LAUSR

Objectives Prenatal alcohol exposure (PAE) affects 8% of U.S. pregnancies and causes persistent growth and neurodevelopmental deficits diagnosed as fetal alcohol spectrum disorders. Clinical trials using prenatal nutritional interventions can mitigate these neurobehavioral deficits. However, these studies are haphazard, because we do not understand how PAE alters nutrient needs and metabolite flux in the mother-child dyad. To address this knowledge gap, we used untargeted metabolomics to identify biochemical features that are significantly altered by PAE. Methods C57Bl/6J female mice fed AIN93G diet were randomly assigned to receive 3 g/Kg body weight alcohol or isocaloric maltodextrin (MD) by daily gavage from embryonic day (E) E8.5 to E17.5. Metabolite analysis of E17.7 maternal plasma was performed at Metabolon using UPLC-MS/MS. Results We detected 813 metabolites in PAE plasma, 713 known and 100 named metabolites. Of these, 218 metabolites were significantly increased and 25 were decreased compared with control dams (p ≤ 0.05; Welch's two-sample t-test). An additional 63 metabolites trended to increase (43) or decrease (20) in response to PAE (0.05 < p < 0.10). Both Principal Component and hierarchical cluster analyses successfully segregated the plasma samples by treatment, affirming these metabolite profiles could predict PAE. PAE altered multiple pathway signatures. PAE elevated multiple indicators of oxidative stress, such as methionine sulfoxide, S-methylcysteine, and S-methylcysteine sulfoxide, along with metabolites involved in redox homeostasis (cysteine-glutathione disulfide, 2-aminobutyrate, 2-hydroxybutyrate/2-hydroxyisobutyrate and cysteinylglycine disulfide). Conjugated metabolites indicative of enhanced Phase I and Phase II hepatic metabolism including 4-methylcatechol sulfate, 4-acetylphenol sulfate, methyl-4-hydroxybenzoate sulfate, 4-allylphenol sulfate, ethyl glucuronide and 4-ethylphenol glucuronide were also significantly increased. Conclusions The oxidative metabolite signatures identified here are consistent with alcohol's known actions. They may have predictive power as a biomarker signature to identify at-risk pregnancies. Funding Sources NIAAA & UNC-NRI.