Detection of Obesogens and Diabetogens by Zebrafish Screening Models

描述（由申请人提供）：肥胖和与肥胖相关的疾病，如2型糖尿病、高血压和心血管疾病，在过去几十年里在西方国家，尤其是美国急剧增加。这种增长的原因可能是多方面的；其中一个新出现的原因是加速暴露于肥胖或诱发糖尿病的化学物质（致肥物或糖尿病原）。然而，在人类接触的数以万计的工业化学品中，很少有化学品进行了致胖或致糖尿病能力的测试，这主要是由于适当筛选模型的可用性有限。在此，我们建议开发基于斑马鱼的筛选来识别肥胖和糖尿病原，并确定剂量-反应效应和暴露的关键窗口。目的：1)建立基于脂质结合荧光染料的斑马鱼致肥原筛选系统；2)建立基于转基因斑马鱼的斑马鱼糖尿病筛选系统；3)研究致肥原和糖尿病原在斑马鱼体内的作用机制。该项目的预期成果是利用斑马鱼体外（子宫外）、胚胎发育快速和透明以及筛选成本效益的优势，建立中等到高通量的肥胖原和糖尿病原筛选模型。这符合美国国家毒理学计划（NTP）在其“完善传统毒理学分析，开发快速、基于机制的环境诱发疾病预测筛查”的21世纪路线图中所描述的愿景（美国国家毒理学路线图“21世纪国家毒理学计划”；：//ntp.niehs.nih.gov/files/ NTPrdmp.pdf）。我们将确定致肥因子和糖尿病因子，暴露的关键窗口和效应剂量。通过将我们生成的结果和模型纳入国家毒理学控制项目和环境保护局在美国开展的其他化学品筛选活动，并通过与化学品安全领域的其他倡议合作，我们将参与大规模筛选

DESCRIPTION (provided by applicant): Obesity and obesity-related disorders, such as type 2 diabetes, hypertension, and cardiovascular disease, have increased dramatically in Western countries, particularly the United States during the past decades. The reasons for this increase are likely to be multifactorial; one of the suggested emerging causes being the accelerated exposure to obesity or diabetes-inducing chemicals (obesogens or diabetogens). However, out of the tens of thousands of industrial chemicals that humans are exposed to, very few have been tested for obesogenic or diabetogenic capacity, mostly due to the limited availability of appropriate screening models. We here propose to develop zebrafish-based screens to identify obesogens and diabetogens and determine dose-response effects and critical windows of exposure. The aims are 1) To develop the zebrafish obesogen screen based on lipid binding fluorochromes 2) To establish the zebrafish diabetogen screen based on transgenic zebrafish, and 3) To characterize the mechanisms of action of obesogens and diabetogens in zebrafish. The expected outcomes of this project are medium to high throughput models for obesogen and diabetogen screening, taking advantage of the external (ex-utero), rapid and transparent embryonic development as well as cost efficiency of zebrafish screens. This is in line with the vision of the National Toxicology Program (NTP) as described in its 21st Century Roadmap to Achieve the NTP Vision in "refining traditional toxicology assays, developing rapid, mechanism-based predictive screens for environmentally induced diseases" (US National Toxicology Roadmap "A national toxicology program for the 21st century"; ://ntp.niehs.nih.gov/files/ NTPrdmp.pdf). We will identify obesogens and diabetogens, critical windows of exposure and effect doses. By incorporating of our generated results and models into other chemical screening activities in the US, performed by NTP and EPA, and through collaborations with other initiatives taken in the field of chemical safety, we will participate in the large screening effort to prioritize chemicals for further risk assessment. The ultimate impact of this project is o contribute to protection of the population from exposure to obesogens and diabetogens during critical periods in life, which is in line with the overall NIH mission to protect human health through prevention of disease, to protect the developing fetus, and to increase the knowledge of biological effects of environmental contaminants (NIH Mission; ://www.nih.gov/about/mission.htm). In addition, this proposal explores the zebrafish model as a tool for toxicity screening, which is supported by NIH's strong advocacy of zebrafish and other animal model systems for biomedical and behavior research (Henken DB, Rasooly RS, Javois L, Hewitt AT. 2004 National Institutes of Health Trans-NIH Zebrafish Coordinating Committee. The National Institutes of Health and the growth of the zebrafish as an experimental model organism. Zebrafish. 1(2):105-10). !