Translational Studies of Fatty Acid Ethyl Esters (FAEE) in Meconium and Hair as Biomarkers of Prenatal Ethanol Exposure Risk

The development of effective maternal and neonatal screening methods to identify individuals at risk for FASD is essential in addressing this substantially prevalent disorder. FAEE are non-oxidative ethanol metabolites validated as biomarkers of chronic ethanol exposure. This thesis presents a series of studies in animals and humans examining meconium and hair FAEE as measures of fetal exposure, population-health, and maternal ethanol use. Characteristics of meconium FAEE production were examined in guinea pig fetuses chronically exposed to a maternal ethanol dose of 4g/kg/day. Fetuses were sacrificed at three gestational ages (GD45, GD55, GD65) and evaluated for FAEE, hippocampal weight, and hepatic CYP2E1 activity. FAEE above 0.642 nmol/g was 96% sensitive and 100% specific in distinguishing ethanol-exposed fetuses from isocaloric-sucrose pair-fed controls (AUCROC = 0.999). FAEE correlated inversely with hippocampal weight at GD45 (rs = -0.943), GD55 (rs = -0.536) and GD65 (rs = -0.549). FAEE exhibited an inverse correlation with fetal hepatic CYP2E1 activity (rs = -0.799, p = 0.002), suggesting variability in CYP2E1 induction as a possible source of intra-litter variability in FAEE concentrations noted in this animal model and similar differences clinically observed in dizygotic twins. Performance of FAEE as a population screening tool was examined through collection of meconium from 93% of live PEI neonates over a one-year period (n=1307). This study, the first provincial incidence assessment of fetal ethanol exposure conducted in Canada; revealed a 3.1-4.4% incidence, 3-to-4 fold higher than estimates locally reported by the PEI Reproductive Care database. Performance of hair FAEE as a measure of maternal ethanol use was evaluated through examination of FAEE-positive hair samples from 199 female and 73 male subjects. Risk of false-positivity through use of ethanol-containing hair products was identified, however no population-level tendency towards higher FAEE in females was observed. Females exhibited lower concentrations of EtG, an alternative biomarker of consumption. FAEE EtG concordance was higher in males (69.9% vs. 36.2%), with evidence of EtG false-negativity in 26% of individuals with discordant results (n=111). These findings suggest that combined analysis of FAEE and EtG is optimal when assessing a female population through hair analysis.Ph.D