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

氧化应激途径和胎盘病理与自闭症谱系障碍和神经发育相关

• 批准号: 9764475
• 负责人: KRISTEN Lyall
• 金额: $ 18.88万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-16 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9764475
• 关键词: 3-nitrotyrosine; Address; Affect; Age; Antioxidants; Biological Markers; Birth; Blood Vessels; Brain; Cell Death; Cell Respiration; Characteristics; Child; Chorion; DNA; DNA Damage; Data; Defense Mechanisms; Deoxyguanosine; Development; Diagnosis; Enrollment; Equilibrium; Etiology; Fetal Development; Fetal Growth; Fibrin; Formalin; Generations; Glutathione; Glutathione Disulfide; Goals; Growth; Growth and Development function; High-Risk Pregnancy; Histology; Immunohistochemistry; Impaired cognition; Impairment; In Situ Nick-End Labeling; Individual; Intervention; Investigation; Isoprostanes; Knowledge; Late pregnancy; Lead; Learning; Linear Regressions; Link; Lipid Peroxidation; Lipids; Location; Measurement; Measures; Mediating; Mediation; Mediator of activation protein; Methods; Morphology; Mothers; Outcome; Oxidants; Oxidative Stress; Oxidative Stress Pathway; Pathology; Pathway interactions; Phenotype; Placenta; Placentation; Plasma; Predisposition; Pregnancy; Pregnancy Complications; Prevention strategy; Process; Prospective cohort; Proteins; Reactive Oxygen Species; Reduced Glutathione; Risk; Sampling; Social Functioning; Structure; Surface; Thick; Tissue Sample; Tissues; Tyrosine; Umbilical cord structure; Vascularization; Villous; Weight; Woman; Work; antioxidant enzyme; autism spectrum disorder; autistic children; cognitive ability; cohort; density; fetal; fluid flow; high risk; neurodevelopment; novel; offspring; oxidation; oxidative damage; placental morphology; polyunsaturated fat; prenatal; primary outcome; prospective; secondary analysis; social; stress state; theories; trait

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.

氧化应激(OS)可能是自闭症发病的关键机制 谱系障碍(ASD)和不利的神经发育，但支持这一理论的经验证据是 有限，特别是在检查可疑的妊娠易感窗口的预期工作中。操作系统是 已知会对DNA、脂质和蛋白质造成损害，发育中的大脑和胎盘都是 易受这种损害的。像OS一样，胎盘受损被假设与ASD有关，并且是 被怀疑是先前工作中与神经发育不良有关的某些妊娠并发症的基础 结果，但很少有研究提供胎盘样本。操作系统是否会影响认知障碍和 ASD表型，通过DNA或蛋白质损伤、抗氧化剂失衡或脂质途径起作用 过氧化导致胎盘生长和功能异常，目前尚不清楚。拟议的项目将 解决这些知识差距，同时检查每个操作系统中的主要产前操作系统生物标记物 途径，以及可能调节OS效应的胎盘形态和血管测量。我们的 这项研究将包括194对来自早期自闭症风险纵向调查(EARLI)的母子 纳入怀孕早期已生育妇女的高风险妊娠队列 患有自闭症。持续、有效的自闭症相关特征和认知能力测量(由Social 早期学习反应性量表(SRS)和马伦量表，早期学习综合评分(ELC)， 分别)将是我们的主要结果；二次分析也将探索 与ASD诊断的相关性。该项目的具体目标是：1)测量OS生物标志物水平(8- 氧-2‘-脱氧鸟苷(8OHdG)、硝基酪氨酸、8-异前列腺素和氧化还原谷胱甘肽(GSSG 和GSH)在孕妇DNA和妊娠中晚期(平均妊娠27周)血浆样本中，AS OS诱导的DNA损伤、蛋白质氧化、脂质过氧化和OS/抗氧化剂平衡的生物标志物 并用多元线性回归检验与SRS和Mullen ELC评分的相关性。 2)检查胎盘形态测量与a)SRS和ELC评分之间的关系；b)OS 生物标志物和c)根据主效应分析的结果，检查胎盘的形态 在OS-神经发育途径中作为潜在的介体。3)评估胎盘病理 可能受到OS的影响，通过表面血管痕迹和福尔马林固定的胎盘组织样本 确定胎盘的流体流动动力学、网络和血管分支特征，以及细胞死亡。 我们将在与胎盘形态分析平行的分析中检查这些血管测量。 (a-c)。这项工作的结果将为产前OS和胎盘病理学提供独特的证据 与受损的神经发育和社会功能有关，以及这些因素在 潜在的致病途径。