Maternal Nanomaterial Exposures: Fetal Microvascular Endpoints and Programming

母体纳米材料暴露：胎儿微血管端点和编程

• 批准号: 9445027
• 负责人: Timothy R Nurkiewicz
• 金额: $ 33.75万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9445027
• 关键词: Address; Adult; Aerosols; Apoptosis; Barker Hypothesis; Blood Circulation; Blood Vessels; Blood flow; Breathing; Cardiac; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Characteristics; Cosmetics; Data; Development; Devices; Diagnostic; Drug Delivery Systems; Electronics; Engineering; Environment; Epigenetic Process; Evaluation; Failure; Fetus; Food; Foundations; Functional disorder; Future; Generations; Genome; Genotype; Goals; Growth; Health; Human; Impairment; Incubated; Industrialization; Inflammation; Inhalation Exposure; Injectable; Injury; Interleukins; Investigation; Ischemia; Knowledge; Leukocyte Trafficking; Life Cycle Stages; Lung; Mediating; Mediator of activation protein; Microcirculation; Microvascular Dysfunction; Morbidity - disease rate; Nanotechnology; Nature; Nitric Oxide; Organ; Outcome; Particulate Matter; Permeability; Placenta; Placentation; Pregnancy; Prevalence; Process; Production; Prostaglandins; Public Health; Rattus; Regulation; Reporting; Research; Risk; Rodent; Safety; Signal Transduction; Techniques; Testing; Tissues; Toxic Environmental Substances; Toxic effect; Uterus; Xenobiotics; arteriole; atherogenesis; building materials; cardiovascular health; clinical application; consumer product; cytokine; design; exposed human population; fetal; implantable device; innovation; intravital microscopy; nano; nanomaterials; nanoparticle; novel; particle; prenatal exposure; product development; programs; pup; rapid growth; reproductive; stem; surface coating; titanium dioxide

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.

项目概要/摘要 尽管工程纳米材料（ENM）在广泛的应用中无处不在，而且它们的 人类活动的预计扩散；母亲吸入 ENM 对发育中的后果 胎儿及其对未来健康的影响充其量是模糊的。纳米技术的进步和“纳米 “启用”设备具有以指数方式促进人类健康的巨大潜力，但它们的未知数 健康影响仍然是关键的速率限制步骤。迄今为止，研究重点是对胎儿的影响 人工注射的 ENM 或共孵育的 ENM 穿过胎盘的能力。这些未能解决大多数问题 相关健康风险：1) 吸入 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？我们来定义胎儿 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 最近进行了重大扩建，以直接满足该项目的独特需求。 目标 1：确定孕产妇吸入 ENM 对子宫微血管健康的影响 妊娠，并描述功能障碍的潜在机制。我们已经定义了影响 通过新颖的活体显微镜研究，吸入 ENM 对处女子宫中微血管健康的影响。我们现在 将这项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 妊娠启动并刺激微血管网络快速生长的机制是易受影响的目标 ENM 吸入激活的肺外介质。目标 2：确定孕产妇 ENM 的影响 妊娠期间吸入对胎盘健康的影响并描述其潜在机制 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，并且是一个全身性的器官。 肺外介质的靶标。第二种新技术，离体灌注胎盘将用于测试 我们的工作假设 – 母体吸入 ENM 通过前列腺素和硝酸破坏胎盘血管的完整性 氧化物介导的机制。目标 3：定义持续存在的心血管健康后果 成年期源于母亲吸入 ENM 期间发生的胎儿表观遗传改变 妊娠。我们假设母亲吸入 ENM 造成的不良妊娠环境 产生的基因型不仅表现出心血管功能受损，而且对 成年期接触外源性物质。项目成果：子宫、 母体 ENM 暴露后的胎盘和胎儿微血管健康状况将得到确定。我们也期望有 澄清了调节这些结果的许多主要机制。识别这些关系将有助于并 促进以下方面的努力：风险评估、暴露控制的制定以及设计安全。整合 这些知识的掌握将是推进可持续纳米技术的关键一步。