Effect of exposure to organochlorine compounds on the development of obesity and

接触有机氯化合物对肥胖和肥胖发展的影响

• 批准号: 8145554
• 负责人: George E Howell
• 金额: $ 5.14万
• 依托单位: MISSISSIPPI STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-21 至 2011-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8145554
• 关键词: Academia; Adipocytes; Adipose tissue; Adult; Affect; Agriculture; American; Animal Model; Animals; Award; Binding; Blood; Body mass index; Cell Culture Techniques; Centers for Disease Control and Prevention (U.S.); Chlorinated Hydrocarbons; Cholesterol; Data; Development; Development Plans; Diabetes Mellitus; Diagnosis; Dichlorodiphenyl Dichloroethylene; Diet; Dioxins; Disease; Drug Formulations; Dyslipidemias; Educational process of instructing; Environmental Health; Environmental Pollution; Epidemic; Epidemiologic Studies; Epidemiology; Etiology; Exercise; Experimental Models; Exposure to; Faculty; Fatty acid glycerol esters; Fellowship; Functional disorder; Gene Expression Regulation; Genes; Genetic Predisposition to Disease; Glucose Transporter; Goals; Health; Health Sciences; Healthcare Systems; Human; Hyperglycemia; Hypertension; In Vitro; Insulin; Insulin Resistance; Interleukin-6; Knowledge; Learning; Leptin; Light; Link; Literature; Mediating; Mentors; Metabolic syndrome; Methods; Mississippi; Modeling; Molecular; Mus; Muscle Fibers; National Health and Nutrition Examination Survey; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity associated disease; Overweight; PPAR gamma; Pharmacology; Pharmacology and Toxicology; Phosphorylation; Plasma; Population; Positioning Attribute; Precipitation; Prevalence; Process; Production; Protein Family; Publications; Rattus; Research; Research Personnel; Research Project Grants; Risk Factors; Rodent Model; Role; Serum; Site; Skeletal Muscle; Societies; Southeastern United States; Techniques; Tennessee; Testing; Tissues; Toxic Actions; Toxicology; Training; United States; Universities; Work; adipocyte differentiation; adipokines; aryldialkylphosphatase; base; bioaccumulation; body system; cardiovascular disorder risk; career; career development; cytokine; diabetic; enhancer binding protein; environmental toxicology; experience; feeding; glucose disposal; glucose uptake; graduate student; in vivo; insulin receptor substrate 1 protein; insulin signaling; lectures; lipid biosynthesis; meetings; member; organochlorine exposure; oxychlordane; pesticide exposure; pollutant; professor; programs; public health relevance; skeletal; skills; stem; transcription factor

DESCRIPTION (provided by applicant): This application proposes a mentoring period of five years that will allow Dr. Howell to make a transition from his basic pharmacology background to the field of environmental toxicology. Dr. Howell joined the Center for Environmental Health Sciences (CEHS) at Mississippi State University in February of 2009 as a non-tenure track assistant research professor. His postdoctoral research at the University of Tennessee Health Sciences Center was on molecular mechanisms of dyslipidemia in hyperinsulinemic states such as type 2 diabetes (T2D). Our current research within the CEHS is examining the relationship between pesticide exposure and cardiovascular disease risk, including paraoxonase activity, in varied subsets of the human population. However, we are also examining the relationship between exposures to persistent organic pollutants, namely the organochlorine compounds, and the occurrence of T2D in these subsets. Thus, Dr. Howell's background in molecular mechanisms of insulin resistance and dyslipidemia provide a basic mechanisms approach to our current human studies. Although Dr. Howell's doctoral degree is in pharmacology and toxicology, his graduate program and postdoctoral fellowship were pharmacologically based and did not provide him with the working knowledge of toxicological mechanisms and concepts that will allow him to excel in a tenure-track faculty position within the CEHS. It is Dr. Howell's long term goal to obtain a tenure track faculty position within the CEHS here at Mississippi State University where he can be a successful researcher and academic professor. To assist Dr. Howell in making his transition, we have outlined a career development/training plan and a research plan that will allow him to obtain the necessary training in toxicological concepts and methods, enhance his competitiveness as a