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.