C60, MWCNTs and the Influence on Cardiovascular, Reproductive, and Developmental

C60、多壁碳纳米管及其对心血管、生殖和发育的影响

• 批准号: 8464701
• 负责人: Harvey Joseph Clewell
• 金额: $ 118.99万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-27 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8464701
• 关键词: 8-hydroxy-2' -deoxyguanosine; Adverse effects; Affect; Alveolar; Animals; Blood Circulation; Blood Pressure; Blood Vessels; Blood flow; Breathing; C14 isotope; Carbon; Carbon Nanotubes; Cardiac Output; Cardiovascular system; Cells; Characteristics; Collaborations; Computer Simulation; Data; Data Collection; Development; Discipline of Nursing; Dose; Drug Kinetics; Endothelial Cells; Epithelial Cells; Evaluation; Excretory function; Exposure to; Female; Fetus; Fostering; Funding; Goals; Health; Health Sciences; Heart; Hormones; Human; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Institutes; Intuition; Investigation; Knowledge; Label; Lactation; Life; Lung; Measurement; Measures; Mediating; Metabolism; Methods; Modeling; Mothers; Mus; National Institute of Environmental Health Sciences; Organ; Oxidative Stress; Particulate; Physiological; Placenta; Pregnancy; Preparation; Process; Production; Property; Rattus; Reaction Time; Reperfusion Injury; Research; Research Personnel; Risk; Rodent; Rodent Model; Route; Scientist; Staging; Structure; Testing; Tissues; Toxic effect; Universities; Uterus; Validation; Vascular Endothelial Cell; absorption; analog; base; cytokine; cytotoxic; design; experience; fullerene C60; in vivo; inflammatory marker; nanomaterials; nanoparticle; neonate; offspring; particle; pharmacodynamic model; pregnant; programs; pup; reproductive; research study; response; uptake

DESCRIPTION (provided by applicant): The proposed U19 Center will foster collaboration between RTI researchers who have developed capabilities to synthesize and characterize unlabeled and uniformly carbon-14 labeled carbon-based nanoparticles and that have investigated the fate of these materials in pregnant and lactating rodent models, with East Carolina University (ECU) researchers who have experimental programs funded by the National Institute of Environmental Health Sciences to investigate the cardiovascular and pulmonary responses of carbon nanotubes. Data developed by RTI and ECU researchers will be used by scientists at The Hamner Institutes for Health Sciences to develop physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) models for assessment of health risks. Experimental data collection with concurrent modeling will greatly enhance the power of the scientific method in that the model will sen/e as a conceptual framework to capture the knowledge and intuitions ofthe investigators in a quantitatively predictive structure. ECU's research demonstrates that pulmonary exposure to MWCNTs can exacerbate an episode of ischemic/reperfusion injury in the heart of normal healthy animals, and that the mechanism underlying this process may be driven by systemic inflammation and changes in vascular reactivity. Pregnancy and lactation may be susceptible conditions with respect to the effects of nanoparticles on the mothers and their offspring, and it is likely that changes in the vasculature can led to alterations in the blood flow to organs and contribute to how nanomaterials distribute to the organs of the mother, fetus, and neonates. Preliminary data developed by RTI demonstrate that carbon-based nanoparticles can transfer from an exposed rodent dam to the fetus and nursing pup. These data raise concerns for potential developmental effects; however, evaluation of the human relevance of these findings requires consideration ofthe physiological differences between rodents and humans. In Project 1, we propose to determine how characteristics of C60 fullerene (C60) and MWCNTs affect cellular uptake, clearance, and responses in endothelial and epithelial cells isolated from the heart, lung, and placenta. In project 2, we propose to determine the PK and absorption, distribution, metabolism, and excretion of these nanoparticles in the female rodent, pregnant rodent (and fetus), and lactating rodent (and neonate), and to determine how exposure affects the vascular reactivity ofthe heart, lung, and uterus. Further, we propose to measure markers of inflammation (cytokines), oxidative stress (8- hydroxydeoxyguanosine), and reproductive and developmental effects (hormones and phenotypic anchors).

描述（由申请人提供）：拟议的 U19 中心将促进 RTI 研究人员之间的合作，这些研究人员已开发出合成和表征未标记和统一碳 14 标记的碳基纳米颗粒的能力，并研究了这些材料在怀孕和哺乳期啮齿动物中的命运模型，与东卡罗来纳大学（ECU）的研究人员合作，他们开展了由国家环境健康科学研究所资助的实验项目，以研究碳纳米管的心血管和肺部反应。哈姆纳健康科学研究所的科学家将使用 RTI 和 ECU 研究人员开发的数据来开发基于生理学的药代动力学/药效学 (PBPK/PD) 模型，以评估健康风险。通过并发建模进行实验数据收集将极大地增强科学方法的力量，因为该模型将被视为概念框架，以定量预测结构捕获研究人员的知识和直觉。 ECU 的研究表明，肺部暴露于多壁碳纳米管会加剧正常健康动物心脏的缺血/再灌注损伤，而这一过程的潜在机制可能是由全身炎症和血管反应性变化驱动的。就纳米颗粒对母亲及其后代的影响而言，怀孕和哺乳期可能是敏感的情况，脉管系统的变化可能会导致流向器官的血流发生变化，并影响纳米材料如何分布到孕妇的器官。母亲、胎儿和新生儿。 RTI 开发的初步数据表明，碳基纳米颗粒可以从暴露的啮齿动物母体转移到胎儿和哺乳期幼崽。这些数据引起了人们对潜在发育影响的担忧；然而，评估这些发现与人类的相关性需要考虑啮齿动物和人类之间的生理差异。在项目 1 中，我们建议确定 C60 富勒烯 (C60) 和 MWCNT 的特性如何影响从心脏、肺和胎盘中分离的内皮和上皮细胞的细胞摄取、清除和反应。在项目2中，我们建议确定这些纳米颗粒在雌性啮齿动物、怀孕啮齿动物（和胎儿）和哺乳啮齿动物（和新生儿）中的PK和吸收、分布、代谢和排泄，并确定暴露如何影响血管心脏、肺和子宫的反应性。此外，我们建议测量炎症标志物（细胞因子）、氧化应激（8-羟基脱氧鸟苷）以及生殖和发育效应（激素和表型锚）。