Maternal Nanomaterial Exposures: Fetal Microvascular Endpoints and Programming

项目摘要/摘要 尽管工程纳米材料(ENM)在广泛的应用中无处不在，而且他们的 人类活动中预计的扩散；母体吸入ENM对发育的影响 胎儿及其对未来健康的影响充其量也是含糊其辞的。纳米技术的进步，以及“纳米-- “使能的”设备具有极大的潜力，可以指数级地提高人类健康，但它们的未知 健康影响仍然是关键的比率限制步骤。到目前为止，研究的重点是胎儿的后果 人工注射ENM或共同孵化的ENM能够穿过胎盘。这些措施未能解决大多数问题 相关的健康风险：1)吸入ENM如何损害健康子宫血管的发育，以及 2)吸入ENM如何损害胎盘发育或损害其功能？我们会给胎儿下定义 母体接触ENM对子宫和胎盘血管机制改变的影响 健康。ENM气溶胶的产生和啮齿动物的暴露将在最先进的吸入暴露中进行 最近进行了重大扩建的设施，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，并描述了功能障碍的潜在机制。我们已经定义了 ENM吸入对处女子宫微血管健康的影响，以及新的活体显微镜研究。我们现在 将这项调查扩展到不同的怀孕阶段。我们假设血管生成和血管生成 妊娠启动的机制和刺激微血管网络的快速生长是 ENM吸入可激活肺外介质。目标2：确定母体新陈代谢的影响 吸入对妊娠期胎盘健康的影响及其潜在机制 功能障碍。胎盘是一个高度血管化的器官，对胎儿的健康/发育至关重要，是一个全身性的器官。 肺外介质的目标。另一项新技术，体外灌流胎盘将用于测试 我们的工作假说--母体吸入ENM通过前列腺素和一氧化氮破坏胎盘血管完整性 氧化物介导的机制。目标3：确定持续存在的心血管健康后果 成年期源于母体吸入ENM期间发生的胎儿表观遗传学变化 怀孕了。我们假设母体吸入新诺明所造成的不良妊娠环境 产生一种不仅表现出心血管功能受损，而且对 成年后的异种生物暴露。项目成果：子宫、 孕妇接触ENM后的胎盘和胎儿微血管健康状况将得到确认。我们还希望有 阐明了调解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、暴露控制的发展和设计安全。整合 这类知识的传播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.