Oxidative stress pathways and placental pathology in association with autism spectrum disorder and neurodevelopment

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It has been hypothesized that oxidative stress (OS) may be a key mechanism involved in the etiology of autism spectrum disorder (ASD) and adverse neurodevelopment, but empirical evidence supporting this theory is limited, particularly in prospective work examining the suspected susceptibility window of gestation. OS is known to cause damage to DNA, lipids, and proteins, and both the developing brain and placenta are susceptible to such damage. Like OS, impaired placentation has been hypothesized to relate to ASD, and is suspected to underlie certain pregnancy complications linked in prior work to adverse neurodevelopmental outcomes, but few studies have placental samples available. Whether OS impacts cognitive impairment and ASD phenotype, acting through pathways of DNA or protein damage, antioxidant imbalance, or lipid peroxidation leading to aberrations in placental growth and functioning, is not known. The proposed project will address these knowledge gaps, concurrently examining main prenatal OS biomarkers in each of these OS pathways, as well as placental morphology and vascularity measures that may mediate OS effects. Our study will include 194 mother-child pairs from the Early Autism Risk Longitudinal Investigation (EARLI), an enriched-risk pregnancy cohort that enrolls women early in pregnancy who have already given birth to a child with ASD. Continuous, validated measures of ASD-related traits and cognitive ability (measured by the Social Responsiveness Scale (SRS) and Mullen Scales of Early Learning, Early Learning Composite (ELC) score, respectively) measured at 36 months will be our primary outcomes; secondary analysis will also explore associations with ASD diagnoses. The specific goals of this project are to: 1) Measure OS biomarker levels (8- Oxo-2'-deoxyguanosine (8OHdG), nitrotyrosine, 8-isoprostane, and oxidized and reduced glutathione (GSSG and GSH) in maternal DNA and mid to late pregnancy (mean of 27 weeks gestation) plasma samples, as biomarkers of OS-induced DNA damage, protein oxidation, lipid peroxidation, and OS/antioxidant balance respectively, and examine associations with SRS and Mullen ELC scores using multivariable linear regression. 2) Examine associations between placental morphology measures and a) SRS and ELC scores; b) the OS biomarkers and c) conditional on results of the main effects analyses, examine the placental morphology measures as a potential mediator in the OS-neurodevelopment pathway. 3) Assess placental pathology that may be impacted by OS, through surface vasculature tracings and formalin-fixed placental tissue samples to determine fluid flow dynamics, network and vascular branching characteristics, and cell death in the placenta. We will examine these vasculature measures in analyses parallel to those conducted for placental morphology (a-c). Results from this work will provide unique evidence as to whether prenatal OS and placental pathology are involved in impaired neurodevelopment and social functioning, as well as how these factors may relate in potential etiologic pathways.