researcher, and establish his own independent line of research. In order to acquire the needed knowledge of toxicological mechanisms and concepts, Dr. Howell will attend the following graduate level courses in the first two years of this award: (CVM 6513) Environmental Toxicology and (CVM 8543) Mechanisms of Toxic Action. Through completion of these two courses, Dr. Howell will gain a working knowledge of the classes of environmental contaminants and how they affect target organ systems. In addition to didactic lecture, Dr. Howell will become a member of the Society of Toxicology and present his research findings at both regional and national toxicology meetings each year. This will allow Dr. Howell to enhance his presentation skills and network within the toxicology field while he learns where the current emphasis is, what work is being done, and how he can apply this to his research. Over the course of this award, Dr. Howell will also be collaborating with the other investigators within the CEHS, especially his mentor Dr. Jan Chambers, on their current research so that he can gain different experimental perspectives as well as enhance his publication record. To prepare Dr. Howell for the transition to a tenure track position, he will provide guest lectures in our graduate student classes during the last three years of this award where he will be responsible for the formulation of his lectures as well as for testing on his material. In addition to lecturing, Dr. Howell will serve on applicable graduate student committees and help guide their research projects. This will allow him to gain experience in the teaching aspect of academia. To establish his own independent line of research, Dr. Howell will be examining the effect of exposure to organochlorine compounds on the development of obesity and T2D. While there is emerging epidemiological evidence that demonstrates a high association between blood levels of organochlorine compounds, namely oxychlordane and/or DDE, and the occurrence of T2D, there is very little empirical evidence to show causality. Therefore, the current research plan will utilize both in vitro cell culture models of insulin sensitive tissues and an in vivo rodent model to determine if exposure to either oxychlordane or DDE decreases insulin signaling, glucose uptake, and production of adipokines/cytokines that can promote insulin resistance. The current preliminary data indicate that exposure to DDE decreases adipogenesis while increasing the release of leptin and interleukin-6 from adipocytes. Thus, the effect of DDE and oxychlordane exposure on expression and function of adipogenic genes will be explored and the effect of bioaccumulation of both DDE and oxychlordane on adipokine/cytokine expression will be assessed. The effect of exposure to OC compounds on insulin signaling in the skeletal muscle has not been delineated. The current preliminary data indicate that exposure to oxychlordane or DDE decreases insulin stimulated glucose transporter 4 (Glut4) translocation in rat skeletal muscle cells. To more closely examine this observation, the effect of exposure to these two compounds on glucose uptake, Glut4 translocation, and insulin signaling in the skeletal muscle cell and the adipocyte will be explored in vitro. In order to determine if there is a causative relationship between environmentally relevant exposure to DDE and the occurrence of T2D, a high fat diet induced model of T2D (high fat fed C57BL/6J mice) will be employed to determine if this exposure causes or worsens the diabetic state of these animals. Taken together, the currently proposed research will determine whether exposure to DDE facilitates insulin resistance and T2D in the whole animal and will provide mechanistic incite from both target tissues and the whole animal. PUBLIC HEALTH RELEVANCE: The presently proposal seeks to prepare the applicant, George Howell, for an independent research career at Mississippi State University as a tenure-track professor. This proposal outlines a career development plan that will be overseen by his mentor, Jan Chambers, as well as a research plan that will examine the effect of exposure to organochlorine compounds on the development of insulin resistance and T2D. This research will determine if exposure to these compounds is a risk factor for development of T2D and if so will provide mechanisms through which these compounds precipitate this disease.

