Maternal Nanomaterial Exposures: Fetal Microvascular Endpoints and Programming

项目总结/摘要 尽管工程纳米材料（ENM）在广泛应用中无处不在， 预计在人类的努力扩散;产妇ENM吸入对发展中国家的影响， 胎儿及其对未来健康的影响充其量是模糊的。纳米技术的进步，以及“纳米- “使能”的设备具有巨大的潜力，可以成倍地促进人类健康，但他们的未知 对健康的影响仍然是关键的速率限制步骤。到目前为止，研究集中在胎儿的后果， 人工注射的ENM或共孵育的ENM穿过胎盘的能力。这些都未能解决最 相关的健康风险：1）吸入性ENM如何损害健康子宫脉管系统的发育，以及 2)吸入ENM如何损害胎盘发育或损害其功能？我们将定义胎儿 母体ENM暴露对子宫和胎盘血管机制改变的影响 健康ENM气溶胶生成和啮齿动物暴露将在最先进的吸入暴露中进行 这些设施最近进行了重大扩建，以直接满足该项目的独特需求。 目的1：确定母体吸入ENM对子宫微血管健康的影响， 妊娠，并表征功能障碍的潜在机制。我们已经定义了 ENM吸入对微血管健康的影响，在处女子宫，与新的活体显微镜研究。我们现在 将调查扩展到怀孕的各个阶段。我们假设血管生成和血管生成 妊娠启动的机制和刺激快速微血管网生长是 吸入ENM激活肺外介质。目的2：确定产妇ENM的影响 吸入对妊娠期间胎盘健康的影响，并描述 功能障碍胎盘是对胎儿健康/发育至关重要的高度血管化的器官，并且是一种全身性的组织器官。 肺外介质的靶点。第二项新技术，离体灌注胎盘将用于测试 我们的工作假设-母体ENM吸入通过前列腺素和硝酸盐破坏胎盘血管完整性 氧化物介导的机制。目的3：定义持续到 成年期源于母体吸入ENM期间发生的胎儿表观遗传改变， 怀孕我们假设母体吸入ENM造成的不良妊娠环境 产生一种基因型，不仅显示心血管功能受损，而且对 在成年期暴露于外源性物质。项目成果：子宫、 将确定母体ENM暴露后的胎盘和胎儿微血管健康。我们还希望 阐明了促成这些结果的许多主要机制。确定这些关系将有助于 促进以下方面的努力：风险评估、制定接触控制措施和设计安全。整合 这些知识的普及将是推进可持续纳米技术的关键一步。

PROJECT SUMMARY/ABSTRACT Despite the ubiquitous inclusion of engineered nanomaterials (ENM) in widespread applications, and their projected proliferation in human endeavors; the consequences of maternal ENM inhalation on the developing fetus and their impacts on future health are at best, vague. The advancement of nanotechnology, and “nano- enabled” devices holds tremendous potential to advance human health exponentially, yet their unknown health effects remain the critical rate limiting step. To date, studies focus on the fetal consequences of artificially injected ENM or the ability of co-incubated ENM to cross the placenta. These fail to address the most relevant health risks: 1) how do inhaled ENM impair the development of a healthy uterine vasculature, and 2) how do inhaled ENM impair placental development, or compromise its function? We will define the fetal consequences of maternal ENM exposure in terms of altered mechanisms of uterine and placental vascular health. ENM aerosol generation and rodent exposures will be performed in state-of-the-art inhalation exposure facilities that have recently undergone significant expansion to directly meet the unique demands of this project. AIM 1: Determine the impact of maternal ENM inhalation on uterine microvascular health during gestation, and characterize the underlying mechanisms of dysfunction. We have defined the impact of ENM inhalation on microvascular health, in the virgin uterus, with novel intravital microscopy studies. We now expand this investigation to discrete stages of pregnancy. We hypothesize that the vasculogenic and angiogenic mechanisms initiated by pregnancy and stimulate rapid microvascular network growth are susceptible targets of the extrapulmonary mediators activated by ENM inhalation. AIM 2: Identify the impact of maternal ENM inhalation on placental health during gestation and characterize the underlying mechanisms of dysfunction. The placenta is a highly vascularized organ critical to fetal health/development, and is a systemic target of extrapulmonary mediators. A second novel technique, the ex vivo perfused placenta will be used to test our working hypothesis – maternal ENM inhalation disrupts placental vascular integrity via prostanoid and nitric oxide mediated mechanisms. AIM 3: Define the cardiovascular health consequences that persist into adulthood that stem from fetal epigenetic alterations that occur during maternal ENM inhalation during gestation. We hypothesize that the hostile gestational environment created by maternal ENM inhalation produces a genotype that not only displays impaired cardiovascular function, but also elevated sensitivity to xenobiotic exposures in adulthood. Project outcomes: the fundamental relationships between uterine, placental, and fetal microvascular health after maternal ENM exposure will be identified. We also expect to have clarified many of the major mechanisms mediating these outcomes. Identifying these relationships will assist and facilitate efforts towards: risk evaluation, development of exposure controls, and safety by design. The integration of such knowledge will be a critical step in advancing sustainable nanotechnologies.