Abstract
BackgroundMeconium fatty acid ethyl esters (FAEE) constitute a biomarker of heavy fetal ethanol exposure. Our objective was to measure meconium FAEE in fetal sheep following daily, relatively moderate-dose ethanol exposure in late gestation, and to evaluate their utility in identifying fetal organ-system injury.MethodsPregnant ewes received ethanol (0.75 g/kg; n = 14) or saline (n = 8) via 1-h IV infusion daily during the third trimester equivalent, while additional pregnant sheep served as untreated controls (n = 6). The daily ethanol regimen produced similar maximal maternal and fetal plasma ethanol concentrations of 0.11–0.12 g/dL. Ewes and fetuses were euthanized shortly before term, and meconium was collected and analyzed for FAEE (ethyl palmitate, stearate, linoleate, and oleate).ResultsMeconium total FAEE concentration was significantly higher in ethanol-exposed fetuses compared with controls, and a positive cut-off of 0.0285 nmol total FAEE/g meconium had 93.3% sensitivity and specificity for detecting fetal ethanol exposure. When the studied animals (ethanol-exposed and controls) were classified according to meconium FAEE concentration, FAEE-positive and FAEE-negative groups frequently differed with respect to previously examined pathological endpoints, including nephron endowment, lung collagen deposition, cardiomyocyte maturation, and tropoelastin gene expression in cerebral vessels. Furthermore, in all studied animals as a group (ethanol-exposed and controls combined), meconium FAEE concentration was correlated with many of these pathological endpoints in fetal organs.ConclusionsWe conclude that, in fetal sheep, meconium FAEE could serve as a biomarker of daily ethanol exposure in late gestation and could identify fetuses with subtle ethanol-induced toxic effects in various organs. This study illustrates the potential for using meconium FAEE to identify neonates at risk for dysfunction of major organs following in-utero ethanol exposure that does not result in overt physical signs of ethanol teratogenicity.
Highlights
Alcohol is a well established human teratogen that can result in a range of physical defects, and cognitive and behavioral deficits, known collectively as fetal alcohol spectrum disorders (FASD) [1]
As meconium was collected from these fetuses, our objective was to determine whether meconium fatty acid ethyl esters (FAEE) concentration is a biomarker of repeated fetal exposure to this ethanol regimen in the third-trimester-equivalent of ovine pregnancy
Our results suggest that meconium FAEE concentrations could serve as a biomarker of daily ethanol exposure in late gestation, and could be used to identify fetuses with subtle ethanol-induced multi-organ pathology, thereby supporting the potential utility of meconium testing as a screening tool for the identification of newborns at risk for FASD
Summary
Alcohol (ethanol) is a well established human teratogen that can result in a range of physical defects, and cognitive and behavioral deficits, known collectively as fetal alcohol spectrum disorders (FASD) [1]. The effects of prenatal alcohol exposure can range in severity from mild to debilitating, with the Fetal Alcohol Syndrome (the most severe end of the spectrum) having the principal features of growth restriction, characteristic craniofacial dysmorphology, and central nervous system dysfunction, including intellectual, neurological and behavioural deficits [2,3,4]. Gestational timing of alcohol exposure, as well as maternal and fetal characteristics, contribute to the multiplicity of the FASD phenotype that presents in postnatal life. Since early diagnosis and intervention are associated with improved outcomes and decreased secondary disabilities in individuals with a FASD [9], the development of a reliable biomarker of fetal ethanol exposure is of great clinical importance as it can enable the early recognition of at-risk individuals, timely diagnosis, and implementation of interventions. Our objective was to measure meconium FAEE in fetal sheep following daily, relatively moderate-dose ethanol exposure in late gestation, and to evaluate their utility in identifying fetal organ-system injury
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