Chronic gestational exposure to ethanol causes insulin and insulin‐like growth factor resistance in the developing brain: link to impaired acetylcholine biosynthesis

Abstract

In an experimental model of fetal alcohol syndrome (FAS), cerebellar hypoplasia was found to be associated with increased apoptosis and impaired insulin-stimulated survival signaling. However, little is known about the effects produced following lower levels of ethanol exposure. This study characterizes the dose-effects of chronic gestational ethanol exposure on cerebellar development and the expression of genes required for insulin and insulin-like growth factor signaling, and also examines upstream mechanisms and downstream consequences of ethanol-impaired insulin and IGF signaling in relation to acetylcholine biosynthesis. Pregnant Long-Evans rats were fed isocaloric liquid diets in which ethanol comprised 0%, 8%, 18%, 26%, or 35.4% of the caloric content beginning on gestation day 6 and continuing throughout pregnancy. After examination of the rat pup cerebella (P0), the results demonstrated ethanol dose-dependent increases in the degree of cerebellar hypoplasia, DNA damage, and neuronal cell loss. In addition, ethanol dose-dependent reductions in brain insulin and choline acetyltransferase (ChAT) expression, and increased expression of acetylcholinesterase were observed. Despite normal receptor expression levels, ligand binding to insulin and IGF receptors was significantly reduced. Further studies linked the ethanol-impaired receptor binding and stimulation of ChAT to reduced membrane cholesterol content. In conclusion, FAS associated cerebellar hypoplasia is correlated with impaired neuronal cell survival and decreased levels of ChAT expression, mediated by pathological alterations in membrane lipid composition that result in impaired ligand-receptor binding.