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.
NIH ExPorter
NIH ExPorter