Maternal Nanomaterial Exposures: Fetal Microvascular Endpoints and Programming

描述（由申请人提供）：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。同样不清楚的是，母体吸入ENM所造成的不良妊娠环境是否会使后代成年后患病和/或ENM敏感性增加。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，这些机制对心血管风险最小，对公共卫生有更大的好处。本应用的目的是确定母体ENM暴露如何影响子宫和胎儿健康。其理由是，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。通过ENM吸入暴露、活体显微观察、分离小动脉、转录组学和表观遗传学，将完成三个特定目标。目的1将确定母体ENM暴露影响子宫微血管功能的机制。假设母体ENM暴露导致微血管功能障碍，这是由炎症机制引起的，如一氧化氮生物利用度改变、氧化和亚硝化应激以及白细胞-内皮相互作用增强。目的2将确定母体ENM暴露影响胎儿微血管功能的机制。该假说认为，由于胎儿循环在很大程度上与其他器官受相同的原理控制，因此母体ENM暴露导致胎儿微血管功能障碍，其机制类似。然而，由于胎儿循环在妊娠末期没有完全活跃和/或整合，患病率和

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.