Mutagenesis and Carcinogenesis of Particulate Arsenic in Lung

肺中颗粒物砷的诱变和致癌作用

• 批准号: 10408033
• 负责人: Xixi Zhou
• 金额: $ 26.05万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10408033
• 关键词: Address; Agar; Amino Acids; Arsenic; Arsenic Trioxide; Arsenites; Base Excision Repairs; Binding; Biochemical; Biological; Biology; Bos taurus PARP protein; Cancer Etiology; Cell Line; Cells; Chronic; Code; Communities; DNA Binding; DNA Damage; DNA Repair; DNA Repair Gene; DNA Repair Inhibition; Development; Dose; Dust; Epithelial; Epithelial Cells; Exposure to; Foundations; GTP-Binding Protein alpha Subunits, Gs; Generations; Genes; Genome; Goals; Growth; Health; Human; Impairment; Ingestion; Inhalation; Knowledge; Lead; Lung; Malignant neoplasm of liver; Malignant neoplasm of lung; Mediating; Medicine; Metals; Modification; Molecular; Mutagenesis; Mutation; Nature; New Mexico; Open Reading Frames; Oxidative Stress; Parents; Particulate; Particulate Matter; Population; Prevention; Process; Property; Proteins; Reactive Oxygen Species; Risk; Risk Assessment; Risk Management; Site; Skin; Solubility; Somatic Mutation; Source; Specificity; Surface; Tail; Testing; Time; Universities; Urinary tract; Urologic Cancer; Work; Zinc; biophysical techniques; cancer stem cell; carcinogenesis; carcinogenicity; cell transformation; cigarette smoke; cytotoxicity; exome sequencing; exposure route; genome sequencing; improved; insight; lung carcinogenesis; mortality; novel; oxidative DNA damage; repaired; uptake; whole genome

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.

概括 砷是增加多种人类健康问题风险的主要因素，包括肝癌、 泌尿道、皮肤和肺部，其中肺癌是癌症死亡的主要原因。颗粒状 三氧化二砷 (PATO) 经常被观察为环境颗粒物 (PM) 的一个组成部分，特别是 未经修复的露天矿场和尾矿堆产生的灰尘，这两种情况在 美国西南部。摄入可溶性亚砷酸盐和吸入低溶解性 pATO 都会导致风险增加 肺癌的发展。尽管 pATO 吸入是一种与肺部更相关的暴露途径 致癌作用方面，很少有研究调查 pATO 的生物学影响。此外， 砷诱发肺癌的潜在分子机制仍不清楚。之前的研究 探索可溶性砷的致癌特性可能会大大低估对人类健康的风险 与 pATO 吸入有关。这项工作的长期目标是提供风险的定量信息 评估并促进预防人类吸入颗粒砷对健康的不利影响 人口。当前提案的目的是阐明 pATO 暴露的致癌机制。 我们的初步研究结果表明，在相同浓度下，pATO 产生的反应性明显更高 与可溶性砷相比，ROS 会产生更高的 DNA 损伤。因此，我们假设 颗粒状砷通过结合比可溶性砷具有更大的诱发肺癌发生的潜力 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， 这是第一次，在环境相关水平上接触砷足以产生独特的 基因组上的体细胞突变谱。目前的提案旨在分析突变特征 由 pATO 暴露引起的突变过程和随后的手术修复的读出 流程。为此，我们提出以下具体目标： 目标 1：评估 pATO 的更高效力 ROS 诱导和氧化 DNA 损伤。目标 2：分析 pATO 的突变特征 暴露和 DNA 修复机制，包括 DNA 修复的 DNA 结合序列特异性的改变 PARP-1 等蛋白质。目标3：评价慢性颗粒物的转化和致突变作用 使用全外显子组测序 (WES) 识别肺上皮细胞中的砷暴露，以识别突变和 与转化相关的蛋白质编码基因的缺失。成功完成这些目标将 通过识别细胞特异性来提高我们对颗粒砷诱导的肺癌发生的科学知识 突变特征及其原因，包括氧化应激、DNA 损伤和 DNA修复抑制。