The effects of engineered nanoparticle ingestion on mineral absorption and small

描述（由申请人提供）：肠上皮的主要功能是形成选择性屏障，保护宿主免受有害管腔内容物的影响，同时允许必需营养素、电解质和水进入循环。口腔接触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，纳米颗粒与人类细胞具有独特的反应性。关于口服暴露于纳米颗粒如何影响小肠功能的知识严重缺乏。我们以前的工作表明，口服暴露于聚苯乙烯纳米颗粒会影响铁的吸收。无论是在体外还是在体内，我们发现铁的吸收是 在暴露于生理学相关剂量的50 nm羧化聚苯乙烯纳米颗粒后数小时抑制。这些结果表明，纳米颗粒暴露有意想不到的生理后果，我们的体外结果和体内确认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选。此应用程序的目标是筛选库 目前用于市售食品和食品包装的纳米颗粒，以确定纳米颗粒摄入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）检查食品和食品包装中常见的工程纳米颗粒库，并建立胃肠道体外细胞培养模型，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）吸收。(2)确定纳米颗粒暴露如何影响矿物质转运蛋白基因和蛋白质表达、肠道发育、炎症激活和粘液层成分。本申请中概述的研究将阐明口服纳米颗粒暴露调节肠上皮功能的机制。我们将确定纳米颗粒是否会干扰铁和锌这两种必需矿物质的吸收。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蛋白或刷状缘膜酶的基因或蛋白质表达。我们将确定在生理上现实的剂量下，食品或食品包装中的纳米颗粒暴露是否会导致免疫激活或活性氧的产生。最后，我们将了解纳米颗粒暴露是否会改变肠道的粘液层，这可能会改变矿物质和营养吸收以及GI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.