Maternal Nanomaterial Exposures: Fetal Microvascular Endpoints and Programming

描述(申请人提供)：工程纳米材料(ENM)吸入对母体和胎儿微循环的影响尚不清楚。目前也不清楚母亲吸入ENM所造成的恶劣妊娠环境是否会产生后代，从而增加患成人疾病和/或ENM敏感性的可能性。长期目标是确定ENM的特征、暴露条件和与宿主组织相互作用的机制，以最大限度地减少心血管风险，从而更好地造福公众健康。这项应用的目的是确定母体ENM暴露如何影响子宫和胎儿的健康。理由是，如果纳米技术要充分发挥其在生殖和发育方面的潜力，那么必须首先确定ENM的毒性。三个特定的目标将在大鼠身上完成：ENM吸入暴露、活体显微镜、分离的小动脉、转录和表观遗传学。目的1确定母体ENM暴露影响子宫微血管功能的机制。假设母体接触ENM会导致微血管功能障碍，这些功能障碍源于炎症机制，如改变一氧化氮的生物利用度、氧化和亚硝化应激，以及增强白细胞-内皮细胞的相互作用。目的2探讨母体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支配，因此母体接触ENM会导致胎儿微血管功能障碍，这是由类似的机制引起的。然而，由于妊娠结束时胎儿循环不是完全活跃和/或整合的，患病率和 这些改变对微血管反应性的影响应该加强。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。假设是在怀孕期间接触ENM会创造一个恶劣的妊娠环境，从而改变胎儿的基因组。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检验了“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，因为它将独特和强大的方法集中在一个尚未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吸入对子宫微血管的影响，以及确定妊娠暴露的胎儿后果，填补了两个主要知识空白。这项拟议的研究具有重要的机械意义，因为这些微血管后果的根源将被阐明；并与可用于预防和/或减少与ENM暴露相关的负面健康后果的表观遗传学成分相关。

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.