# Mutagenesis and Carcinogenesis of Particulate Arsenic in Lung

> **NIH NIH P20** · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · 2020 · $265,125

## Abstract

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.

## Key facts

- **NIH application ID:** 9854031
- **Project number:** 1P20GM130422-01A1
- **Recipient organization:** UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
- **Principal Investigator:** Karen Cooper
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $265,125
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9854031

## Citation

> US National Institutes of Health, RePORTER application 9854031, Mutagenesis and Carcinogenesis of Particulate Arsenic in Lung (1P20GM130422-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9854031. Licensed CC0.

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