Influence of Prenatal Folate on Placental mtDNA and Autism Risk

产前叶酸对胎盘 mtDNA 和自闭症风险的影响

• 批准号: 9019993
• 负责人: CECILIA GIULIVI
• 金额: $ 23.51万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9019993
• 关键词: 3 year old; 4 year old; Address; Adverse effects; Affect; Age; Apoptosis; Autistic Disorder; Behavior; Behavior Therapy; Bioenergetics; Biological Markers; Cells; Child; Cohort Studies; Complex; DNA Repair; DNA biosynthesis; Data; Development; Diagnosis; Diagnostic; Diet; Dose; Environment; Environmental Risk Factor; Etiology; Fetal Development; Fetus; First Pregnancy Trimester; Folic Acid; Funding; Genes; Health; High-Risk Pregnancy; Incidence; Intake; Language Delays; Lead; Learning; Life Style; Link; Long-Term Effects; Measurement; Mediating; Mitochondria; Mitochondrial DNA; Morbidity - disease rate; Mothers; Nuclear; Outcome; Oxidative Phosphorylation; Oxidative Stress; Oxygen; Pathway interactions; Perinatal; Placenta; Policies; Pregnancy; Prevention strategy; Problem behavior; Process; Risk; Role; Sampling; Serum; Siblings; Speech; TP53 gene; Therapeutic; Time; United States; United States National Institutes of Health; Uracil; Work; autism spectrum disorder; base; disorder prevention; disorder risk; in utero; insight; mitochondrial dysfunction; neurobehavioral; neurodevelopment; nutrition; peripheral blood; pregnant; prenatal influence; prevent; trophoblast

PROJECT ABSTRACT Autism spectrum disorders (ASD) are a growing concern, with more than 1 in every 68 children affected in the US by the age of eight years. Complex interactions between genes and environmental factors are thought to contribute to ASD risk. Evidence is accumulating for a potentially large role in ASD etiology and/or morbidity for the early in-utero environment, including gestational nutrition. Maternal folic acid is one of the first modifiable factors identified to date with the potential to reduce the risk of ASD by ~40%. In addition to being essential for neurodevelopment, folate is critical for preventing apoptosis, and is involved in nuclear and mitochondrial DNA synthesis and repair. Folic acid is associated with reduced ASD risk at a time in early pregnancy when impaired mitochondrial function may influence processes highly dependent on energy, such as neurodevelopment. In addition, our work was first to show that children with ASD are more likely to have mitochondrial dysfunction (MD), mtDNA overreplication, and mtDNA deletions than typically developing children. To this end, we propose to leverage data and samples from mother-child pairs in a large NIH-funded cohort study to examine protection against mitochondrial abnormalities in placenta samples as a potential pathway for ASD prevention through maternal dietary and supplemental folate intake. Samples will be obtained from the Markers of Autism Risk in Babies: Learning Early Signs (MARBLES) study of >300 mothers who have a child with confirmed ASD and became pregnant with another child, in order to understand what influences the outcome of the younger sibling and to identify early markers of ASD. This is a significant advantage given that samples and data on demographic, lifestyle, health, interpregnancy interval, dietary, and other potentially relevant factors have been prospectively collected in this study since 2006, and children’s developmental assessments and clinically confirmed diagnoses will be available. This project will provide evidence on whether maternal and placental folate affects mitochondrial DNA and function, which then influence the developing child’s neurobehavioral outcomes including ASD. Findings will inform folic acid prevention strategies.

项目摘要 自闭症谱系障碍 (ASD) 日益受到关注，每 68 名儿童中就有超过 1 名受到影响 八岁时到美国。人们认为基因和环境因素之间的复杂相互作用 增加 ASD 风险。越来越多的证据表明 ASD 病因和/或发病率具有潜在的重要作用 用于早期宫内环境，包括妊娠营养。母体叶酸是最重要的之一 迄今为止已确定的可修改因素有可能将自闭症谱系障碍 (ASD) 风险降低约 40%。除了是 叶酸对于神经发育至关重要，对于防止细胞凋亡至关重要，并且参与细胞核和 线粒体DNA的合成和修复。叶酸与早期 ASD 风险降低有关 怀孕时线粒体功能受损可能会影响高度依赖能量的过程，例如 作为神经发育。此外，我们的工作首先表明患有自闭症谱系障碍的儿童更有可能患有自闭症谱系障碍（ASD）。 线粒体功能障碍 (MD)、mtDNA 过度复制和 mtDNA 缺失 孩子们。为此，我们建议利用 NIH 资助的大型母子对的数据和样本 队列研究检查胎盘样本中针对线粒体异常的潜在保护作用 通过母亲饮食和补充叶酸摄入来预防 ASD 的途径。将获得样品 摘自“婴儿自闭症风险标记：学习早期迹象”(MABLES) 研究，对象为超过 300 名患有自闭症的母亲 一名确诊患有自闭症谱系障碍 (ASD) 的孩子并怀上了另一个孩子，以了解影响因素 弟弟妹妹的结果并确定自闭症谱系障碍的早期标志物。这是一个显着的优势 有关人口、生活方式、健康、怀孕间隔、饮食和其他潜在因素的样本和数据 本研究自2006年起前瞻性收集相关因素， 将提供评估和临床确认的诊断。该项目将提供证据证明 母体和胎盘叶酸影响线粒体 DNA 和功能，进而影响发育中的胎儿 儿童的神经行为结果，包括自闭症谱系障碍（ASD）。研究结果将为叶酸预防策略提供信息。