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: 10629358
• 负责人: Xixi Zhou
• 金额: $ 25.85万
• 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/10629358
• 关键词: Address; Agar; Amino Acids; Arsenic; Arsenic Trioxide; Arsenites; Base Excision Repairs; Binding; Biochemical; Biological; Biology; Cancer Etiology; Cell Line; Cells; Chronic; Classification; Code; Communities; DNA Binding; DNA Damage; DNA Repair; DNA Repair Gene; DNA Repair Inhibition; Development; Dose; Dust; Environment; Epithelial Cells; Epithelium; Exposure to; Foundations; Generations; Genes; Genome; Goals; Growth; Health; Human; Impairment; Ingestion; Inhalation; Knowledge; 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; Poly(ADP-ribose) Polymerases; 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.

总结 砷是增加几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，其中肺癌是癌症死亡的主要原因。颗粒 三氧化二砷（pATO）经常被观察到作为环境颗粒物（PM）的组分，特别是 未经补救的露天矿址和尾矿堆产生的粉尘，这两种情况在非洲都很常见。 美国西南部。可溶性亚砷酸盐摄入和低溶解度pATO吸入均导致风险增加 肺癌的发展。尽管吸入pATO是一种与肺更相关的暴露途径， 尽管pATO具有致癌作用，但很少有研究调查pATO的生物学影响。而且 砷诱导的肺癌发生的潜在分子机制仍不清楚。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风险 与吸入pATO相关。这项工作的长期目标是为风险提供量化信息 评估吸入颗粒砷对人体健康的不良影响，并协助预防 人口。本提案的目的是阐明pATO暴露的致癌机制。 我们的初步研究结果表明，在相同的浓度下，pATO产生的反应性明显更高， 氧物种（ROS）和产生更高的DNA损伤比可溶性砷。因此，我们假设， 颗粒态砷比可溶态砷更有可能诱发肺癌， 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， 这是第一次，在环境相关水平的砷暴露足以产生独特的 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，作为突变过程的读出和随后的手术修复 流程.为此，我们提出了以下具体目标：目标1：评估pATO的更高效价 在ROS诱导和氧化性DNA损伤方面。目的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 蛋白质如PARP-1。目的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）鉴定肺上皮细胞中的砷暴露突变， 与转化相关的蛋白质编码基因的缺失。成功实现这些目标将 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。