt normal development and cause some of the phenotypes seen in FAS. The other known cDNA encodes heat shock protein 47 (HSP47) which is involved in pro-collagen processing. The expression of the HSP47 gene was shown to be induced by ischemia in the adult rat brain. Ischemia has been noted as a possible mechanism of FAS as it has been shown that injection of bolus doses of ethanol into monkeys causes the collapse of the umbilical cord and decreased blood flow. We have recently used cDNA microarrays to identify additional mRNAs, which are altered during the early stages of FAS. The identification of these mRNAs will increase our understanding of the teratogenic actions of ethanol and the chances for effective treatment.