UC Davis

During pregnancy, maternal, placental, and fetal metabolism are highly coordinated to support healthy fetal development, including brain development. Prenatal environmental factors such as endocrine-disrupting chemicals or maternal nutritional status have been linked to increased risk of neurodevelopmental disorders, including autism spectrum disorder (ASD). Maternal, placental, and fetal metabolomics is a valuable tool for understanding both physiological and disrupted metabolism. Further, a growing body of evidence suggests that prenatal metabolic disruption may provide insight into mechanisms underlying ASD risk.

The purpose of this dissertation is to characterize the relationships between maternal, placental, and fetal metabolism; maternal prenatal exposures to endocrine-disrupting chemicals known as phthalates and prenatal vitamin supplements (PNV); and neurodevelopmental outcomes in a prospective birth cohort recruited from families with risk of ASD recurrence. In Chapter 2, investigation of the correlations between the maternal serum, placental, and fetal umbilical cord serum metabolomes revealed that placental and fetal metabolism were highly correlated with each other and with non-typically developing (Non-TD) outcomes. Across all three tissues, 3-hydroxybutyrate was identified as an important metabolite associated with Non-TD risk. In Chapter 3, the relationships between prenatal phthalate exposure, maternal and placental metabolism, and neurodevelopmental outcomes were evaluated. Phthalate exposure was associated with changes in the placental metabolome, including lipid-related metabolites, but these changes were not associated with neurodevelopmental outcomes. In Chapters 4 and 5, the relationships between PNV use in the first month of pregnancy, neurodevelopmental outcomes, and placental and fetal metabolism, respectively, were investigated. PNV use in the first month of pregnancy was associated with placental and fetal amino acid and energy metabolism and these metabolic changes partially explained the relationship between PNV use in the first month of pregnancy and Non-TD risk. Indeed, while the effects of PNV use on the placental metabolome were associated with reduced Non-TD risk, the effects of PNV use on the umbilical cord serum metabolome were associated with increased Non-TD risk.

Across these analyses, three key themes emerged. First, the placental metabolome serves as an important source of information related to neurodevelopment. Second, prenatal disruptions in lipid metabolism appear to be a promising predictor of Non-TD risk. Third, PNV use in the earliest stages of pregnancy exerts programming effects on placental and fetal metabolism that are associated with Non-TD risk and these effects are not entirely protective. These findings support a call-to-action to further investigate and ultimately regulate PNV formulations. This dissertation contributes new information on metabolism in the maternal-placental-fetal unit, the impacts of prenatal environmental exposures, and neurodevelopmental outcomes in a cohort with high-familial ASD risk.