描述（由申请人提供）：这份申请提出了一个为期五年的指导期，这将允许Dr. Howell从他的基本药理学背景过渡到环境毒理学领域。Howell博士于2009年2月加入密西西比州立大学环境健康科学中心（CEHS），担任非终身助理研究教授。他在田纳西大学健康科学中心的博士后研究是关于高胰岛素状态（如2型糖尿病）血脂异常的分子机制。我们目前在CEHS内的研究正在检查农药暴露与心血管疾病风险之间的关系，包括对氧磷酶活性，在不同的人群中。然而，我们也在研究暴露于持久性有机污染物（即有机氯化合物）与这些亚群中T2D发生之间的关系。因此，Howell博士在胰岛素抵抗和血脂异常分子机制方面的背景为我们目前的人类研究提供了基本的机制方法。虽然Howell博士的博士学位是药理学和毒理学，但他的研究生课程和博士后奖学金是基于药理学的，并没有为他提供毒理学机制和概念的工作知识，这将使他在CEHS的终身教职中脱颖而出。Howell博士的长期目标是获得密西西比州立大学CEHS的终身教职在那里他可以成为一名成功的研究员和学术教授。为了帮助Howell博士完成他的过渡，我们概述了一个职业发展/培训计划和一个研究计划，这将使他能够获得毒理学概念和方法的必要培训，增强他作为研究人员的竞争力，并建立自己的独立研究线。为了获得毒理学机制和概念所需的知识，Howell博士将在该奖项的前两年参加以下研究生水平的课程：（CVM 6513）环境毒理学和（CVM 8543）毒性作用机制。通过完成这两门课程，Howell博士将获得环境污染物类别以及它们如何影响目标器官系统的工作知识。除了教学讲座，Howell博士将成为毒理学学会的成员，并在每年的地区和国家毒理学会议上展示他的研究成果。这将使豪威尔博士提高他的演讲技巧和在毒理学领域的网络，同时他了解当前的重点是什么，正在做什么工作，以及如何将其应用到他的研究中。在获得该奖项的过程中，Howell博士还将与CEHS的其他研究人员，特别是他的导师Jan Chambers博士，就他们目前的研究进行合作，以便他可以获得不同的实验视角，并提高他的发表记录。为了让Howell博士做好向终身职位过渡的准备，他将在该奖项的最后三年在我们的研究生班提供客座讲座，在那里他将负责制定他的讲座以及对他的材料进行测试。除了授课，豪威尔博士还将在研究生委员会任职，并帮助指导他们的研究项目。这将使他在学术教学方面获得经验。为了建立自己的独立研究方向，豪厄尔博士将研究接触有机氯化合物对肥胖和糖尿病发展的影响。虽然有新的流行病学证据表明，血液中有机氯化合物（即oxychlordane和/或DDE）的含量与T2D的发生之间存在高度关联，但很少有经验证据表明两者之间存在因果关系。因此，目前的研究计划将利用胰岛素敏感组织的体外细胞培养模型和体内啮齿动物模型来确定暴露于氧氯丹或DDE是否会降低胰岛素信号传导、葡萄糖摄取和可促进胰岛素抵抗的脂肪因子/细胞因子的产生。目前的初步数据表明，暴露于DDE可减少脂肪生成，同时增加脂肪细胞中瘦素和白细胞介素-6的释放。因此，我们将探讨DDE和oxychlordan暴露对脂肪生成基因表达和功能的影响，并评估DDE和oxychlordan的生物积累对脂肪因子/细胞因子表达的影响。暴露于OC化合物对骨骼肌胰岛素信号传导的影响尚未明确。目前的初步数据表明，暴露于oxychlordane或DDE会降低大鼠骨骼肌细胞中胰岛素刺激的葡萄糖转运蛋白4 （Glut4）的易位。为了更仔细地检验这一观察结果，我们将在体外探索暴露于这两种化合物对骨骼肌细胞和脂肪细胞中葡萄糖摄取、Glut4易位和胰岛素信号传导的影响。为了确定环境相关的DDE暴露与T2D的发生之间是否存在因果关系，我们将采用高脂肪饮食诱导的T2D模型（高脂肪喂养的C57BL/6J小鼠）来确定这种暴露是否会导致或加重这些动物的糖尿病状态。综上所述，目前提出的研究将确定暴露于DDE是否会促进整个动物的胰岛素抵抗和T2D，并将从靶组织和整个动物中提供机制刺激。