Early life ENM-exposure and the impact on neurobehavioral and cardiovascular outcomes and biochemical mechanisms

生命早期 ENM 暴露及其对神经行为和心血管结果以及生化机制的影响

• 批准号: 9769724
• 负责人: TIMOTHY RAYMOND FENNELL
• 金额: $ 49.9万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769724
• 关键词: Adolescent; Adult; Affect; Amino Acids; Area; Benign; Biochemical; Biochemistry; Biogenic Amines; Biological; Biological Assay; Biological Markers; Brain; Cardiovascular system; Cecum; Cell model; Cells; Chemicals; Control Groups; Data; Development; Dose; Drug Kinetics; Drug or chemical Tissue Distribution; Electrocardiogram; Engineering; Enterocytes; Evaluation; Exposure to; Female; Fetus; Fullerenes; Funding; Glycerophospholipids; Goblet Cells; Grant; Health; Hexoses; Human; Image; In Vitro; Intestinal permeability; Intestines; Investigation; Lactation; Lecithin; Life; M cell; Measurement; Metabolism; Methods; Microscopy; Modeling; Nanotechnology; National Institute of Environmental Health Sciences; Neonatal; Neurologic; Neurotransmitters; Oral; Outcome; Permeability; Physiological; Population Group; Property; Proteome; Rattus; Research; Research Personnel; Resources; Risk; Rodent; Serum; Small Intestines; Sphingolipids; System; Testing; Tight Junctions; Time; Tissues; Transmission Electron Microscopy; United States National Institutes of Health; Weaning; Work; acylcarnitine; biological systems; brain tissue; cytotoxicity; early life exposure; gastrointestinal function; in vivo; male; member; metabolomics; metabolomics resource; microbiome; multi walled carbon nanotube; nano; nanomaterials; nanoparticle; nanosilver; neonatal exposure; neonatal period; neonate; neurobehavioral; offspring; postnatal; postnatal period; pregnant; pup; response; sample collection; uptake

Project Summary This submission is prepared in response to RFA-ES-15-013, which will establish a National Institute of Environmental Health Sciences - Nanotechnology Health Implications Research (NHIR) Consortium: Comprehensive Evaluation of Interactions Between Engineered Nanomaterials (ENMs) and Biological System U01s. The NHIR Consortium will collaborate to investigate the interaction between ENMs and biological systems to provide comprehensive response profiles of ENM exposures to guide development of benign ENMs and support safe and sustainable use of nanotechnology. The aim of this proposal is to investigate Consortium-selected ENMs, with a broad range of physicochemical properties, to reveal how early life ENM exposure impacts neurobehavioral and cardiovascular outcomes and cause changes in biochemistry. The developing neonate has immature gastrointestinal function, with a developing barrier function, that may allow greater uptake of ENMs than in an adult. The developing brain can be impacted by exposure to chemicals both directly and indirectly. The cardiovascular system has also been shown to be particularly sensitive to the effects of ENMs. The project will consist of three inter-related areas of investigation with the following aims: 1. To investigate the impact of ENMs on the integrity and permeability of the intestinal barrier in vitro. We will test the Consortium-selected ENMs in two well-established models of the small intestine using 1) enterocytes and goblet cells, and 2) enterocytes and M cells. 2. To determine the ENM tissue distribution and cellular localization in exposed neonatal and juvenile rats with determination of neurobehavioral and cardiovascular effects. The biological response to ENMs will be studied in female and male neonatal and juvenile rats with daily ENMs administered orally from postnatal day (PND) 2-20, and euthanized at PND 4, 9, and 21. Comprehensive assessment of the ENM tissue distribution, functional neurobehavioral observations, cardiovascular measurements, neurotransmitter measurement, and untargeted and targeted metabolomics analysis (aim 3) will be conducted on PND 4, 9 and 21. 3. To characterize perturbations in biochemical profiles of serum, brain tissue, and cecal contents associated with ENM exposure, and with neurological and cardiovascular assessments. Studies will focus on determining how ENMs perturb the biochemical profiles of the serum, brain tissue, and cecal contents of male and female rat pups. Assessments will include the use of NMR metabolomics, a 16 channel ECD CoulArray to simultaneously quantitate 20 neurotransmitters, and a quantitative assay for 188 compounds including acylcarnitines, amino acids, biogenic amines, hexose, glycerophospholipids, phosphatidylcholines, and sphingolipids.

项目摘要 本呈件是根据RFA-ES-15-013号文件编写的，该文件将建立一个国家 环境健康科学-纳米技术健康影响研究（NHIR）联盟： 工程纳米材料与生物系统相互作用的综合评价 U01 NHIR联盟将合作研究ENM与生物学之间的相互作用。 提供ENM暴露的全面反应概况的系统，以指导良性ENM的开发 并支持安全和可持续地使用纳米技术。这项提案的目的是调查 财团选择的ENM，具有广泛的物理化学性质，以揭示如何早期生活ENM 接触会影响神经行为和心血管结果，并引起生物化学变化。的 发育中的新生儿具有不成熟的胃肠道功能，具有发育中的屏障功能，这可能允许 比成年人摄取更多的ENM。发育中的大脑会受到化学物质的影响 直接和间接的。心血管系统也已被证明是特别敏感的， 的影响。 该项目将包括三个相互关联的调查领域，目标如下： 1.研究ENM对体外肠屏障完整性和通透性的影响。我们 将在两个成熟的小肠模型中测试联合会选择的ENM，使用1） 肠上皮细胞和杯状细胞，以及2）肠上皮细胞和M细胞。 2.确定新生大鼠和幼年大鼠ENM的组织分布和细胞定位 并测定其对神经行为和心血管的影响。对ENM的生物学反应将是 在雌性和雄性新生大鼠和幼龄大鼠中研究，从出生后开始每日经口给予ENM (PND)2-20，并在PND 4、9和21处以安乐死。ENM组织分布的综合评估， 功能性神经行为观察、心血管测量、神经递质测量，以及 将在PND 4、9和21进行非靶向和靶向代谢组学分析（目的3）。 3.描述血清、脑组织和盲肠内容物生化特征的扰动 与ENM暴露以及神经和心血管评估相关。研究将集中在 确定ENM如何干扰雄性小鼠血清、脑组织和盲肠内容物的生化谱， 和雌性幼鼠。评估将包括使用NMR代谢组学，16通道ECD CoulArray， 同时定量20种神经递质，定量测定188种化合物，包括 酰基肉毒碱、氨基酸、生物胺、己糖、甘油磷脂、磷脂酰胆碱和 鞘脂