Abstract:
Cholesterol plays a pivotal role in many aspects of brain development, such as activation of the sonic hedgehog pathway that regulates the patterning of central nervous system, neurite outgrowth, synaptogenesis, and cell proliferation. All these events are inhibited by ethanol through putative pathways with similar effects as cholesterol depletion on developing brain. In vitro studies have shown that ethanol causes a decrease in total cholesterol in astrocytes, which appears to be due to upregulation of the cholesterol transporters ATP-binding cassette A1 (ABCA1) and ABCG1, resulting in an increase of cholesterol efflux from these cells. The aim of this study was to investigate the effect of prenatal alcohol exposure on ATP cholesterol transporters and cholesterol levels in an in vivo animal model. We hypothesized that, similar to what was observed in in vitro studies, ethanol may upregulate ABC cholesterol transporters in the brains of rat fetuses exposed to ethanol during gestation, which may lead to brain cholesterol depletion. To test this hypothesis, we optimized an in vivo model of in utero alcohol exposure. Pregnant Sprague Dawley rats were fed, from gestational day (GD) 6 to GD 22, with liquid diets containing 37% of the calories from ethanol; the control group consisted of pregnant rats paired to the alcohol-fed rats and fed with an isocaloric diet. Cholesterol levels, as well as ABCA1 and ABCG1 expression were measured in the neocortex of fetuses at GD 22. Blood alcohol concentration in dams consuming the ethanol diet was also determined. We observed a significant increase in ABCG1 protein levels in the neocortex of ethanol-exposed fetuses and a slight decrease in the total cholesterol levels. Surprisingly we did not detect an increase in the expression of ABCA1, although these results are not finalized yet. A significant decrease in fetus bodyweight was observed, in agreement with growth retardation observed in individuals affected by fetal alcohol syndrome. These results suggest that maternal ethanol consumption may affect fetal brain development by interfering with cholesterol homeostasis.