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Metabolic Mechanisms of Naphthalene Toxicity in Lung

Award Number: R01ES020867
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: 08/20/2013
PERIOD OF PERFORMANCE END DATE: 11/30/2029

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Metabolic Mechanisms of Naphthalene Toxicity in Lung - Naphthalene (NA) is a ubiquitous and highly abundant pollutant found in vehicle exhaust, fossil fuels and wildfire smoke. NA causes nasal and lung toxicity, including tumors, in rats and mice, respectively, and is a possible human carcinogen. The mechanism of NA carcinogenicity, which may involve both genotoxic and non- genotoxic events, is not clear and may involve several reactive NA metabolites. A prerequisite for NA toxicity is bioactivation by cytochrome P450 (CYP) to form NA-epoxide (NAO) which can undergo further metabolism in the lung and liver to 1,2-naphthoquinone (1,2-NQ). Both NAO and 1,2-NQ can react with DNA. We have recently uncovered a significant contribution of liver-generated NA metabolites to acute lung toxicity in vivo; identified several NQ-DNA adducts in the mouse lung, liver, and blood following NA exposure and in blood samples from human firefighters and lung biopsy samples of lung cancer patients; and gained novel insights on the toxicokinetics of various NA metabolites. These exciting findings led to the current proposal, to test the novel hypothesis that liver-generated reactive NA metabolites are transported to the lung where they contribute to NA's cytotoxicity, genotoxicity, and carcinogenesis. We are well positioned to address this hypothesis due to the genetically modified mouse models we have developed, the recent methodologic advances we have made in metabolite and DNA adduct characterization, and the exposure systems we have in place to expose mice acutely and/or chronically to NA vapor at defined doses. A series of mechanistic and translational studies will be carried out in four Specific Aims that will 1) identify key metabolic events that control NA DNA adduct formation in the lung, 2) determine whether serum albumin facilitates transport of liver-generated reactive NA metabolites to the lung, 3) identify whether key metabolic events in the liver mediate NA-induced lung tumorigenesis in vivo, and 4) characterize profiles of NA metabolites and DNA adducts in blood and urine from firefighters. Our long-term goal is to identify metabolic mechanisms that benefit risk assessment for chemical-induced lung toxicity and carcinogenesis in humans. The proposed studies remain focused on metabolic mechanisms underlying NA respiratory toxicity and address mechanisms for the hepatic contribution to lung toxicity, link hepatic NA metabolism to lung tumorigenesis, and examine biomarkers of NA's genotoxicity in humans. These studies define key metabolic events that influence NA-mediated lung toxicity and carcinogenesis. Success of the proposed studies will move the field of mechanistic toxicology forward toward a better understanding of fate and importance of circulating reactive metabolites and shift the paradigm for NA risk assessment, by providing proof- of-principle evidence for the importance of circulating (as well as locally generated) NA metabolites in NA's genotoxicity and lung tumorigenesis, identifying accessible biomarkers for monitoring potential NA genotoxicity in humans, and advancing the understanding of hepatic NA bioactivation as a risk factor that may predispose individuals to NA-induced lung carcinogenesis.


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 = $661,562 )
2025	2025	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Environmental Health	003	13	5/15/2025	COMPETING CONTINUATION	$1,642
2025	2025	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Environmental Health	001	13	12/4/2024	COMPETING CONTINUATION	$661,562
2025	2023	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Environmental Health	000	12	11/26/2024	NON-COMPETING CONTINUATION	$0
2025	2023	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Environmental Health	002	12	5/15/2025	NON-COMPETING CONTINUATION	-$1,642
														Subtotal = $661,562

Issue Date FY: 2023 ( Subtotal = $420,876 )
2023	2023	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Environmental Health	000	12	4/5/2023	NON-COMPETING CONTINUATION	$420,876
														Subtotal = $420,876

Issue Date FY: 2022 ( Subtotal = $419,542 )
2022	2022	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Environmental Health	000	11	4/21/2022	NON-COMPETING CONTINUATION	$419,542
														Subtotal = $419,542

