Environmental effects on dermatoxicities of polycyclic aromatic hydrocarbons

项目摘要 多环芳烃污染已成为环境健康的一大威胁 因为它们对包括人类在内的各种生物体都有毒性。以往的流行病学研究 多环芳烃暴露与人类许多急慢性疾病密切相关。 近年来环境应激源作用下多环芳烃毒性变化的证据 考虑到由以下因素导致的快速变化的环境条件，对改性多环芳烃风险的更大担忧 气候变化。然而，人们在了解环境影响方面的努力非常有限。 多环芳烃对人类健康毒性的变化。我们研究的长期目标是了解分子 多环芳烃化合物引起人类炎症性皮肤病的机制，以及如何环境 影响这些化合物的皮肤毒性的因素。拟议研究的中心假设是 环境对多环芳烃化合物结构的影响将改变其对人体皮肤的毒性。三 必须实现特定的目标才能完成对这一假设的检验。三个具体目标 包括，1)确定水中多环芳烃在水盐和酸化影响下的光降解 大气二氧化碳水平升高引发的水分状况；2)发现多环芳烃对皮肤的毒害途径 环境影响下的人角质形成细胞；3)验证环境修饰的多环芳烃 体内皮肤毒性途径。为了解决这些具体目标，将在#年建立标准化的PAH协议 这项研究。选定的多环芳烃化合物在不同环境下的光曝光下将被降解 盐度和二氧化碳水平。这些环境因素预计会与光降解产生相互作用 这些化学物质。不同盐度和二氧化碳条件下光修饰多环芳烃化合物的毒性 将使用三维人类角质形成细胞培养和角质形成细胞/成纤维细胞联合培养来评估水平。 文化典范。角质形成细胞中推测的多环芳烃致病途径将使用3D 角质形成细胞构建结合siRNA或基因过表达分析的基因功能分析。 已确定的途径和皮肤炎症反应之间的关系将用 小鼠皮肤炎症模型。作为一项预测毒理学的研究，这项研究的方法是 利用生物途径的基本知识来开发体外实验和基于动物的测试来预测 化学品暴露的不利影响，这是环境健康科学的一个优先组成部分。

Project Summary The pollution of polycyclic aromatic hydrocarbons has become a threat in environmental health because of their toxicities to a variety of organisms including humans. Previous epidemiological studies demonstrated a close relationship between PAH exposures and many acute and chronic human diseases. Evidence in the toxicity changes of PAHs under effects of environmental stressors in the past few years raised a bigger concern in the risk of modified PAHs considering the fast-changing environment conditions led by climate change. However, very limited efforts have been made to understand the effects of environmental changes on PAH toxicities to human health. The long-term goal of our study is to understand the molecular mechanism of human inflammatory skin diseases caused by the PAH compounds, and how environmental factors affect the dermatoxicities of these compounds. The central hypothesis of the proposed study is that environmental impacts on structures of PAH compounds will change their toxicities to human skin. Three specific aims will have to be accomplished to complete the test of the hypothesis. The three specific aims include, 1) to identify the photodegradation of aqueous PAHs under the effects of water salinity and acidified water condition initiated by increased atmospheric CO2 level; 2) to discover the dermatoxic pathway of PAHs to human keratinocytes under the environmental impact; and 3) to verify the environment-modified PAH dermatoxic pathway in vivo. To address these specific aims, a standardized PAH protocol will be established in this study. Selected PAH compounds will be degraded under photo exposure within different surrounding salinity and pCO2 levels. These environmental factors are expected to interact with the photodegradation of these chemicals. The toxicities of the PAH chemicals with photo-modification at different salinity and pCO2 levels will be evaluated using three-dimensional human keratinocyte culture and keratinocyte/fibroblast co- culture models. A putative PAH pathogenic pathway in keratinocytes will be validated using the 3D keratinocytes constructs combined with gene functional analyses with siRNA or gene overexpression assays. The relationship between the identified pathway and the skin inflammatory responses will be investigated using a mouse skin inflammation model. As a study in predictive toxicology, the approach of this study takes advantage of the basic knowledge of biological pathways to develop in vitro and animal-based tests to predict adverse effects of chemical exposure, which is a priority component of the Environmental Health Sciences.