The mechanism by which ethanol acts as a teratogen is not well understood and may be multifactorial. Insulin like growth factors (IGF-I and IGF- II) are mitogenic peptides with fundamental roles in embryonic, fetal and neonatal development; abnormalities of IGF production, IGF-binding proteins (IGFBP) or the altered sensitivity of target cells during critical ontogenic periods have been implicated in growth retardation. The principal investigator has reported altered fuel-hormone homeostasis in growth-retarded offspring of rats exposed to ethanol in utero. Recently we observed decreases in hepatic and brain IGF-I and -II levels and IGF-II mRNA, but an increase in circulating IGFBP-2 in fetuses of ethanol-fed rats. Fetal body and organ weights were decreased as well. In brain cell cultures, ethanol increased IGFBP-2 secretion into the medium. IGFs have been studied in other growth disorders, but there is a paucity of information regarding their role in ethanol-induced growth retardation. This objective is the basis of this proposal with the following aims:
AIM 1. To characterize developmental changes in the levels of IGF-I, IGF- II, their binding proteins and specific receptors in the offspring of ethanol-fed rats.
AIM 2. To investigate the effect of maternal ethanol ingestion on the expression of genes for IGF-I, IGF-II and IGFBP-2 in fetal liver and brain.
AIM 3. To study the direct effects of ethanol on insulin-like growth factors in rat brain cell cultures. The studies will use rats, fed liquid diet containing ethanol, and weight-matched pair-fed and ad libitum-fed rats given isocaloric control diet. Immunohistochemical analysis will be used to survey IGF distribution in fetal liver and selected areas of the fetal brain at different ages. IGFs and their binding proteins will be quantitated in serum and tissues by radioimmunoassay and ligand blot procedures. Changes in distribution of IGF receptors will be quantitated by autoradiography in tissue sections. Developmental effects of ethanol on IGF gene expression will be studied by Northern blot analysis, run-on transcription assays, and in situ hybridization histochemistry. Parallel studies in astroglial cell cultures will delineate effects of ethanol independent of nutritional and maternal influences on IGF, IGFBP expression and their receptor levels. These studies should provide insight into the role of somatomedins in growth abnormalities of FAS.
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