Fetal-Derived Exosome Cargos in Maternal Blood to Predict Fetal Alcohol Syndrome

Abstract This molecular most is a proposal to use fetal-derived exosomes isolated non-invasively from maternal blood as a source of biomarkers that predict whether an at-risk fetus will be born with fetal alcohol syndrome (FAS), the involved end of the fetal alcohol spectrum disorders ( FASD), or one of the partial forms . Prenatal alcohol exposure is the most common cause of intellectual disability in the US. Other features of FAS include small eyes, face, and brain, as well as neurobehavioral deficits. These syndromes are not readily detected early in pregnancy with available imaging techniques, but early diagnosis could facilitate development of therapeutic interventions. We previously studied banked human fetal brains and eyes at 9-22 weeks' gestation paired with maternal blood samples from pregnancies affected by maternal alcohol use (assessed by self-report) compared with non- exposed controls and demonstrated high correlations between altered expression of several protein, RNA and apoptotic signaling molecular markers and morphometric abnormalities consistent with FAS, such as reduced eye diameter and brain size. The molecular abnormalities were detectable in fetal brain-derived exosomes (FB- E) isolated from the maternal blood. Now, we propose a follow-up clinical study to determine whether these biomarkers will predict the postnatal emergence of FAS/FASD. In collaboration with the Department of OB/GYN and the Section of Neonatology at Temple University Hospital, FB-E will be isolated from maternal blood and analyzed for protein, RNA, and apoptotic markers throughout the pregnancy, and correlated with morphological observations to detect features of FAS/D (small eye globes, small head circumference, longer upper lip, absent philtrum, etc.) in newborn infants, with follow-up pediatric exams for 2 years. We will compare findings in 150 EtOH-exposed pregnancies with 75 unexposed pregnancies, controlling for infant sex, maternal obesity, age, race/socioeconomic status, and tobacco use, and excluding cases in which the mother used other substances of abuse, to determine which biomarkers are most predictive of FAS/FASD in at risk newborns. Pregnant women will fill out a standard survey about their use of alcohol, and cell-type specific (oligodendrocyte, neuronal, microglial, astroglial, synaptic) FB-Es will be isolated from their blood. The molecular contents of these exosomes will be assayed for biomarkers, particularly ones associated with dysmyelination, e.g., MBP, reductions of which showed the most consistent correlation with alcohol-associated reductions in eye diameter in our previous studies. The findings will be correlated with morphological abnormalities characteristic for FAS/D in neonates. If it works in FAS/D, this approach might be useful to predict other disorders of neurological development.