# Novel markers of exposure and pathways of response to Chromium

> **NIH NIH R01** · HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH · 2020 · $474,512

## Abstract

Abstract
Cr(VI) is a human carcinogen of significant public health concern, and a substantial exposure in a number of
occupational settings. Cr(VI) induces mutations, changes in gene copy number, and exposure has been
associated with humans cancers in exposed populations and animal models. Our novel preliminary data
demonstrate that Cr(VI) exposure causes amplification in ribosomal DNA (rDNA) copy number and changes in
the nucleolus (the crudely understood nuclear organelle that is the site of ribosomal RNA (rRNA) transcription,
and integration of myriad cellular functions). A crucial element of nucleolar function is rDNA copy number
(rDNA CN). rDNA CN modulates (i) epigenetic states across the genome, (ii) DNA damage responses, (iii) cell
cycle progression, (iv) chromosome segregation, and (v) global genetic stability. Furthermore, disruption of
rDNA arrays, ribosome biogenesis, and the nucleolus are central to carcinogenesis. Our central medical
hypothesis is that Cr-induced changes in rDNA CN are responsible for Cr-induced carcinogenesis. Our central
basic hypothesis is that rDNA arrays are not fixed, but rather a genetically dynamic component of the nuclear
genome with copy number that is modulated by Cr exposure. Our proposal examines rDNA changes upon
Cr(VI) exposure to reveal a novel pathway of Cr toxicity with medical and basic relevance. Key elements are a
careful investigation of the toxicology of Cr-induced-rDNA-amplification (Cr-i-rDNA-a), hypotheses-driven
functional genomic analysis the rDNA and the nucleolus upon Cr(VI) exposure, and extensive genetic analyses
of Cr-i-rDNA-a using a powerful model organism. Our first aim will investigate the toxicology of Chromium-
induced-rDNA-amplification (Cr-i-rDNA-a) in a human lung epithelial cell model. We will determine dose-
responses of Cr-i-rDNA-a, map amplification boundaries in Cr-i-rDNA-a, examine temporal profiles and
recovery from Cr(VI) exposure, and examine whether Chromium-induced CN changes are responsible for Cr-
induced carcinogenesis. Our second aim investigates the functional genomics of Cr-induced nucleolar stress
and Cr induced transformation in a human lung epithelial cell model. Examining genome-wide responses to Cr
exposure is critical to understand how Cr induces rDNA amplification, nuclelar stress, and carcinogenesis. Our
third aim addresses the genetic determinants of Chromium-rDNA interactions. We will examine Cr-i-rDNA-a in
specific cells, quantify the extent of copy number change, isolate the affected tissues, and use high-throughput
techniques to characterize the changes. Our efforts will shed light on Cr-rDNA interactions, with research that
is directly relevant to the human health mission of the NIH. The manifold effects of rDNA CN indicate that
perturbing this central regulator with Cr will have profound consequences to cellular function. We anticipate
that determinants of complex human diseases with strong environmental components such as cancer will
ultimate...

## Key facts

- **NIH application ID:** 9830653
- **Project number:** 5R01ES027981-03
- **Recipient organization:** HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH
- **Principal Investigator:** Bernardo Lemos
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $474,512
- **Award type:** 5
- **Project period:** 2018-02-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9830653

## Citation

> US National Institutes of Health, RePORTER application 9830653, Novel markers of exposure and pathways of response to Chromium (5R01ES027981-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9830653. Licensed CC0.

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