Influence of Particulate Matter on Fetal Mitochondrial Programming

项目摘要 工程纳米材料（ENM）在消费品、制造工艺和临床应用中的分布 尽管我们对诊断对人类健康的影响了解有限，但诊断正在迅速增加。ENM暴露 在胎儿发育过程中尤其令人关注，并且它可以影响以后对病理性损伤的易感性， 生活线粒体在胎儿发育过程中起着重要作用，并受到环境因素的影响 条件，这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，因为它们影响细胞器的蛋白质组组成， 负责其结构、功能和氧化还原平衡。然而，线粒体编程在这种情况下， 的发展被低估。我们的实验室初步观察到， 暴露会导致心脏收缩功能障碍，并破坏发育中的线粒体生物能量学。 胎儿这些影响一直持续到成年。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（m6 A），并且在较小程度上导致胞嘧啶，导致5-甲基胞嘧啶（m5 C）。 在这项拨款申请的初步数据表明，母亲ENM吸入暴露影响胎儿 心脏线粒体编程通过增强氧化剂的产生和线粒体功能障碍，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和线粒体蛋白的丢失。拟议的研究集中在这方面的知识差距 它们旨在确定母体ENM吸入暴露是否会对 线粒体编程在胎儿心脏和未来心脏病理损伤的易感性，通过 氧化剂驱动机制。这些研究解决了这一具体需求，因为它们将确定驱动 母体ENM吸入暴露导致的胎儿线粒体功能障碍以及对 在以后的生活中发生的继发性心脏病理损伤。正在测试的中心假设是， 母体ENM吸入暴露通过氧化剂对胎儿心脏线粒体进行表观遗传学重编程- 驱动机制，导致成年后对继发性心血管损伤的易感性增强。的 本申请的目的是确定母体ENM吸入暴露的影响以及 增强氧化剂清除对（1）胎儿心脏线粒体编程，影响线粒体 结构、功能和氧化还原平衡;（2）胎儿心脏核基因组编码的表观遗传甲基化 编码线粒体蛋白质的mRNA;和（3）对继发性心血管损伤的易感性， 成年这些研究的完成有望提供关于胎儿的基本机制见解 母体暴露模型中的线粒体编程和对未来心脏病变的易感性。

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.