Project 2 - Coupling Bioengineered and Computational Models of Thyroid Homeostasis to Support Human PCDD/F Risk-Assessment

项目总结/摘要 甲状腺激素（TH）通过控制能量消耗来调节整个身体的能量平衡 在每个细胞内。TH的循环水平是通过激素的产生和反馈来控制的， 下丘脑-垂体-甲状腺（HPT）轴与肝脏也发挥了重要作用。不同类别的 化学物质通过调节参与TH合成，运输， 接收、新陈代谢、再循环和反馈。神经发育缺陷、听力和视力发育 功能障碍、代谢紊乱和癌症等危害归因于TH失衡。多氯 二苯并二恶英和二苯并呋喃（PCDD/Fs）在人群和动物模型中引起TH失衡 尽管机制尚未解决。多氯二苯并对二恶英/多氯二苯并呋喃激活 最近，肝细胞中的芳香烃受体（AHR）诱导TH-葡糖苷酸的形成和清除， 基于葡萄糖醛酸化缺陷啮齿动物模型中生成的数据，该项目旨在 阐明PCDD/F暴露通过以下方式破坏人类甲状腺动力学和作用的机制： 开发计算模型和微生理甲状腺细胞/肝细胞筛选模型， 通过将基于人类的培养系统中的实验数据与 从人口层面了解对人类健康的潜在影响。阐明PCDD/F的作用机理 诱导的甲状腺失衡，我们在人肝细胞中模拟甲状腺catenation和作用， PCDD/Fs暴露。为了扩大检测范围，我们开发并测试了甲状腺细胞/肝细胞模型， 结合TH合成。确定多氯二苯并对二恶英和多氯二苯并呋喃与常见的 通过交替的分子引发事件共同暴露的化学品，我们测试目标化学混合物。 除了假设检验，该提案还改进了计算和微生理模型，以评估 化学品对人类甲状腺信号的影响，可供利益攸关方在监管、 研究和规范的社区。提高微生理体外化学的预测潜力 通过计算建模与人口健康结果相联系的测试是支持 多氯二苯并对二恶英/多氯二苯并呋喃风险评估。改进的风险评估可以指导有针对性的干预战略， 防止对敏感人群的健康产生不良影响。

PROJECT SUMMARY/ABSTRACT Thyroid hormones (TH) act to regulate energy balance throughout the body by controlling energy expenditure inside each cell. Circulating levels of TH are controlled through hormone production and feedback in the hypothalamic-pituitary-thyroid (HPT) axis with the liver also playing a significant role. Diverse classes of chemicals cause TH imbalance through modulations of molecular targets involved in TH synthesis, transport, reception, metabolism, recycling, and feedback. Neurodevelopmental deficits, developmental hearing and vision dysfunction, metabolic disorders, and cancer among other harms are attributed to TH imbalance. Polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) cause TH imbalance in human populations and animal models although the mechanism is unresolved. The long-standing mechanistic paradigm whereby PCDD/Fs activate the aryl hydrocarbon receptor (AHR) in hepatocytes inducing TH-glucuronide formation and clearance has recently been put into question based on data generated in glucuronidation deficient rodent models. This project aims to elucidate the mechanism by which PCDD/F exposures disrupt human thyroid kinetics and action through the co- development of computational models and a microphysiological thyrocyte/hepatocyte screening model that together can support risk-assessment by bridging experimental data in human based culture systems with a population level understanding of potential effects on human health. To elucidate the mechanism of PCDD/F induced thyroid imbalance, we model thyroid catabolism and action in human hepatocytes and determine effects of PCDD/Fs exposure. To broaden assay coverage, we develop and test a thyrocyte/hepatocyte model that incorporates TH synthesis. To determine the potential for synergistic effects between PCDD/Fs and commonly co-exposed chemicals acting through alternate molecular initiating events, we test targeted chemical mixtures. In addition to hypothesis testing, this proposal refines computational and microphysiological models to evaluate the effects of chemicals on human thyroid signaling that could be used by stakeholders in the regulatory, research and regulated community. The improved predictive potential of microphysiological in vitro chemical testing linked through computational modeling to population health outcomes is a critical step toward supporting PCDD/F risk-assessment. Improved risk-assessment can then guide targeted intervention strategies that prevent adverse health effects in sensitive populations.