Maternal Nanomaterial Exposures: Fetal Microvascular Endpoints and Programming

描述（由申请方提供）：吸入工程纳米材料（ENM）对母体和胎儿微循环的影响尚不清楚。也不清楚母体吸入ENM所产生的不良妊娠环境是否会产生具有成人疾病和/或ENM敏感性增加的可能性的后代。长期目标是确定ENM的特征，暴露条件和与宿主组织的相互作用机制，从而使心血管风险最小化，从而为公共卫生带来更大的益处。本申请的目的是确定母体ENM暴露如何影响子宫和胎儿健康。其基本原理是，如果纳米技术要充分发挥其在生殖和发育健康方面的潜力，那么必须首先确定ENM的毒性。将在大鼠中完成ENM吸入暴露、活体显微镜检查、离体小动脉、转录组学和表观遗传学的三个具体目标。目的1将确定母体ENM暴露影响子宫微血管功能的机制。假设是母体ENM暴露导致微血管功能障碍，其源于炎症机制，如改变的一氧化氮生物利用度、氧化和亚硝化应激以及增强的白细胞-内皮相互作用。目的2将确定母体ENM暴露影响胎儿微血管功能的机制。假设是，由于胎儿循环在很大程度上受与其他器官相同的原理控制，因此母体ENM暴露导致源于类似机制的胎儿微血管功能障碍。然而，由于胎儿循环在妊娠结束时并不完全活跃和/或整合， 这些改变对微血管反应性的强度应该增加。目的3将确定母体ENM暴露是否改变胎儿转录组和/或表观基因组，并使成人微循环对随后的ENM暴露敏感。假设是，ENM暴露在怀孕期间创造了一个敌对的妊娠环境，改变了胎儿的基因组。这些遗传成分也应该与微血管功能障碍或病理学机制相关，并可能有助于成人疾病和/或ENM敏感性的基础。这项研究在概念上是创新的，因为它从微血管的角度测试了“巴克假说”，这是一系列生理参数和病理的血管系统的主要水平。这一建议在技术上是创新的，因为它将独特而强大的方法集中在一个未经研究的关键需求领域。这项研究直接响应国家纳米技术倡议，对人类健康具有重要意义，因为它通过确定ENM吸入的子宫微血管后果以及确定妊娠期暴露的胎儿后果填补了两个主要的知识空白。拟议的研究在机制上具有重要意义，因为这些微血管后果的根源将被阐明;并且与可用于预防和/或减少与ENM暴露相关的负面健康结果的表观遗传成分相关。

DESCRIPTION (provided by applicant): The effects of engineered nanomaterial (ENM) inhalation on the maternal and fetal microcirculations are unknown. It is also unknown if the hostile gestational environment created by maternal ENM inhalation produces progeny with an increased likelihood of adult disease and/or ENM sensitivity. The long term goal is to identify ENM characteristics, exposure conditions and mechanisms of interactions with host tissues that pose minimal cardiovascular risk for the greater benefit of public health. The objective of this application is to determine how maternal ENM exposure influences uterine and fetal health. The rationale is that if nanotechnology is to reach its full potential in reproductive and developmenta health, then ENM toxicity must first be established. Three specific aims will be completed in rats with ENM inhalation exposure, intravital microscopy, isolated arterioles, transcriptomics and epigenetics. Aim 1 will identify the mechanisms through which maternal ENM exposures influence uterine microvascular function. The hypothesis is that maternal ENM exposure results in microvascular dysfunction stemming from inflammatory mechanisms such as altered nitric oxide bioavailability, oxidative and nitrosative stress, and enhanced leukocyte-endothelium interactions. Aim 2 will identify the mechanisms through which maternal ENM exposures influence fetal microvascular function. The hypothesis is that because the fetal circulation is governed largely by the same principles as other organs, then maternal ENM exposure leads to fetal microvascular dysfunction that stems from similar mechanisms. However, because the fetal circulation is not fully active and/or integrated at the end of gestation, the prevalence and intensity of these alterations on microvascular reactivity should be augmented. Aim 3 will determine if maternal ENM exposure alters the fetal transcriptome and/or epigenome, and sensitizes the adult microcirculation to subsequent ENM exposures. The hypothesis is that ENM exposure during pregnancy creates a hostile gestational environment that alters the fetal genome. These genetic components should also correlate with mechanisms of microvascular dysfunction, or pathology, and may contribute to the basis of adult disease and/or ENM sensitivity. This research is conceptually innovative because it tests the "Barker Hypothesis" from a microvascular perspective, which is the principal level of the vasculature for a host of physiological parameters and pathologies. This proposal is technically innovative because it focuses unique and powerful methodologies on an unstudied area of critical need. This research is directly responsive to the National Nanotechnology Initiative and is significant to human health because it fills two major knowledge gaps by identifying the uterine microvascular consequences of ENM inhalation, and also determining the fetal consequences of gestational exposures. The proposed research is mechanistically significant because the roots of these microvascular consequences will be elucidated; and correlated with an epigenetic component that may be used to prevent and/or diminish negative health outcomes associated with ENM exposures.