Linking PAH Exposure to Health Outcomes Using Human Primary In Vitro Respiratory Model

项目摘要-Tilton项目 环境健康面临的最大挑战之一是评估接触化学品的危害。 混合物。环境健康科学界认识到，越来越有必要对 结构多样的多环芳烃及其在复杂混合物中的转化和分解产物，使用 与人类相关的代谢能力强的研究模型。这项生物医学科学研究项目将 在3D人肺模型中评估与超级基金部位相关的复杂混合物中多环芳烃的毒性 由在气液界面分化的原代人支气管上皮细胞(HBEC)组成。我们会 多环芳烃和多环芳烃混合物通过与多次暴露相关的终点靶向肺部的毒性量化 途径(吸入、饮食、皮肤)。我们将依靠基准剂量建模来确定阈值响应 比较一下。我们将应用整合的RNAseq和功能蛋白质组学来确定 多环芳烃在暴露人群中对健康造成不良后果，并在这些人群中识别易感人群 人口。这个项目的总体目标是了解单个多环芳烃是如何对环境中的 并建立化学品暴露与毒性之间的关系。我们将应用以下成果 这些研究旨在评估和传达人类健康风险，并评估相关疾病的易感性 人口。我们建议实现这些目标：1)在3D中量化多环芳烃和多环芳烃混合物的毒性 肺模型，2)在3D人肺模型中评估代谢对单个多环芳烃毒性的作用 3)阐明多环芳烃在三维人体肺模型中的毒性机制。

PROJECT SUMMARY – TILTON PROJECT One of the most difficult challenges for environmental health is to evaluate hazards from exposure to chemical mixtures. The environmental health science community recognizes a growing need to evaluate toxicity for structurally diverse PAHs and their transformation and breakdown products in complex mixtures, using human-relevant and metabolically competent research models. This Biomedical Science Research Project will assess the toxicity of PAHs in complex mixtures associated with Superfund sites in a 3D human lung model composed of primary human bronchial epithelial cells (HBEC) differentiated at the air-liquid interface. We will quantify the toxicity of PAHs and PAH mixtures targeting lungs via endpoints relevant for multiple exposure routes (inhalation, diet, dermal). We will rely on benchmark dose modeling to identify a threshold response for comparison. We will apply integrated RNAseq and functional proteomics to identify mechanisms by which PAHs exert adverse health outcomes in exposed populations and to identify susceptible individuals in those populations. The overall goal of this project is to understand how individual PAHs contribute to toxicity in mixtures and to establish a relationship between chemical exposure and toxicity. We will apply the outcomes of these studies to assess and communicate human health risk and to evaluate susceptibility for relevant populations. We propose to achieve these aims: 1) quantify the toxicity of PAHs and PAH mixtures in the 3D lung model, 2) assess the role of metabolism on the toxicity of individual PAHs in the 3D human lung model and 3) elucidate the mechanisms of PAH toxicity in the 3D human lung model.