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

摘要：项目2--代谢综合征 多氯联苯在脂肪中积累，并与代谢综合征(METS)的发展有关，但 多氯联苯诱导的脂肪内分泌信号中断在蛋氨酸综合征发生中的具体作用尚不清楚。 流行病学研究表明，暴露于多氯联苯和甲型肝炎之间存在关联，一系列 肥胖、高血压、血脂异常和高血糖等情况会增加患心脏病的风险 疾病、中风和II型糖尿病。爱荷华州超级基金研究计划(ISRP)显示，儿童 在学校暴露于高水平的空气中的多氯联苯，使他们处于患METS的潜在风险中。 此外，ISRP表明，暴露在空气中的多氯联苯会导致多氯联苯在脂肪中积累。 组织。我们已经证明，二恶英样多氯联苯可以扰乱脂肪生成，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对甲硫氨酸代谢综合征的发展做出贡献尚不清楚。我们假设 空气中的多氯联苯及其代谢物通过一种机制促进蛋氨酸代谢综合征的发展 脂肪生成和脂肪细胞内分泌功能的中断。我们开发了独特的工具，包括 多个独特的永生人类前脂肪细胞系和3D器官模型系统，使这项研究成为可能 多氯联苯诱导的人类脂肪组织在培养中成熟和功能的变化。人类 在三维器官模型系统中培养的前脂肪细胞可以成熟，储存脂肪，并更多地分泌脂肪因子 比2D培养中的更有效。该系统以一种文化模型来挑战2D文化的现状 这与人类接触更相关。在目标1中，我们将利用3D系统来阐明功能 接触多氯联苯(个别同系物和相关混合物)对脂肪形成和 脂肪细胞的功能。在目标2中，我们将开发一种人类脂肪-肝脏仿生芯片，它允许人类- 多氯联苯的肝脏特异性代谢用于检测多氯联苯及其代谢物对脂肪的影响 功能。在目标3中，我们将评估空气中常见的两种多氯联苯PCB11和PCB52对脂肪的影响 使用大鼠模型进行体内功能、肥胖和新陈代谢的研究，将我们的结果与3D的结果进行比较 系统。这些研究将受到其他ISRP项目的指导，以确定哪些多氯联苯在空气中最普遍 以及脂肪组织中存在哪些多氯联苯和多氯联苯代谢物。此外，我们的工作将依赖于ISRP核心 用于研究样品中多氯联苯的合成和分析评估。我们的项目与SRP相关 授权，因为它将导致开发一种创新技术，以评估多氯联苯如何作为 内分泌干扰物通过它们对脂肪组织的影响，这反过来将对评估 暴露于甲型肝炎发展的风险。我们的发现将引起监管机构和 社区关注多氯联苯暴露如何影响儿童、青少年和年轻人的MET。

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.