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: 10246378
• 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/10246378
• 关键词: Address; Adult; Aerosols; Apoptosis; Barker Hypothesis; Blood Circulation; Blood Vessels; Blood flow; Cardiac; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Characteristics; Cosmetics; Data; Development; Devices; Diagnostic; Drug Delivery Systems; Electronics; Engineering; Environment; Epigenetic Process; Evaluation; Exposure to; Failure; Fetal Development; Fetal health; Fetus; Food; Foundations; Functional disorder; Future; Generations; Genome; Genotype; Goals; Growth; Health; Human; Impairment; Incubated; Industrialization; Inflammation; Inhalation; Inhalation Exposure; 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; cardioprotection; 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.

项目摘要/摘要 尽管无处不在的纳米材料（ENM）在宽度应用中及其及其 预计人类努力的扩散；产妇吸入对发展的后果 胎儿及其对未来健康的影响充其量是投票。纳米技术的进步和“纳米 - 启用”设备具有巨大的潜力，可以呈指数级进步，但他们的未知 健康效应仍然是关键限制步骤。迄今为止，研究重点是 人为地注射ENM或共孵育ENM越过plapeta的能力。这些无法解决 相关的健康风险：1）纳入ENM如何损害健康的子宫脉管系统的发展，以及 2）吸入的ENM如何损害位置的发育或损害其功能？我们将定义胎儿 孕产妇ENM暴露于子宫和斑点血管的改变方面 健康。 ENM气溶胶产生和啮齿动物暴露将在最新的吸入暴露中进行 最近经历了重大扩展的设施，可以直接满足该项目的独特需求。 目标1：确定母体ENM吸入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 对维生子宫中的微血管健康吸入的ENM吸入，并通过新颖的插入式显微镜研究。我们现在 将这项投资扩展到妊娠的离散阶段。我们假设血管生成和血管生成 怀孕和刺激快速微血管网络生长引发的机制是易感目标 通过ENM吸入激活的肺外介体。目标2：确定母体ENM的影响 妊娠期间对占地健康的吸入并表征了的基本机制 功能障碍。 lopeta是一种高度血管化的有机物，对胎儿健康/发育至关重要，并且是一种系统性的 肺外介体的目标。第二种新颖的技术，将使用体内灌注的placeta测试 我们的工作假设 - 母体ENM吸入通过前列腺素和硝酸 氧化物介导的机制。目标3：定义持续到的心血管健康后果 源于在母校吸入期间发生的胎儿表观遗传改变的成年 妊娠。我们假设物物ENM吸入创造的敌对妊娠环境 产生的基因型不仅显示出心血管功能受损，而且对 成年后的异种生物暴露。项目成果：子宫之间的基本关系， 将确定胎盘和胎儿微血管健康。我们也希望有 阐明了许多介导这些结果的主要机制。确定这些关系将有助于 促进努力：风险评估，曝光控制的发展以及设计安全性。整合 这种知识将是促进可持续纳米技术的关键一步。

项目成果

Reactive oxygen species damage drives cardiac and mitochondrial dysfunction following acute nano-titanium dioxide inhalation exposure.

• DOI: 10.1080/17435390.2017.1416202
• 发表时间: 2018-03
• 期刊: Nanotoxicology
• 影响因子: 5
• 作者: Nichols CE;Shepherd DL;Hathaway QA;Durr AJ;Thapa D;Abukabda A;Yi J;Nurkiewicz TR;Hollander JM
• 通讯作者: Hollander JM

Xenobiotic pulmonary exposure and systemic cardiovascular response via neurological links.

• DOI: 10.1152/ajpheart.00546.2015
• 发表时间: 2015-11
• 期刊: American journal of physiology. Heart and circulatory physiology
• 作者: P. Stapleton;A. Abukabda;S. Hardy;T. Nurkiewicz

Nanoparticle inhalation impairs coronary microvascular reactivity via a local reactive oxygen species-dependent mechanism.

• DOI: 10.1007/s12012-009-9060-4
• 发表时间: 2010-03
• 期刊: CARDIOVASCULAR TOXICOLOGY
• 影响因子: 3.2
• 作者: LeBlanc, A. J.;Moseley, A. M.;Chen, B. T.;Frazer, D.;Castranova, V.;Nurkiewicz, T. R.
• 通讯作者: Nurkiewicz, T. R.

Vascular distribution of nanomaterials.

纳米材料的血管分布。

• DOI: 10.1002/wnan.1271
• 发表时间: 2014
• 期刊: Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology
• 作者: Stapleton,PhoebeA;Nurkiewicz,TimothyR
• 通讯作者: Nurkiewicz,TimothyR

Characterization of chemical contaminants generated by a desktop fused deposition modeling 3-dimensional Printer.

• DOI: 10.1080/15459624.2017.1302589
• 发表时间: 2017-07
• 期刊: Journal of occupational and environmental hygiene
• 影响因子: 2
• 作者: Stefaniak AB;LeBouf RF;Yi J;Ham J;Nurkewicz T;Schwegler-Berry DE;Chen BT;Wells JR;Duling MG;Lawrence RB;Martin SB Jr;Johnson AR;Virji MA
• 通讯作者: Virji MA