Alcohol-Related Alterations in Placental Imprinted Gene Expression in Humans Mediate Effects of Prenatal Alcohol Exposure on Postnatal Growth

BackgroundA growing body of evidence in animal models has implicated alcohol-induced alterations in epigenetic programming as an important mechanism in fetal alcohol spectrum disorders (FASD). Imprinted genes, a subset of epigenetically regulated genes that are sensitive to the prenatal environment, are chiefly involved in growth and neurobehavior. We tested the hypothesis that alterations in placental imprinted gene expression mediate fetal alcohol growth restriction. MethodsPlacental expression of 109 genes previously shown to be imprinted and expressed in the placenta was assessed using the NanoString nCounter Analysis System in flash-frozen samples from 34 heavy drinkers and 31 control women in Cape Town, South Africa, from whom prospective pregnancy alcohol consumption data had been obtained. Length/height, weight, and head circumference were measured at 6.5 and 12months and at an FASD diagnostic clinic (at ages 1.1 to 4.6years) that we organized. Imprinted gene expression between exposed and control placentas was compared using the limma R package. The relation of alcohol exposure to World Health Organization length-for-age z-scores was examined before and after inclusion of expression for each alcohol-related imprinted gene, using hierarchical mixed regression models with repeated measures. ResultsHeavy drinkers averaged 8 standard drinks on 2 to 3days/wk (vs. 0 for controls). Prenatal alcohol exposure was associated with smaller length/height and weight during the postnatal period. Heavy exposure was related to alterations in expression of 11 of 93 expressed imprinted genes, including increased expression of 5 genes found to be negatively associated with growth and decreased expression of 3 genes positively associated with growth. Alcohol-related alterations in expression of 5 genes statistically mediated the effect of prenatal alcohol exposure on length. ConclusionsThese findings identify alcohol-related alterations in placental imprinted gene expression as potential biomarkers of adverse effect in FASD and suggest that these alterations may play a mechanistic role in fetal alcohol growth restriction. Future studies are needed to determine whether alterations in imprinted gene expression also mediate FASD neurobehavioral deficits and whether such alterations are amenable to intervention. In this prospective longitudinal cohort of 34 heavy drinking mothers and 31 controls, prenatal alcohol exposure (PAE) was related to alterations in placental gene expression of 11 of 93 imprinted genes previously shown to be expressed in the placenta. For 8 of these genes, these alterations statistically mediated the relation of PAE to postnatal growth. These findings suggest that PAE-related alterations in placental imprinted gene expression may play a mechanistic role in FASD and may serve as biomarkers of effect.