Influence of Particulate Matter on Fetal Mitochondrial Programming

颗粒物对胎儿线粒体编程的影响

• 批准号: 10734403
• 负责人: John M Hollander
• 金额: $ 34.2万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-07 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734403
• 关键词: Acute; Address; Adenosine; Adult; Adult Children; Affect; Antioxidants; Applications Grants; Area; Automobile Driving; Bioenergetics; Biomedical Research; Cardiac; Cardiovascular system; Cytosine; Data; Development; Diet; Disease; Engineering; Environmental Impact; Epigenetic Process; Equilibrium; Evaluation; Exhibits; Exposure to; Fetal Development; Fetal Heart; Functional disorder; Future; Genome; Goals; Health; Human; Industrialization; Inhalation Exposure; Knowledge; Laboratories; Life; Link; Maternal Exposure; Messenger RNA; Metabolic syndrome; Methylation; Mission; Mitochondria; Mitochondrial Proteins; Modeling; Myocardial dysfunction; Nanotechnology; Nature; Nuclear; Organ; Organelles; Outcome; Oxidants; Oxidation-Reduction; Particulate Matter; Pathogenesis; Pathologic; Pathology; Play; Predisposition; Production; Proteins; Proteomics; Public Health; Reporting; Research; Risk; Role; Signal Transduction; Structure; Supplementation; Technology; Testing; Transgenic Mice; United States National Institutes of Health; Xenobiotics; biomarker development; burden of illness; clinical diagnostics; consumer product; design; developmental plasticity; epigenetic regulation; experimental study; fetal; hazard; innovation; insight; manufacturing process; mitochondrial dysfunction; mitochondrial messenger RNA; mouse model; nano; nanoengineering; nanomaterials; novel; particle exposure; programs; prophylactic; therapy design; titanium dioxide; ultrafine particle

PROJECT SUMMARY The distribution of engineered nanomaterials (ENM) in consumer products, manufacturing processes and clinical diagnostics is rising rapidly, despite our limited understanding of their impacts on human health. ENM exposure is of particular concern during fetal development and it can influence susceptibility to pathological insults later in life. Mitochondria play an important role in fetal developmental and they can be impacted by environmental conditions, which has led to the novel concept of mitochondrial programming. Epigenetic changes are important determinants of mitochondrial programming, as they influence the organelle's proteomic make-up, which is responsible for its structure, function and redox balance. Nevertheless, mitochondrial programming in the context of development is understudied. Our laboratory made the initial observation that maternal ENM inhalation exposure causes cardiac contractile dysfunction and disruption to mitochondrial bioenergetics in the developing fetus. These effects were sustained into adulthood. We also reported that maternal ENM inhalation exposure increases epigenetic methylation of mRNAs in the fetal heart. MRNA methylation occurs primarily to adenosine leading to N6-methyladenosine (m6A), and to a lesser extent to cytosine, leading to 5-methylcytosine (m5C). The preliminary data in this grant application suggest that maternal ENM inhalation exposure influences fetal cardiac mitochondrial programming by enhancing oxidant production and mitochondrial dysfunction, but it is unclear whether this is mechanistically linked by epigenetic methylation to nuclear genome-encoded mitochondrial mRNAs and loss of mitochondrial proteins. The proposed studies focus on this gap in knowledge and they are designed to determine whether maternal ENM inhalation exposure negatively influences mitochondrial programming in the fetal heart and the susceptibility to future cardiac pathological insult, through an oxidant driven mechanism. The studies address this specific need, as they will identify mechanisms driving fetal mitochondrial dysfunction resulting from maternal ENM inhalation exposure as well as the susceptibility to a secondary cardiac pathological insult that occurs later in life. The central hypothesis being tested is that maternal ENM inhalation exposure epigenetically reprograms fetal cardiac mitochondria through an oxidant- driven mechanism that results in enhanced susceptibility to a secondary cardiovascular insult at adulthood. The objectives of this application are to determine the influence of maternal ENM inhalation exposure and the impact of enhanced oxidant scavenging on (1) fetal cardiac mitochondrial programming that influence mitochondrial structure, function and redox balance; (2) fetal cardiac epigenetic methylation of nuclear genome-encoded mRNAs that encode for mitochondrial proteins; and (3) the susceptibility to a secondary cardiovascular insult at adulthood. Completion of these studies is expected to provide fundamental mechanistic insight regarding fetal mitochondrial programming in maternal exposure models and the susceptibility to future cardiac pathologies.

项目摘要 工程纳米材料（ENM）在消费产品，制造过程和临床上的分布 尽管我们对它们对人类健康的影响有限，但诊断迅速迅速增加。 ENM暴露 在胎儿发育期间特别关注，它会影响后来对病理侮辱的敏感性 生活。线粒体在胎儿发育中起重要作用，它们可能受到环境的影响 条件，导致了线粒体编程的新概念。表观遗传变化很重要 线粒体编程的决定因素，因为它们会影响细胞器的蛋白质组学化妆，这是 负责其结构，功能和氧化还原平衡。但是，线粒体在上下文中 发展的研究不足。我们的实验室最初的观察结果是母体吸入 暴露会导致心脏收缩功能障碍和发育中线粒体生物能的破坏 胎儿。这些影响持续到成年。我们还报道了母体ENM吸入暴露 增加胎儿心脏中mRNA的表观遗传甲基化。 mRNA甲基化主要发生在腺苷 导致N6-甲基腺苷（M6A），并在较小程度上导致胞嘧啶，导致5-甲基胞嘧啶（M5C）。 本赠款应用中的初步数据表明，母体ENM吸入暴露会影响胎儿 通过增强氧化剂的产生和线粒体功能障碍，心脏线粒体编程，但它是 尚不清楚这是否是通过表观遗传甲基化与核基因组编码的 线粒体mRNA和线粒体蛋白的丧失。拟议的研究重点是知识的差距 它们旨在确定母体ENM吸入暴露是否会对影响负面影响 胎儿心脏中的线粒体编程以及对未来心脏病理侮辱的敏感性， 氧化剂驱动的机制。研究满足了这一特定需求，因为它们将确定驱动机制 胎儿线粒体功能障碍，导致母体吸入暴露以及对 次生心脏病理侮辱，发生在以后的生活中。测试的中心假设是 母体ENM吸入暴露在表观上重新编程胎儿心脏线粒体通过氧化剂 - 驱动机制，导致对成年后继发性心血管侮辱的敏感性增强。这 本应用的目标是确定母体ENM吸入暴露的影响和影响 （1）胎儿心脏线粒体编程的增强的氧化剂清除 结构，功能和氧化还原平衡； （2）核基因组编码的胎儿心脏表观遗传甲基化 编码线粒体蛋白的mRNA； （3）对继发性心血管侮辱的敏感性 成年。这些研究的完成预计将提供有关胎儿的基本机械洞察力 孕产妇暴露模型中的线粒体编程以及对未来心脏病理的敏感性。