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

基本信息

批准号：
10005355
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
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-30 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10005355
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 double walled carbon nanotube early life exposure gastrointestinal function in vivo intestinal barrier intestinal maturation male member metabolomics metabolomics resource microbiome nano nanomaterials nanoparticle nanosilver neonatal exposure neonatal period neonate neurobehavioral offspring postnatal postnatal period pregnant pup response sample collection uptake

项目摘要

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.

项目概要本意见书是为了回应 RFA-ES-15-013 而准备的，该文件将建立一个国家研究所环境健康科学 - 纳米技术健康影响研究 (NHIR) 联盟：工程纳米材料（ENM）与生物系统相互作用的综合评价 U01。 NHIR 联盟将合作研究 ENM 与生物之间的相互作用系统提供 ENM 暴露的全面反应概况，以指导良性 ENM 的开发支持纳米技术的安全和可持续利用。该提案的目的是调查联盟选择的 ENM 具有广泛的理化特性，可揭示早期生命 ENM 的作用暴露会影响神经行为和心血管结果并导致生物化学变化。这发育中的新生儿胃肠道功能不成熟，屏障功能正在发育，这可能允许 ENM 的吸收量高于成人。接触化学物质可能会影响发育中的大脑直接和间接。心血管系统也被证明对 ENM 的影响。该项目将包括三个相互关联的调查领域，其目标如下： 1. 体外研究ENMs对肠屏障完整性和通透性的影响。我们将使用 1) 在两个成熟的小肠模型中测试联盟选择的 ENM 肠上皮细胞和杯状细胞，以及2)肠上皮细胞和M细胞。 2. 确定暴露的新生和幼年大鼠的 ENM 组织分布和细胞定位确定神经行为和心血管影响。对 ENM 的生物反应将是对雌性和雄性新生大鼠和幼年大鼠进行研究，从出生后每天口服 ENM (PND) 2-20，并在 PND 4、9 和 21 时安乐死。ENM 组织分布的综合评估，功能性神经行为观察、心血管测量、神经递质测量和非靶向和靶向代谢组学分析（目标 3）将在 PND 4、9 和 21 上进行。 3. 表征血清、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。研究将集中于确定 ENM 如何干扰男性血清、脑组织和盲肠内容物的生化特征和雌性大鼠幼崽。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，并对 188 种化合物进行定量分析，包括酰基肉碱、氨基酸、生物胺、己糖、甘油磷脂、磷脂酰胆碱和鞘脂。