The role of exposure to bioaccumulative organochlorine compounds on the occurrenc

接触生物累积性有机氯化合物对发生的作用

• 批准号: 8726530
• 负责人: George E Howell
• 金额: $ 4.95万
• 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: 2010-09-27 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8726530
• 关键词: role; exposure; bioaccumulative; organochlorine; compounds

DESCRIPTION (provided by applicant): The prevalence of obesity and type 2 diabetes is increasing at alarming rate and represents a growing burden on the health care system of the United States. Type 2 diabetes accounts for 90 to 95% of all diagnosed cases of diabetes mellitus and is characterized by the occurrence of insulin resistance and subsequent hyperglycemia. Until recently, an environmental mediator of type 2 diabetes had not been postulated. However, recent studies from retrospective analysis of data gathered by the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2001 have suggested that high serum concentrations of certain persistent organic pollutants, including the organochlorine compounds DDE and oxychlordane, are significantly correlated with increased prevalence of insulin resistance and diabetes. The current preliminary data suggest that exposure to DDE alters adipogenesis, promotes the release of both IL-6 and leptin from mature adipocytes, and prevents insulin-stimulated glucose transporter 4 translocation in skeletal muscle myotubules. Thus the following proposal seeks to determine if exposure to the organochlorine compounds DDE and oxychlordane promotes the occurrence of insulin resistance and type 2 diabetes through altering adipocyte maturation and inducing insulin resistance in the adipose tissue and skeletal muscle. To examine the molecular mechanisms involved in DDE-mediated decreases in adipocyte maturation, NIH3T3-L1 cells will be exposed to DDE prior to and during differentiation into mature adipocytes and the expression and DNA binding of adipogenic transcription factors will be assessed. Insulin stimulated glucose uptake following exposure to DDE or oxychlordane in mature NIH3T3-L1 adipocytes and L6 rat skeletal muscle myotubules will be used as in vitro cell culture models for the adipose tissue and skeletal muscle, respectively. In order to determine if exposure to DDE promotes the occurrence of type 2 diabetes in the whole animal, a high fat fed animal model of type 2 diabetes will be employed. Male C57BL/6J mice will be exposed to DDE weekly prior to and during consumption of either a normal or high fat diet for 16 weeks. Weight gain and insulin resistance will be monitored over the course of the dietary regimen to determine if exposure to DDE promotes the occurrence of hyperinsulinemia and hyperglycemia. Taken together, the current proposal seeks to empirically determine whether exposure to either DDE or oxychlordane, two prevalent bioaccumulative environmental contaminants, promotes the occurrence of type 2 diabetes. This line of investigation is of particular importance given that the origins of insulin resistance remain an enigma. PUBLIC HEALTH RELEVANCE: The presently proposal seeks to examine the effect of exposure to bioaccumulative organochlorine compounds that are present in the serum of a vast majority of the United States population on the development of insulin resistance and type 2 diabetes. This research will utilize cell culture models of adipose tissue and skeletal muscle as well as an animal model of type 2 diabetes to determine if exposure to these persistent compounds promotes the formation of insulin resistance. If so, the present study will provide mechanisms through which these compounds promote this disease and will establish exposure to certain organochlorine compounds as a risk factor for the development of type 2 diabetes.

描述（由申请人提供）：肥胖症和2型糖尿病的患病率正以惊人的速度增加，并对美国的医疗保健系统造成越来越大的负担。2型糖尿病占所有糖尿病诊断病例的90 - 95%，其特征在于发生胰岛素抵抗和随后的高血糖症。直到最近，2型糖尿病的环境介质还没有被假定。然而，最近对1999年至2001年国家健康和营养检查调查收集的数据进行的回顾性分析研究表明，某些持久性有机污染物，包括有机氯化合物DDE和氧氯噻嗪的高血清浓度与胰岛素抵抗和糖尿病的发病率增加密切相关。目前的初步数据表明，暴露于DDE改变脂肪形成，促进成熟脂肪细胞释放IL-6和瘦素，并阻止骨骼肌肌管中胰岛素刺激的葡萄糖转运蛋白4易位。因此，以下建议旨在确定暴露于有机氯化合物DDE和氧氯噻嗪是否会通过改变脂肪细胞成熟和诱导脂肪组织和骨骼肌中的胰岛素抵抗来促进胰岛素抵抗和2型糖尿病的发生。为了检查DDE介导的脂肪细胞成熟降低中涉及的分子机制，将在分化为成熟脂肪细胞之前和期间将NIH 3 T3-L1细胞暴露于DDE，并将评估成脂转录因子的表达和DNA结合。在成熟的NIH 3 T3-L1脂肪细胞和L 6大鼠骨骼肌肌管中暴露于DDE或氧氯噻嗪后，胰岛素刺激的葡萄糖摄取将分别用作脂肪组织和骨骼肌的体外细胞培养模型。为了确定暴露于DDE是否会促进整个动物发生2型糖尿病，将采用高脂肪喂养的2型糖尿病动物模型。雄性C57 BL/6 J小鼠在食用正常或高脂肪饲料之前和期间每周暴露于DDE，持续16周。将在饮食方案过程中监测体重增加和胰岛素抵抗，以确定DDE暴露是否促进高胰岛素血症和高血糖症的发生。综上所述，目前的建议旨在经验性地确定暴露于DDE或羟氯噻嗪（两种普遍的生物累积性环境污染物）是否会促进2型糖尿病的发生。由于胰岛素抵抗的起源仍然是一个谜，这条调查路线特别重要。 公共卫生关系：目前的提案旨在研究接触存在于绝大多数美国人口血清中的生物累积性有机氯化合物对胰岛素抵抗和2型糖尿病的影响。这项研究将利用脂肪组织和骨骼肌的细胞培养模型以及2型糖尿病的动物模型来确定暴露于这些持久性化合物是否会促进胰岛素抵抗的形成。如果是这样的话，本研究将提供这些化合物促进这种疾病的机制，并将建立暴露于某些有机氯化合物作为发展2型糖尿病的风险因素。

项目成果

Exposure to p,p'-dichlorodiphenyldichloroethylene (DDE) induces fasting hyperglycemia without insulin resistance in male C57BL/6H mice.

• DOI: 10.1016/j.tox.2014.02.004
• 发表时间: 2014-06-05
• 期刊: TOXICOLOGY
• 影响因子: 4.5
• 作者: Howell, George E., III;Meek, Edward;Kilic, Jessica;Mohns, Mariel;Mulligan, Charlee;Chambers, Janice E.
• 通讯作者: Chambers, Janice E.

Exposure to p,p'-DDE enhances differentiation of 3T3-L1 preadipocytes in a model of sub-optimal differentiation.

• DOI: 10.1016/j.toxlet.2015.07.009
• 发表时间: 2015-10-14
• 期刊: Toxicology letters
• 影响因子: 3.5
• 作者: Mangum LH;Howell GE 3rd;Chambers JE
• 通讯作者: Chambers JE

Effect of chronic p,p'-dichlorodiphenyldichloroethylene (DDE) exposure on high fat diet-induced alterations in glucose and lipid metabolism in male C57BL/6H mice.

慢性P，P'-二氯二苯基氯乙烯（DDE）暴露对雄性C57BL/6H小鼠葡萄糖和脂质代谢的高脂肪饮食诱导的改变。

• DOI: 10.1016/j.tox.2014.12.017
• 发表时间: 2015-02-03
• 期刊: Toxicology
• 影响因子: 4.5
• 作者: Howell GE 3rd;Mulligan C;Meek E;Chambers JE
• 通讯作者: Chambers JE