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

项目概要- TILTON项目 环境卫生面临的最困难的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，越来越需要评估毒性， 复杂混合物中结构多样的多环芳烃及其转化和分解产物， 人类相关的和代谢能力的研究模型。该生物医学科学研究项目将 在三维人体肺部模型中评估与超级基金站点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。我们将 通过与多次接触相关的终点，量化多环芳烃和多环芳烃混合物对肺部的毒性 途径（吸入、饮食、皮肤）。我们将依靠基准剂量建模来确定阈值反应， 对比我们将应用整合的RNAseq和功能蛋白质组学来确定 多环芳烃在暴露人群中产生不利的健康结果，并在这些人群中识别易感个体 人口。该项目的总体目标是了解单个多环芳烃如何对 混合物，并建立化学品接触和毒性之间的关系。我们将应用 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。我们的目标是：1）在三维空间中定量研究多环芳烃及其混合物的毒性， 肺模型，2）评估代谢对3D人体肺模型中单个PAHs毒性的作用 3）在三维人肺模型中阐明PAH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.