Metal/Metal Oxide Nanomaterials and Oxidative Stress- Are there Harmful Health Effects in Fish for Environmental Exposures?

纳米技术产业为全球经济带来数十亿美元的价值。然而，在纳米级（至少一个维度小于100 nm的颗粒）下表现出的独特性质（例如表面反应性）以及在这些行业中使用的独特性质可能导致毒性，并且对此有越来越多的实验证据。从机理的角度来看，产生活性氧（ROS）和诱导氧化应激的能力越来越被认为是解释金属/金属氧化物纳米材料[NM]颗粒相关毒性效应的范例。在这个项目中，我们将承担鱼类模型暴露于一些最广泛使用和商业上重要的纳米材料，银（Ag）和氧化铈（CeO 2），并调查环境现实的情况下，以确定潜在的有害健康影响，通过氧化应激。通过使用高浓缩稳定同位素标记的纳米物质，能够在环境水平上检测、量化和分析复杂环境介质和生物体中的纳米物质，先进的成像方法（例如相干反斯托克斯拉曼散射）本研究将建立一种生物传感器斑马鱼模型，该生物传感器具有方便的响应系统，可用于检测氧化应激，应力在斑马鱼模型中，ROS触发亲电反应元件（EpRE）报告基因-通常存在于保护细胞免受氧化损伤的基因的“启动子”（启动子）序列中-这将诱导可通过成像检测到的绿色荧光蛋白（GFP）。遗传方法，以开发这种新的生物传感器鱼已成功地应用于其他污染物的埃克塞特。该模型将能够真实的识别氧化反应的靶组织。转录组学-测量成千上万个基因的反应-将用于确定选定NM暴露的反应（绿色发光）组织中的效应机制（分子途径）。转基因斑马鱼研究的结果将告知NM在天然水中的暴露情况，其中有一种原产于英国河流的鱼类（鲤鱼），以与西南水合作评估慢性健康。将对水中的颗粒进行详细表征，以了解颗粒的命运和行为，并帮助了解它们是否可被鱼类吸收。该项目将建立在跨学科团队的重要跟踪记录和出版物的基础上，汇集广泛的基础设施和技术能力以及行业伙伴关系，以促进对商业上重要的NM在现实环境条件下引起危害的潜力的理解。这项工作将支持北地中海风险评估，以保护淡水水生环境和纳米技术产业的可持续发展。所产生的所有数据将在同行评审的文献、主要期刊上发表，并通过公共论坛和联络小组向利益攸关方（例如公众、监管机构、行业）传播，合作伙伴与这些利益攸关方有着广泛的现有联系。该项目与NERC的生物多样性，自然资源和环境的可持续利用，污染和人类健康的科学主题直接相关，也与EC欧洲水框架指令直接相关-以提高我们对污染和废物的环境风险和危害的理解。该项目还支持NERC的使命的目标，以促进创新，跨学科的高质量研究，涉及到生物系统的理解和利用。

The nanotechnology industry is worth $ billions to the global economy. Unique properties (e.g. surface reactivity) exhibited at the nanoscale (particles with at least one dimension less than 100nm) and exploited for use in these industries, however, can result in toxic properties and there is increasing experimental evidence for this. From a mechanistic perspective the ability to generate reactive oxygen species (ROS) and induce oxidative stress is increasingly being recognized as a paradigm to explain some of the toxic effects related to the particle for metal/metal oxide nanomaterials [NMs]. In this project we will undertake exposures of fish models to some of the most widely used and commercially important NMs, silver (Ag) and cerium oxide (CeO2), and investigate environmentally realistic scenarios to identify potentially harmful health effects via oxidative stress. This work will be enhanced greatly by the ability to detect, quantify and characterise NMs in complex environmental media and organisms at ambient levels, through the use of NMs that are labelled with highly enriched stable isotopes, advanced imaging methods (e.g. Coherent Antistoke Raman Scattering) and the development of a novel biosensor zebrafish model.A biosensor zebrafish will be developed with a convenient response system for detecting oxidative stress. In the zebrafish model, ROS triggers an electrophile responsive element (EpRE) reporter - normally found in the 'starter' (promoter) sequences of genes involved in protecting the cell from oxidative damage - and this will induce a green fluorescent protein (GFP) that can be detected via imaging. The genetic approach to develop this new biosensor fish has been applied successfully at Exeter for other pollutants. The model will enable identification of the target tissues for oxidative responses in real time. Transcriptomics - measuring the responses of many thousands of genes - will be used to identify the effect mechanisms (molecular pathways) in the responsive (green glowing) tissues for selected NM exposures. Findings from the studies with transgenic zebrafish will inform a NM exposure in a natural water with a fish species native to UK rivers (carp) to assess for chronic health in a partnership with South West Water. Detailed characterisation of the particles in the water will be undertaken to inform on particle fate and behaviour and help inform on their availability for uptake into fish. This project will build upon the significant track records and publications of the interdisciplinary team, bringing together extensive infrastructure and technological capability, and industry partnerships, to advance understanding on the potential for commercially important NMs to induce harm under realistic environmental conditions. The work will support NM risk assessment for both protection of the freshwater aquatic environment and sustainable development of the nanotech industry. All data generated will be published in the peer reviewed literature, in leading journals, and disseminated via public fora and liaison groups to stakeholders (e.g. public, regulators, industry), with which the partners have extensive existing links. The project proposed is directly relevant to NERC's science themes for Biodiversity, Sustainable use of natural resources and Environment, Pollution and Human health, and also to the EC European Water framework Directive - to develop our understanding of the environmental risks and hazards of pollution and wastes. The project furthermore supports the objectives of NERC's mission to promote innovative, interdisciplinary high quality research that relates to the understanding and exploitation of biological systems.