Monday, June 30, 2025 6/30/2025

Novel markers of exposure and pathways of response to Chromium

Award Number: R01ES027981
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/09/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Novel markers of exposure and pathways of response to Chromium - 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 ultimately be traced to environmentally triggered variation in rDNA segments of the genome.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2022	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Environmental Health	000	6	3/10/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Environmental Health	000	6	2/20/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Environmental Health	002	6	6/10/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$295,573
2023	2022	HARVARD COLLEGE PRESIDENT & FELLOWS OF	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Environmental Health	001	5	6/10/2023	NON-COMPETING CONTINUATION	-$147,173
2023	2021	HARVARD COLLEGE PRESIDENT & FELLOWS OF	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Environmental Health	000	4	6/10/2023	NON-COMPETING CONTINUATION	-$148,400
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $354,642 )
2022	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Environmental Health	000	5	11/23/2021	NON-COMPETING CONTINUATION	$355,731
2022	2022	HARVARD COLLEGE PRESIDENT & FELLOWS OF	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Environmental Health	001	5	8/8/2022	NON-COMPETING CONTINUATION	-$208,558
2022	2022	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Environmental Health	002	6	8/8/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$207,469
														Subtotal = $354,642

Issue Date FY: 2021 ( Subtotal = $352,774 )
2021	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Environmental Health	000	4	11/26/2020	NON-COMPETING CONTINUATION	$352,774
														Subtotal = $352,774

Issue Date FY: 2020 ( Subtotal = $474,512 )
2020	2020	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Environmental Health	001	3	1/14/2020	NON-COMPETING CONTINUATION	$474,512
2020	2019	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Environmental Health	000	2	11/28/2019	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $474,512

Issue Date FY: 2019 ( Subtotal = $479,115 )
2019	2019	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Environmental Health	001	2	7/30/2019	NON-COMPETING CONTINUATION	$0
2019	2019	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Environmental Health	000	2	11/30/2018	NON-COMPETING CONTINUATION	$359,490
2019	2019	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Environmental Health	002	2	7/31/2019	SUPPLEMENT FOR EXPANSION	$119,625
														Subtotal = $479,115

Issue Date FY: 2018 ( Subtotal = $361,906 )
2018	2018	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Environmental Health	000	1	1/16/2018	NEW	$361,906
														Subtotal = $361,906

Grand Total All Awards = $2,022,949

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Novel markers of exposure and pathways of response to Chromium

Award Number: R01ES027981

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/09/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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