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)是一个日益令人担忧的问题，每68名儿童中就有1名以上受到影响 在他八岁的时候，他就来到了美国。基因和环境因素之间复杂的相互作用被认为 增加ASD风险。越来越多的证据表明ASD的病因学和/或发病率中存在潜在的巨大作用 对于早期的宫内环境，包括妊娠营养。母亲的叶酸是最早的 到目前为止，已确定的可修改因素有可能将ASD的风险降低约40%。除了存在之外 叶酸对神经发育至关重要，是防止细胞凋亡的关键，并参与核和 线粒体DNA的合成和修复。叶酸在早期与降低ASD风险有关 当线粒体功能受损时，怀孕可能会影响高度依赖能量的过程，如 作为神经发育。此外，我们的工作首次表明，患有自闭症的儿童更有可能患有 线粒体功能障碍(MD)、线粒体DNA过度复制和线粒体DNA缺失 孩子们。为此，我们建议利用来自美国国立卫生研究院资助的大型母婴配对的数据和样本 检测胎盘样本对线粒体异常的保护作用的队列研究 通过母体饮食和补充叶酸摄入预防自闭症的途径。将获得样本 从婴儿自闭症风险的标记物：对300名患有自闭症的母亲的早期体征(大理石)研究 一名确诊患有自闭症的孩子，并怀上了另一个孩子，以了解是什么影响了 并确定ASD的早期标记物。这是一个显著的优势，因为 关于人口统计、生活方式、健康、解释间隔、饮食和其他潜在因素的样本和数据 本研究自2006年起前瞻性收集了相关因素，并对儿童的发展状况进行了分析。 将提供评估和临床确认的诊断。该项目将提供证据表明 母体和胎盘的叶酸影响线粒体DNA和功能，进而影响发育 儿童的神经行为结果，包括自闭症。研究结果将为叶酸预防策略提供依据。