Mutagenesis and Carcinogenesis of Particulate Arsenic in Lung

摘要 砷是增加几种人类健康问题风险的主要因素，包括肝癌， 尿路、皮肤和肺，其中肺癌是癌症死亡的主要原因。颗粒物 三氧化二砷(PAO)作为环境颗粒物(PM)的一种成分经常被观察到，特别是 未经治理的露天矿场和尾矿堆产生的粉尘，这两种粉尘在 美国西南部。摄入可溶性亚砷酸盐和吸入低溶解性帕托都会增加患病风险 肺癌的发展。尽管帕托吸入是一种与肺部更相关的暴露途径 在致癌方面，研究PATO的生物影响的研究很少。此外， 砷诱发肺癌的潜在分子机制尚不清楚。以前的研究 探索可溶性砷的致癌特性可能会大大低估人类健康的风险 与帕托吸入有关。这项工作的长期目标是为风险提供量化信息 评估和促进预防吸入颗粒物砷对人体健康的不利影响 人口。目前这项提议的目的是阐明PATO暴露的致癌机制。 我们的初步研究结果显示，在相同的浓度下，帕托产生的反应性明显更高 氧物种(ROS)和产生比可溶性砷更高的DNA损伤。因此，我们假设 颗粒态砷比可溶性态砷通过结合作用更有可能引发肺癌。 氧化应激的影响；DNA损伤和DNA修复抑制。此外，我们的初步结果证实， 第一次，暴露在与环境相关的水平上的砷足以产生独特的 基因组上的体细胞突变谱。目前的提案旨在分析突变签名 由PATO暴露引起的，作为突变过程和随后的手术修复的读数 流程。为此，我们提出了以下具体目标：目标1：评估帕托的更高效力 在ROS诱导和DNA氧化损伤方面。目的2：分析帕托的突变特征 暴露和DNA修复机制，包括DNA修复的DNA结合序列特异性的变化 PARP-1等蛋白质。目的3：评价慢性颗粒物的转化和致突变作用 用全外显子组测序(WES)检测砷暴露于肺上皮细胞的突变和 与转化相关的蛋白质编码基因的缺失。这些目标的成功实现将 通过鉴定细胞特异性提高我们对颗粒性砷诱发肺癌的科学认识 突变特征及其原因，包括氧化应激、DNA损伤和 DNA修复抑制。

Summary Arsenic is a major factor for increased risk of several human health problems, including cancers of the liver, urinary tract, skin, and lung, among which lung cancer is the leading cause of cancer mortality. Particulate arsenic trioxide (pATO) is frequently observed as a component of ambient particulate matter (PM), specifically in dust arising from unremediated surface mine sites and tailings piles, both of which are common in the southwestern US. Soluble arsenite ingestion and low-solubility pATO inhalation both lead to an increased risk of lung cancer development. Although pATO inhalation is an exposure route more relevant to lung carcinogenesis, there are very few studies investigating the biological impact of pATO. Moreover, the underlying molecular mechanisms of arsenic-induced lung carcinogenesis remain unknown. Previous studies exploring the carcinogenic properties of soluble arsenic may significantly underestimate the human health risks associated with pATO inhalation. The long-term goal of this work is to provide quantitative information for risk assessment and to facilitate prevention of the adverse health effects of inhaled particulate arsenic in human populations. The aim of the current proposal is to elucidate the carcinogenic mechanisms of pATO exposure. Our preliminary findings reveal that at the same concentration, pATO generates significantly more reactive oxygen species (ROS) and yields higher DNA damage than soluble arsenic. Thus, we hypothesize that particulate arsenic has greater potential to incite lung carcinogenesis than soluble arsenic through combination effects of oxidative stress; DNA damage and DNA repair inhibition. Moreover, our preliminary results confirm, for the first time, that exposure to arsenic at an environmentally relevant level is sufficient to generate a unique spectrum of somatic mutations on the genome. The current proposal aims to analyze mutational signatures arising from pATO exposure as the readout of mutational processes and subsequent operative repair processes. To this end, we propose the following specific aims: Aim 1: To assess the higher potency of pATO in terms of ROS induction and oxidative DNA damage. Aim 2: To analyze mutational signatures of pATO exposure and DNA repair mechanisms including alterations in DNA binding sequence specificity of DNA repair proteins such as PARP-1. Aim 3: To evaluate the transformation and mutagenicity effect of chronic particulate arsenic exposure in lung epithelial cells using whole exome sequencing (WES) to identify mutations and deletions on protein-coding genes associated with transformation. Successful completion of these aims will improve our scientific knowledge of particulate arsenic-induced lung carcinogenesis by identifying cell specific mutational signatures and their causes, including synergistic actions of oxidative stress, DNA damage, and DNA repair inhibition.