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: 8724501
• 负责人: Timothy R Nurkiewicz
• 金额: $ 29.3万
• 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 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8724501
• 关键词: Address; Adult; Aerosols; Area; Barker Hypothesis; Biological Availability; Blood Circulation; Breathing; Cardiovascular Physiology; Cardiovascular system; Characteristics; Complex; Coronary; Cosmetics; Data; Development; Disease; Endothelium; Engineering; Environment; Epigenetic Process; Event; Exposure to; Failure; Fetal Weight; Fill-It; Food; Future; Gene Expression Profile; Genetic; Genome; Goals; Health; Human; Human Activities; Implantable Infusion Pumps; Inflammatory; Inhalation Exposure; Ischemia; Knowledge; Lead; Leukocytes; Link; Lung; Mediating; Medical Device; Mesentery; Methodology; Microcirculation; Microvascular Dysfunction; Mission; Morbidity - disease rate; Mothers; Nanotechnology; National Institute of Environmental Health Sciences; Nitric Oxide; Organ; Outcome; Oxidative Stress; Particulate Matter; Pathology; Perinatal Exposure; Peroxidases; Physiological; Plant Roots; Pregnancy; Prevalence; Production; Public Health; Rattus; Relative (related person); Research; Skeletal Muscle; Sunscreening Agents; Testing; Tissues; Toxic effect; arteriole; base; biological systems; cardiovascular risk factor; epigenome; experience; fetal; fetal programming; innovation; intravital microscopy; mortality; nano; nanomaterials; nitrosative stress; offspring; pollutant; prevent; programs; public health relevance; reproductive; stem; titanium dioxide; transcriptomics

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.

描述（由申请人提供）：吸入工程纳米材料（ENM）对母体和胎儿微循环的影响尚不清楚。尚不清楚母体吸入 ENM 所产生的恶劣妊娠环境是否会增加后代患成人疾病和/或 ENM 敏感性的可能性。长期目标是确定 ENM 特征、暴露条件以及与宿主组织相互作用的机制，将心血管风险降至最低，从而为公众健康带来更大利益。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。其基本原理是，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、活体显微镜检查、分离小动脉、转录组学和表观遗传学，将在大鼠中完成三个具体目标。目标 1 将确定母体 ENM 暴露影响子宫微血管功能的机制。该假设认为，母体 ENM 暴露会导致微血管功能障碍，其原因是炎症机制，例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。目标 2 将确定母体 ENM 暴露影响胎儿微血管功能的机制。该假设是，由于胎儿循环在很大程度上受与其他器官相同的原理控制，因此母体 ENM 暴露会导致胎儿微血管功能障碍，其源于类似的机制。然而，由于胎儿循环在妊娠末期尚未完全活跃和/或整合，因此患病率和 应增强这些改变对微血管反应性的强度。目标 3 将确定母体 ENM 暴露是否会改变胎儿转录组和/或表观基因组，并使成人微循环对随后的 ENM 暴露敏感。该假设认为，怀孕期间接触 ENM 会产生不利的妊娠环境，从而改变胎儿基因组。这些遗传成分还应与微血管功能障碍或病理学机制相关，并可能有助于成人疾病和/或 ENM 敏感性的基础。这项研究在概念上具有创新性，因为它从微血管的角度测试了“巴克假说”，这是许多生理参数和病理的脉管系统的主要水平。该提案在技术上具有创新性，因为它将独特而强大的方法论集中在未研究的关键需求领域。这项研究直接响应国家纳米技术计划，对人类健康具有重要意义，因为它通过确定 ENM 吸入对子宫微血管的影响以及确定妊娠期暴露对胎儿的影响，填补了两大知识空白。拟议的研究在机制上具有重要意义，因为这些微血管后果的根源将得到阐明。并与可用于预防和/或减少与 ENM 暴露相关的负面健康结果的表观遗传成分相关。