Ethanol-induced changes in insulin-like growth factors and IGF gene expression in the fetal brain.

Abstract

Brain growth retardation is a major feature of the fetal alcohol syndrome (FAS). Insulin-like growth factors (IGF-I and IGF-II) have been shown to exert significant metabolic and growth-promoting effects. Previously, we showed that circulating levels of IGF-I as well as hepatic gene expression of both IGFs were decreased in newborn offspring of rats fed ethanol during pregnancy. This study investigated the effects of maternal ethanol ingestion on fetal rat brain growth and on levels of IGF-I and IGF-II, as well as their mRNAs, in fetal brain. IGF-binding protein (IGFBP) levels also were determined. Rats were fed 5% w/v ethanol in a liquid diet during gestation (EF group). Weight-matched animals were pair-fed equicaloric control diet (PF group) or were fed ad libitum (AF group). The mean fetal brain weight of EF offspring was 13% and 16% lower (P < 0.01) than that of PF and AF offspring, respectively. Body weight of EF pups was decreased to a greater extent, resulting in higher brain to body weight ratios in EF pups than in either control group (P < 0.05). IGF-I levels in EF pups decreased by 33% and 41% compared with the corresponding PF and AF values (P < 0.01). IGF-I mRNA levels decreased by 27% and 40% compared with PF and AF values, respectively. A positive correlation was observed between brain IGF-I level and brain weight (r = 0.561, P < 0.01). IGF-II levels were not affected despite a 50% decrease in IGF-II expression. In PF animals, the fetal brain IGF-I and IGF-II mRNA levels were reduced by 28% and 21%, apparently in response to undernutrition. IGF-binding proteins levels were low in the EF group but not statistically significant compared with control values. The diminished fetal brain concentration of IGF-I and decreased gene expression of IGFs may play a role in brain growth retardation associated with FAS.