Effects of DDE exposure on adipose tissue function, weight loss and metabolic improvement after bariatric surgery: A new paradigm for study of lipophilic chemicals

DDE 暴露对减肥手术后脂肪组织功能、体重减轻和代谢改善的影响：亲脂性化学物质研究的新范式

• 批准号: 10087930
• 负责人: VAIA LIDA CHATZI
• 金额: $ 63.81万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10087930
• 关键词: Address; Adipocytes; Adipose tissue; Adolescent; Adolescent obesity; Adult; Age; Animal Model; Animals; Archives; Attenuated; Behavioral; Biometry; Blood; Body Weight decreased; Body mass index; Cell Line; Cells; Chemicals; Child; Chlorinated Hydrocarbons; Clinical; Clinical Data; Cohort Effect; Complement; Data; Diabetes prevention; Dichlorodiphenyl Dichloroethylene; Dose; Dyslipidemias; Energy Metabolism; Environmental Epidemiology; Experimental Models; Exposure to; Fatty acid glycerol esters; Functional disorder; Future; Gene Expression; Glucose; Goals; Health; Homeostasis; Human; Hyperglycemia; Impairment; In Vitro; Insecticides; Insulin; Insulin Resistance; Intervention; Lead; Lipolysis; Measures; Metabolic; Metabolic Diseases; Modeling; Molecular; Morbid Obesity; Natural experiment; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Observational Study; Outcome; Participant; Pathway interactions; Predisposition; Prevalence; Prevention; Prospective Studies; Regulation; Research; Research Design; Research Personnel; Rodent; Subgroup; System; Teenagers; Testing; Thermogenesis; Tissue Sample; Tissue-Specific Gene Expression; Tissues; Toxic effect; Toxicology; Visceral; Youth; adult obesity; bariatric surgery; base; clinically relevant; cohort; dichlorodiphenyltrichloroethane; epidemiology study; experimental study; human study; innovation; insulin regulation; insulin signaling; interest; lipid biosynthesis; lipophilicity; metabolome; metabolomics; multiple omics; novel; novel strategies; obesity in children; obesogen; obesogenic; persistent organic pollutants; polybrominated diphenyl ether; primary outcome; sociodemographics; tissue archive; tool; toxicant; transcriptome; translational study; treatment strategy

Abstract The environmental obesogen hypothesis posits that lipophilic persistent organic pollutants (POPs) accumulate in adipose tissue (AT) and can disrupt metabolic systems. However, the underlying molecular mechanisms of these toxicants on AT function remain poorly understood. As the most studied POP, dichlorodiphenyl- dichloroethylene (DDE), a persistent metabolite of the insecticide dichlorodiphenyl-trichloroethane (DDT), provides a model for assessing the metabolic health impact of lipophilic POPs. Almost all U.S. children and adolescents have detectable DDE blood levels. Despite abundant evidence from experimental studies showing that DDE disrupts metabolic homeostasis, mechanisms underlying metabolic disruption by DDE in humans are unclear. We therefore propose a novel study design for investigating mechanisms of DDE metabolic effects in humans, based on a remarkable archive of clinical data and visceral AT samples from the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study and an in vitro human adipocyte experimental model. We hypothesize that the large metabolic changes after bariatric surgery provide a “natural experiment” that will magnify effects of the prototypical obesogen DDE, and that DDE in visceral AT will attenuate the reduction in body mass index and insulin resistance after bariatric surgery in a concentration-dependent manner (Aim 1). Although we know that high doses of DDE impair thermogenesis and insulin signaling in animal models, we still do not know whether these mechanisms underlie metabolic disruption by DDE in humans. We will assess effects of DDE on these pathways in a human primary adipocyte cell line, an experimental model that will be free from the potential for uncontrolled confounding in human observational studies and that may also identify new pathways (Aim 2). We will then test these pathways in metabolome and transcriptome profiles of human AT from Teen-LABS study participants, using a hierarchical modeling approach (Aim 3). Finally, we will integrate results from the DDE omics analyses in human AT and in the adipocyte cell line, using a novel latent variable modeling framework, to identify subgroups of adolescents who have less weight loss and less improvement in insulin resistance after bariatric surgery, based on their DDE exposure and multi-omics profile in AT (Aim 4). The proposed research will be the first human study to examine mechanisms of DDE toxicity to AT in humans, using adipose tissue-specific exposure and omic measures, and clinically relevant metabolic outcomes such as BMI and insulin resistance. A strong interdisciplinary team of investigators brings expertise in environmental epidemiology, bariatric surgery, toxicology, omics, and biostatistics. Our study, integrating in vitro and human observational approaches, has the potential to establish a new paradigm for the study of lipophilic obesogenic chemicals and to advance our understanding of environmental contributions to obesity and type 2 diabetes.

摘要 环境致肥胖假说认为，亲脂性持久性有机污染物（POP） 在脂肪组织（AT）中，并可破坏代谢系统。然而，潜在的分子机制， 这些毒物对AT功能的影响仍知之甚少。作为研究最多的持久性有机污染物， 二氯乙烯（DDE），杀虫剂二氯二苯基三氯乙烷（DDT）的持久性代谢物， 提供了一个评估亲脂性持久性有机污染物对代谢健康影响的模型。几乎所有的美国儿童和 青少年血液中的DDE含量可检测到。尽管大量的实验研究表明 DDE破坏代谢稳态，人体内DDE代谢破坏的潜在机制是 不清楚因此，我们提出了一个新的研究设计，调查DDE代谢作用的机制， 人类，基于来自青少年纵向研究的临床数据和内脏AT样本的显着档案 减肥手术（Teen-LABS）研究和体外人脂肪细胞实验模型的评估。我们 假设减肥手术后代谢的巨大变化提供了一个“自然实验”， 放大了典型的致肥剂DDE的作用，内脏AT中的DDE将减弱 体重指数和胰岛素抵抗减肥手术后以浓度依赖性方式（目的1）。 虽然我们知道高剂量的DDE会损害动物模型中的产热和胰岛素信号，但我们仍然认为， 目前尚不清楚这些机制是否是DDE破坏人体代谢的基础。我们将评估影响 DDE对人类原代脂肪细胞系中这些通路的影响，这是一个实验模型， 在人类观察性研究中可能存在不受控制的混淆， 路径（目标2）。然后，我们将在人类AT的代谢组和转录组谱中测试这些途径 从青少年实验室研究参与者，使用分层建模方法（目标3）。最后，我们将整合 结果从DDE组学分析在人类AT和脂肪细胞系，使用一种新的潜在变量 建模框架，以确定体重减轻较少和改善较少的青少年亚组， 肥胖手术后的胰岛素抵抗，基于他们的DDE暴露和AT中的多组学特征（目的4）。 这项拟议中的研究将是第一项研究DDE对人类AT毒性机制的人类研究， 使用脂肪组织特异性暴露和组学测量，以及临床相关的代谢结果， BMI与胰岛素抵抗强大的跨学科调查团队带来了环境方面的专业知识 流行病学、减肥手术、毒理学、组学和生物统计学。我们的研究，整合体外和人体 观察方法，有可能建立一个新的范式，研究亲脂性肥胖 化学品，并促进我们对肥胖和2型糖尿病的环境贡献的理解。