The effects of engineered nanoparticle ingestion on mineral absorption and small

描述(申请人提供)：肠上皮的主要功能是形成一种选择性屏障，保护宿主免受有害的管腔内容物的影响，同时允许必要的营养、电解质和水进入循环。口腔接触基因工程纳米材料可能会打破这种微妙的平衡。纳米颗粒越来越多地用于食品和食品包装应用，纳米颗粒对人体细胞具有独特的反应能力。目前严重缺乏关于口服暴露于纳米颗粒如何影响小肠功能的知识。我们之前的工作表明，口腔暴露于聚苯乙烯纳米颗粒会影响铁的吸收。在体外和体内，我们都发现铁的吸收是 在暴露于50 nm的生理剂量的羧化聚苯乙烯纳米颗粒几个小时后被抑制。这些结果表明，纳米颗粒暴露有意想不到的生理后果，我们的体外结果与体内验证研究之间的一致性表明，我们的体外肠上皮模型是一个强大的工具。 用于高通量毒理学筛查。这个应用程序的目标是筛选图书馆 对目前在商业食品和食品包装中使用的纳米颗粒进行评估，以确定摄入纳米颗粒对小肠健康和功能的影响。这将通过以下具体目标来实现：(1)利用胃肠道体外细胞培养模型检查食品和食品包装中常见的工程纳米颗粒文库，以确定消化如何改变纳米材料的特性，以及暴露于纳米材料如何影响矿物质(铁和锌)的吸收。(2)确定纳米颗粒暴露对矿物转运蛋白基因和蛋白表达、肠道发育、炎症激活和粘液层组成的影响。在本申请中概述的研究将阐明口服纳米颗粒暴露调节肠道上皮功能的机制。我们将确定纳米颗粒是否会干扰铁和锌这两种基本矿物质的吸收。我们将确定纳米颗粒暴露是否会改变矿物质和营养蛋白转运体或刷状边界膜酶的基因或蛋白质表达。我们将确定从食品或食品包装中暴露出的纳米颗粒在生理上可行的剂量是否会导致免疫激活或活性氧物种的产生。最后，我们将了解接触纳米颗粒是否会改变肠道的粘液层，从而改变矿物质和营养的吸收以及胃肠道的健康和功能。这些有价值的信息对于健康和安全、政策和监管决策是必要的。

DESCRIPTION (provided by applicant): The main function of the intestinal epithelium is to form a selective barrier that protects the host from harmful luminal content while allowing essential nutrients, electrolytes, and water to pass into circulation. Oral exposure to engineered nanomaterials could upset this delicate balance. Nanoparticles are increasingly used in food and food packaging applications and nanoparticles are uniquely reactive with human cells. There is a critical lack of knowledge on how oral exposure to nanoparticles effects small intestinal functionality. Our previous work has shown that oral exposure to polystyrene nanoparticles affects iron absorption. Both in vitro and in vivo, we found that iron absorption was inhibited several hours after exposure to physiologically relevant doses of 50 nm, carboxylated polystyrene nanoparticles. These results demonstrate that there are unexpected physiological consequences to nanoparticle exposure, and the agreement between our in vitro results and in vivo confirmation studies suggests that our in vitro intestinal epithelium model is a powerful tool for high- throughput toxicology screening. The objective of this application is to screen a library of nanoparticles currently used in commercially available food and food packaging to determine the effects of nanoparticle ingestion on small intestinal health and function. This will be accomplished through following specific aims: (1) Examine libraries of engineered nanoparticles commonly found in food and food packaging with an in vitro cell culture model of the GI tract to identify how digestion changes the properties of nanomaterials and how exposure to nanomaterials affects mineral (iron and zinc) absorption. (2) Determine how mineral transporter gene and protein expression, intestinal development, inflammatory activation, and mucus layer composition are affected by nanoparticle exposure. The studies outlined in this application will elucidate the mechanisms by which oral nanoparticle exposure modulates the functionality of the intestinal epithelium. We will determine whether nanoparticles can interfere with the absorption of iron and zinc, two essential minerals. We will establish whether nanoparticle exposure alters gene or protein expression of mineral and nutrient protein transporters or brush border membrane enzymes. We will determine if nanoparticle exposure from food or food packaging at physiologically realistic doses leads to immune activation or reactive oxygen species generation. Finally, we will learn if nanoparticle exposure alters the mucus layer of the gut, which can change mineral and nutrient absorption and GI health and functionality. This valuable information is necessary for health and safety, policy, and regulatory decisions.