Prenatal Extracellular Vesicles and Steroid Hormones as Biological Mechanisms Underlying Gestational Factors Associated with Neurodevelopmental Risk

Project Summary/Abstract The applicant's career goal is to lead a multidisciplinary research program that will investigate a network of perinatal pathways through which maternal, fetal, and placental physiology impacts fetal brain development and risk for neurodevelopmental disorders, including autism spectrum disorder (ASD). The research will implement translational and clinical research approaches to uncover early-emerging biomarkers that may serve as tools for early identification of at-risk children. To effectively establish and lead this research program, intensive training in longitudinal study design, molecular biology, endocrinology, clinical psychology/psychiatry, and statistics is required. The K99 study aims to address a crucial gap by evaluating the independent and interactive effects of prenatal maternal/fetal EVs and maternal/fetal steroid hormones as potential biological mechanisms underlying infant neurobehavioral and social-emotional development. Postnatally, elevated EV- associated protein (EV-AP) levels and upregulation of EV microRNAs (miRNAs) have been observed in individuals with neuropsychiatric conditions including ASD. However, no prior studies have evaluated the relationship between prenatal maternal/fetal EV-AP levels and later child neurodevelopment. It has also been shown that higher levels of the Δ4 steroid hormones (progesterone, 17α-hydroxy-progesterone, androstenedione and testosterone) in amniotic fluid are associated with greater ASD-related behaviors. Therefore, aberrant levels of both EVs and steroid hormones have been implicated in ASD pathophysiology. The proposed K99 study will use biological data (maternal/fetal EVs, maternal/fetal steroid hormones) and data obtained through neurodevelopmental assessments as part of a large, longitudinal pregnancy cohort study to determine the interactive effect of elevated EV-AP levels and elevated levels of the Δ4 steroids on infant neurobehavioral and social-emotional development. Elevated levels of EV-AP and Δ4 steroid hormones have also been observed in women diagnosed with a hypertensive disorder of pregnancy or gestational diabetes mellitus, conditions that are associated with increased neurodevelopmental risk in offspring, suggesting that these biological mechanisms may mediate the neurodevelopment risk associated with these gestational conditions. The R00 study will involve a moderated mediation analysis to evaluate whether the level of EV-APs and Δ4 steroids contributes to the observed association between hypertensive disorders of pregnancy/gestational diabetes mellitus and offspring neurobehavioral and social-emotional development. This approach will elucidate new biological mechanisms underlying neurobehavioral development and may provide important tools to identify children in need of early intervention services.