EFFECT OF ETHANOL EXPOSURE ON CIRCULATING LEVELS OF INSULIN-LIKE GROWTH-FACTOR-I AND GROWTH-FACTOR-II, AND INSULIN-LIKE GROWTH-FACTOR BINDING-PROTEINS IN FETAL RATS

Maternal ethanol (ETOH) exposure is associated with impaired fetal gro wth. Because insulin-like growth factors (IGFs) are thought to be impo rtant in the regulation of fetal somatic growth, we examined the influ ence of maternal ETOH exposure on fetal growth and plasma levels of IG F-I, IGF-II, and IGF binding proteins (IGFBPs) in the rat model. Contr ol (A) dams were fed a standard rat chow ad libitum. ETOH (E) consumin g darns were fed a 36% ETOH diet, and pair-fed (P) dams were fed isoca loric amounts of a control liquid diet. All animals were killed on cla y 20 of gestation. Plasma concentrations of IGF-I and -II were determi ned by radioimmunoassay after formic acid-acetone extraction and heat inactivation of IGFBPs. Levels of IGFBPs in fetal plasma were estimate d by Western ligand blotting after protein separation by SDS-PAGE and electrotransfer to nitro cellulose. Membranes were probed with [I-125] IGF-I, and IGFBPs were identified by autoradiography, quantified by sc anning densitometry and results expressed relative to corresponding IG FBPs in control fetal plasma. Maternal weight gain from conception to 20 days of pregnancy was reduced for E compared to P and A dams (p < 0 .05 E vs. P or A). The same pattern was reflected in fetal weight that tended to be lower in P compared with A pups, and was significantly r educed in E pups compared with both groups (p < 0.0001 E vs. P or A). Thus, fetal growth was more retarded in E animals despite equal calori c and protein intake by E and P dams. Radioimmunoassay of fetal plasma revealed that there was no difference in circulating levels of IGF-II in A (65.5 +/- 8.7 ng/ml) and P (65.9 +/- 9.8 ng/ml) plasma. However, levels of IGF-II were higher in E (87.1 +/- 6.2 ng/ml) than in corres ponding P animals. At the same time, there were no differences in IGF- I levels between any of the treatment groups. Western ligand blotting demonstrated that levels of 32-34 kDa IGFBPs were elevated in plasma o f P compared with A fetal plasma, consistent with an effect of reduced maternal nutrition. In contrast, levels of 32-34 kDa IGFBPs were redu ced in E plasma compared with P and A(p < 0.04 and p < 0.02, respectiv ely). These data suggest that circulating levels of IGF-II (but not IG F-I) and specific IGFBPs are altered in growth-retarded fetuses expose d to ETOH. Comparison to fetal plasma obtained from pair-fed litters d emonstrate that these effects on IGF and IGFBP levels are specific to ETOH, and not simply due to maternal nutrient intake. Taken together, these observations indicate that ETOH has unique effects on fetal IGF physiology compared with previously studied models of fetal growth ret ardation. Alterations in the expression and levels of IGFs and IGFBPs may contribute to ETOH-induced fetal growth deficiency.