# Particulate Cr(VI) Toxicology in Human Lung Epithelial Cells and Fibroblasts

> **NIH NIH R01** · UNIVERSITY OF LOUISVILLE · 2020 · $515,069

## Abstract

PROJECT SUMMARY
Lung cancer continues to be the leading cause of cancer death in the U.S. One of the key strategies to combating
it is to better understand its causes. Hexavalent chromium [Cr(VI)] is a human lung carcinogen of major public
health concern because exposure to it is common in the workplace and in the general environment. Our study
focuses on investigating the mechanisms of Cr(VI)-induced carcinogenesis, which are currently unknown. In
particular, this work focuses on the particulate Cr(VI) compounds, because they are the most potent Cr(VI)
carcinogens. Recent studies indicate particulate Cr(VI) induces chromosome instability and causes cells to
evade DNA double strand break repair, which are hallmarks of human lung cancer. Thus, this research focuses
on how particulate Cr(VI) induces cells to evade DNA double strand break repair leading to chromosome
instability and carcinogenesis. Our data show prolonged exposure to particulate Cr(VI) specifically impacts the
effector arm of homologous recombination (HR repair), disrupting RAD51 nucleoprotein filament formation, loss
of which can cause chromosome instability. Therefore, the goal of this research is to characterize this impact on
HR repair and the underlying changes in order to understand the mechanisms involved. Our hypothesis is:
particulate Cr(VI) disrupts the underlying mechanisms of RAD51 nucleoprotein filament formation inactivating
HR repair of Cr(VI)-induced DNA breaks resulting in CIN and neoplastic transformation. We will test this
hypothesis through three interrelated specific aims. Aim 1 will determine how Cr(VI) impacts BRCA2, DSS1,
RAD51B, RAD51C, RAD51D, RPA, and XRCC2 to disrupt RAD51 nucleoprotein filament formation in human
lung cells. Aim 2 determines the persistence and cellular heritability of disrupted RAD51 filament formation in
human lung cells neoplastically transformed by Cr(VI), and the protein levels of BRCA2, DSS1, RAD51B,
RAD51C, RAD51D, RPA, and XRCC2 in lung tumors from human Cr(VI) workers. Aim 3 determines the impact
of Cr(VI) on protein levels of BRCA2, DSS1, RAD51B, RAD51C, RAD51D, RPA, and XRCC2 in the lungs and
lung tumors of Cr(VI)-exposed animals. Results will lead to the first reports of detailed information of the
interactions of Cr(VI) with the effector arm of HR repair at a cellular and molecular level and the first
characterizations of these aspects in neoplastic outcomes including tumors from Cr(VI)-exposed workers.
Results will also show which changes are transient and depend on exposure and which changes persist in cells
that escape cell death and progress to neoplastic outcomes. This research is significant because it provides: 1)
An understanding of Cr(VI)’s carcinogenic mechanism; 2) Essential information to better assess exposure risk
to particulates; and 3) A mechanistic approach for further study of Cr(VI), other metals and lung cancer in general.

## Key facts

- **NIH application ID:** 9857599
- **Project number:** 5R01ES016893-13
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** John Pierce Wise
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $515,069
- **Award type:** 5
- **Project period:** 2009-07-06 → 2023-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9857599

## Citation

> US National Institutes of Health, RePORTER application 9857599, Particulate Cr(VI) Toxicology in Human Lung Epithelial Cells and Fibroblasts (5R01ES016893-13). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9857599. Licensed CC0.

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