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

描述（申请人提供）：拟议的U19中心将促进RTI研究人员之间的合作，这些研究人员已经开发出合成和表征未标记和均匀碳-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啮齿动物模型中的命运，东卡罗莱纳大学（ECU）由国家环境健康科学研究所资助的实验项目的研究人员，研究碳对心血管和肺的反应。纳米管。RTI和ECU研究人员开发的数据将由Hamner健康科学研究所的科学家用于开发基于生理学的药代动力学/药效学（PBPK/PD）模型，用于评估健康风险。实验数据收集与并行建模将大大增强科学方法的力量，因为模型将作为一个概念框架，以定量预测结构捕获调查人员的知识和直觉。ECU的研究表明，肺部暴露于多壁碳纳米管可以加剧正常健康动物心脏的缺血/再灌注损伤，并且该过程的机制可能是由全身炎症和血管反应性变化驱动的。妊娠和哺乳可能是纳米颗粒对母亲及其后代影响的易感条件，并且血管系统的变化可能导致器官血流的改变，并影响纳米材料如何分布到母亲、胎儿和新生儿的器官。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犬。这些数据引起了对潜在发育影响的担忧;然而，评估这些发现的人类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）和多壁碳纳米管的特性如何影响从心脏，肺和胎盘分离的内皮细胞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、妊娠啮齿动物（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心脏、肺和子宫的血管反应性。此外，我们建议测量炎症（细胞因子），氧化应激（8-羟基脱氧鸟苷），生殖和发育影响（激素和表型锚）的标志物。

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).