Detection of Obesogens and Diabetogens by Zebrafish Screening Models

描述(申请人提供)：肥胖和肥胖相关疾病，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，特别是美国急剧增加。这一增长的原因可能是多因素的；建议的新原因之一是加速接触肥胖症或糖尿病致病化学品(肥胖或糖尿病原)。然而，在人类接触的数以万计的工业化学品中，很少有接受过肥胖或糖尿病能力测试的，主要是由于适当的筛查模型有限。我们在这里建议开发基于斑马鱼的筛查来识别肥胖和糖尿病病原体，并确定剂量-反应效应和暴露的临界窗口。本研究的目的是：1)建立基于脂结合荧光蛋白的斑马鱼肥胖原筛选体系；2)建立转基因斑马鱼糖尿病原筛选体系；3)研究肥胖和糖尿病原在斑马鱼中的作用机制。该项目的预期成果是利用斑马鱼筛查的外部(体外)、快速和透明的胚胎发育以及斑马鱼筛查的成本效益，建立中到高通量的肥胖和糖尿病原筛查模型。这与国家毒理学计划(NTP)在其21世纪路线图中所描述的实现NTP愿景的愿景是一致的，该计划的愿景是“完善传统毒理学分析，为环境引起的疾病开发快速、基于机制的预测筛查”(美国国家毒理学路线图“21世纪的国家毒理学计划”；：//ntp.niehs.nih.gov/files/NTPrdmp.pdf)。我们将确定肥胖和糖尿病病因、暴露的临界窗口和影响剂量。通过将我们产生的结果和模型纳入由NTP和EPA执行的美国其他化学品筛查活动，并通过与化学安全领域的其他倡议合作，我们将参与大型筛查 努力确定化学品的优先次序，以便进行进一步的风险评估。该项目的最终影响是帮助保护人口在生命的关键时期免受肥胖和糖尿病原的影响，这符合美国国立卫生研究院通过预防疾病保护人类健康、保护发育中的胎儿以及增加对环境污染物生物影响的知识的总体使命(NIH使命；：//www.nih.gov/About/mission.htm)。此外，这项建议探索斑马鱼模型作为毒性筛选的工具，这得到了美国国立卫生研究院对斑马鱼和其他用于生物医学和行为研究的动物模型系统的大力支持(亨肯DB，Rasooly RS，Jvois L，休伊特AT。2004年美国国立卫生研究院转基因斑马鱼协调委员会。美国国立卫生与生长研究院将斑马鱼作为实验模式生物。斑马鱼。1(2)：105-10)。好了！ 公共卫生相关性：肥胖和肥胖相关疾病，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，特别是美国急剧增加。增加的一个新的原因可能是我们暴露在促进肥胖的工业化学品中。然而，在我们接触到的数万种化学物质中，很少有人接受过它们导致肥胖或糖尿病的能力测试，这主要是因为缺乏筛选这些化合物的模型。在这个项目中，我们将制作一个筛选模型来识别导致肥胖和糖尿病的化学物质。该筛选模型是以斑马鱼为基础的，尽管斑马鱼与人类有明显的差异，但它们在制造和储存脂肪以及产生胰岛素的生物方式上相似。这些模型将用于筛选化学物质，并预测人类接触化学物质的风险。好了！

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). ! PUBLIC HEALTH RELEVANCE: 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. One emerging cause of the increase might be that we are exposed to industrial chemicals that promote obesity. However, out of the tens of thousands of chemicals that we are exposed to, very few have been tested for their capacity to cause obesity or diabetes, largely due to the lack of models to screen these compounds. In this project, we will produce a screening model to identify chemicals that induce obesity and diabetes. The screening model is based upon zebrafish, which, despite their apparent difference to humans, have similar biological ways of making and storing fat, and producing insulin. These models will be used to screen chemicals and to predict the risk of chemical exposure to humans. !