The Role of Airborne PCBs in Adipogenesis, Adipose Function, and Metabolic Syndrome

空气中 PCB 在脂肪生成、脂肪功能和代谢综合征中的作用

• 批准号: 10559684
• 负责人: ALOYSIUS John KLINGELHUTZ
• 金额: $ 26.03万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-12 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10559684
• 关键词: 3-Dimensional; Address; Adipocytes; Adipose tissue; Adolescent; Adolescent and Young Adult; Affect; Air; Biochemical; Biological; Biological Models; Biomimetics; Brain; Cell Line; Cells; Child; Chronic; Communities; Deposition; Development; Devices; Dioxins; Dyslipidemias; Endocrine; Endocrine Disruptors; Endocrine disruption; Energy Metabolism; Evaluation; Exposure to; Fatty Liver; Fatty acid glycerol esters; Female; Functional disorder; Gases; Genetic Transcription; Health; Hepatocyte; Human; Hyperglycemia; Hypertension; Hypertrophy; In Vitro; Individual; Inflammation; Inflammatory Response; Inhalation; Insulin Resistance; Iowa; Lipids; Liver; Male Adolescents; Metabolic syndrome; Metabolism; Methods; Modeling; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organoids; Pathway interactions; Phase; Physiological; Play; Polychlorinated Biphenyls; Process; Program Research Project Grants; Rattus; Research; Research Personnel; Risk; Risk Assessment; Role; Route; Sampling Studies; Schools; Signal Pathway; Signal Recognition Particle; Signal Transduction; Site; Skeletal Muscle; Source; Stroke; Superfund; System; Techniques; Technology; Testing; Tissues; Toxic Environmental Substances; Toxic effect; Transcriptional Regulation; Visceral; Volatilization; Work; adipokines; cell immortalization; cell type; epidemiology study; exposed human population; glucose metabolism; glucose tolerance; heart disease risk; in vivo; in vivo Model; innovative technologies; insulin tolerance; interest; lipid biosynthesis; programs; remediation; response; screening; subcutaneous; three dimensional cell culture; tool

SUMMARY: Project 2 – Metabolic Syndrome PCBs accumulate in fat and are associated with the development of metabolic syndrome (MetS), yet the specific role of PCB-induced disruption of adipose endocrine signaling in the development of MetS is unknown. Epidemiological studies have demonstrated an association between exposure to PCBs and MetS, a cluster of conditions including obesity, hypertension, dyslipidemia, and hyperglycemia, which increase the risk of heart disease, stroke, and type II diabetes. The Iowa Superfund Research Program (ISRP) has shown children are exposed to high levels of airborne PCBs in schools, putting them at potential risk for the development of MetS. In addition, the ISRP demonstrated that airborne PCB exposure results in the accumulation of PCBs in adipose tissue. We have shown that dioxin-like PCBs can disrupt adipogenesis, leading to aberrant adipocyte function. How volatile PCBs affect adipose tissue to contribute to the development of MetS is unknown. We hypothesize that airborne PCBs and their metabolites contribute to the development of MetS via a mechanism that involves disruption of adipogenesis and adipocyte endocrine function. We have developed unique tools, including multiple unique immortal human preadipocyte cell lines and a 3D organoid model system, that enable the study of PCB-induced alterations in the maturation and function of human adipose tissue in culture. Human preadipocytes cultured in the 3D organoid model system can mature, store lipids, and secrete adipokines more efficiently than those in 2D cultures. This system challenges the status quo of 2D culture with a culture model that is more relevant to human exposure. In Aim 1, we will utilize the 3D system to elucidate the functional consequences of exposure to PCBs (individual congeners and relevant mixtures) on adipogenesis and adipocyte function. In Aim 2, we will develop a human adipose-liver biomimetic on-chip that allows for human- liver specific metabolism of PCBs for facile testing of the effects of PCB and PCB-metabolites on adipose function. In Aim 3, we will assess how PCB11 and PCB52, two PCBs commonly found in air, affect adipose function, adiposity, and metabolism in vivo using a rat model, comparing our results to those found with our 3D system. The studies will be guided by other ISRP projects to determine which PCBs are most prevalent in air and which PCBs and PCB-metabolites are present in adipose tissue. Further, our work will rely on ISRP cores for synthesis and analytical assessment of PCBs in study samples. Our project is relevant to the SRP mandates because it will result in the development of an innovative technology to assess how PCBs act as endocrine disruptors through their effects on adipose tissue, which, in turn, will be important for assessment of exposure risk to the development of MetS. Our findings will be of significant interest to regulatory agencies and communities concerned about how PCB exposure affects MetS in children, adolescents, and young adults.

摘要：项目 2 – 代谢综合症 PCB 在脂肪中积聚并与代谢综合征 (MetS) 的发生有关，但 PCB 诱导的脂肪内分泌信号干扰在 MetS 发展中的具体作用尚不清楚。 流行病学研究表明，接触 PCB 与 MetS 之间存在关联，MetS 是一组 肥胖、高血压、血脂异常和高血糖等疾病会增加心脏病风险 爱荷华州超级基金研究计划 (ISRP) 表明，儿童患有疾病、中风和 II 型糖尿病。 在学校中接触空气中高含量的多氯联苯，使他们面临发生代谢综合征的潜在风险。 此外，ISRP 证明空气中的 PCB 暴露会导致 PCB 在脂肪中积累 我们已经证明，二恶英样多氯联苯会破坏脂肪生成，导致脂肪细胞功能异常。 挥发性多氯联苯如何影响脂肪组织从而促进代谢综合征的发生尚不清楚。 空气中的 PCB 及其代谢物通过一种机制促进 MetS 的发展，其中涉及 我们开发了独特的工具，包括破坏脂肪生成和脂肪细胞内分泌功能。 多种独特的永生人类前脂肪细胞系和 3D 类器官模型系统，使研究成为可能 PCB 引起的人类脂肪组织成熟和功能改变的研究。 在3D类器官模型系统中培养的前脂肪细胞可以成熟、储存脂质并分泌更多脂肪因子 该系统通过文化模型挑战了 2D 文化的现状。 在目标 1 中，我们将利用 3D 系统来阐明功能。 接触多氯联苯（单个同系物和相关混合物）对脂肪生成的影响和 在目标 2 中，我们将开发一种人类脂肪肝仿生芯片，可实现人类脂肪细胞功能。 PCB 的肝脏特异性代谢，可轻松测试 PCB 和 PCB 代谢物对脂肪的影响 在目标 3 中，我们将评估空气中常见的两种 PCB PCB11 和 PCB52 如何影响脂肪。 使用大鼠模型对体内功能、肥胖和代谢进行比较，将我们的结果与 3D 发现的结果进行比较 该研究将在其他 ISRP 项目的指导下进行，以确定哪些 PCB 在空气中最常见。 以及脂肪组织中存在哪些 PCB 和 PCB 代谢物 此外，我们的工作将依赖于 ISRP 核心。 用于研究样品中 PCB 的合成和分析评估 我们的项目与 SRP 相关。 强制要求，因为它将导致创新技术的开发，以评估 PCB 如何发挥作用 内分泌干​​扰物通过其对脂肪组织的影响，反过来，这对于评估 MetS 发展面临的风险 我们的研究结果将引起监管机构和机构的极大兴趣。 社区关注 PCB 暴露如何影响儿童、青少年和年轻人的 MetS。