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Indirect Genotoxicity in Metal Carcinogenesis

Award Number: R01ES031002
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: 01/15/2020
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Indirect Genotoxicity in Metal Carcinogenesis - 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.


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: 2024 ( Subtotal = $365,625 )
2024	2024	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Environmental Health	000	5	11/8/2023	NON-COMPETING CONTINUATION	$365,625
														Subtotal = $365,625

Issue Date FY: 2023 ( Subtotal = $365,625 )
2023	2023	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Environmental Health	000	4	12/2/2022	NON-COMPETING CONTINUATION	$365,625
														Subtotal = $365,625

Issue Date FY: 2022 ( Subtotal = $365,625 )
2022	2022	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Environmental Health	000	3	11/16/2021	NON-COMPETING CONTINUATION	$365,625
2022	2022	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Environmental Health	001	3	3/28/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $365,625

Issue Date FY: 2021 ( Subtotal = $365,625 )
2021	2021	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Environmental Health	000	2	11/18/2020	NON-COMPETING CONTINUATION	$365,625
														Subtotal = $365,625

Issue Date FY: 2020 ( Subtotal = $365,625 )
2020	2020	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Environmental Health	000	1	1/15/2020	NEW	$365,625
														Subtotal = $365,625

Grand Total All Awards = $1,828,125

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Indirect Genotoxicity in Metal Carcinogenesis

Award Number: R01ES031002

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: 01/15/2020

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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