# Indirect Genotoxicity in Metal Carcinogenesis

> **NIH NIH R01** · BROWN UNIVERSITY · 2022 · $365,625

## Abstract

Project Summary
Mutations in various oncogenes and tumor-suppressor genes as well as other genome rearrangements
are a principal cause of human cancers. Lung tumors have especially high burdens of mutations.
Despite this dependence of cancer development on multiple genetic events, many human lung
carcinogens are tested as nonmutagenic in standard assays. Our current lack of knowledge about the
causes of genetic damage by seemingly nonmutagenic carcinogens negatively impacts public health
actions and precludes early detection of this class of dangerous chemicals. Metals is one important
group of widespread carcinogens that are largely nonmutagenic, including lung cancer-causing nickel
(Ni). Ni is a large-volume industrial metal with inhalation exposures occurring daily among millions of
workers. This metal is also a common environmental pollutant that is abundantly released during fossil
fuel burning, incineration of municipal waste and many other processes. Ni is found at > 50% of
Superfund toxic sites. In this project, we will test a conceptually novel hypothesis that Ni(II) disrupts a
unique biochemical process and the resulting metabolic dysfunction causes gross genetic alterations
and cancerous transformation of human lung cells. Our main hypothesis will be tested in three
complementary aims. The proposed studies will determine (1) mechanisms of Ni(II)-induced changes
in cell metabolites, (2) initial and secondary genetic abnormalities resulting from Ni(II)-altered
metabolism and protective functions of ATR kinase, and (3) importance of Ni-induced metabolic
dysfunction in tumorigenic cell transformation. The completion of the proposed work is expected to
establish a novel mechanism for indirect genotoxicity by a major human carcinogen. This mechanism
can be applicable to other nonmutagenic carcinogens possessing a specific chemical reactivity. The
project should also provide a valuable mechanistic information needed for modeling of cancer risks at
low-dose Ni exposures and identify targets for development of potential chemopreventive approaches.

## Key facts

- **NIH application ID:** 10304906
- **Project number:** 5R01ES031002-03
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** Anatoly Zhitkovich
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $365,625
- **Award type:** 5
- **Project period:** 2020-01-15 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10304906

## Citation

> US National Institutes of Health, RePORTER application 10304906, Indirect Genotoxicity in Metal Carcinogenesis (5R01ES031002-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10304906. Licensed CC0.

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