Issue Date FY: 2021 ( Subtotal = $439,585 )
2021	2021	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Environmental Health	000	10	5/11/2021	NON-COMPETING CONTINUATION	$439,585
														Subtotal = $439,585

Issue Date FY: 2020 ( Subtotal = $442,236 )
2020	2020	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Environmental Health	000	9	4/9/2020	NON-COMPETING CONTINUATION	$442,236
														Subtotal = $442,236

Issue Date FY: 2019 ( Subtotal = $474,624 )
2019	2019	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Environmental Health	000	8	4/25/2019	COMPETING CONTINUATION	$474,624
2019	2019	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Environmental Health	002	8	9/25/2019	COMPETING CONTINUATION	$1,661
2019	2017	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Environmental Health	001	7	9/25/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$1,661
														Subtotal = $474,624

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2017	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	257 FULLER RD	ALBANY	NY	12203	ALBANY	USA	Environmental Health	002	6	4/23/2018	NON-COMPETING CONTINUATION	-$64,008
2018	2017	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	257 FULLER RD	ALBANY	NY	12203	ALBANY	USA	Environmental Health	000	6	3/19/2018	NON-COMPETING CONTINUATION	-$468,807
2018	2017	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Environmental Health	005	7	9/24/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$12,840
2018	2017	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	257 FULLER RD	ALBANY	NY	12203	ALBANY	USA	Environmental Health	004	6	9/24/2018	NON-COMPETING CONTINUATION	-$12,840
2018	2017	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Environmental Health	003	7	4/23/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$64,008
2018	2017	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Environmental Health	001	7	3/19/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$468,807
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $724,838 )
2017	2017	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	257 FULLER RD	ALBANY	NY	12203	ALBANY	USA	Environmental Health	005	6	4/20/2017	NON-COMPETING CONTINUATION	$724,838
2017	2016	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	257 FULLER RD	ALBANY	NY	12203	ALBANY	USA	Environmental Health	004	5	4/11/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$309,017
2017	2016	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Environmental Health	003	4	4/11/2017	NON-COMPETING CONTINUATION	-$133,521
2017	2016	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	257 FULLER RD	ALBANY	NY	12203	ALBANY	USA	Environmental Health	001	5	12/7/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$595,076
2017	2016	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Environmental Health	000	4	12/5/2016	NON-COMPETING CONTINUATION	-$595,076
2017	2015	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Environmental Health	002	3	4/11/2017	SUPPLEMENT FOR EXPANSION	-$175,496
														Subtotal = $724,838

Issue Date FY: 2016 ( Subtotal = $728,597 )
2016	2016	RESEARCH FOUNDATION OF STATE UNIV OF NEW YORK (SUNY)	P.O. BOX 9	ALBANY	NY	12201	ALBANY	USA	Environmental Health	000	4	5/3/2016	NON-COMPETING CONTINUATION	$728,597
														Subtotal = $728,597

Issue Date FY: 2015 ( Subtotal = $760,908 )
2015	2015	RESEARCH FOUNDATION OF STATE UNIV OF NEW YORK (SUNY)	P.O. BOX 9	ALBANY	NY	12201	ALBANY	USA	Environmental Health	000	3	4/20/2015	NON-COMPETING CONTINUATION	$333,246
2015	2015	RESEARCH FOUNDATION OF STATE UNIV OF NEW YORK (SUNY)	P.O. BOX 9	ALBANY	NY	12201	ALBANY	USA	Environmental Health	001	3	5/12/2015	SUPPLEMENT FOR EXPANSION	$427,662
														Subtotal = $760,908

Issue Date FY: 2014 ( Subtotal = $359,167 )
2014	2014	RESEARCH FOUNDATION OF STATE UNIV OF NEW YORK (SUNY)	P.O. BOX 9	ALBANY	NY	12201	ALBANY	USA	Environmental Health	000	2	5/22/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$359,167
														Subtotal = $359,167

Issue Date FY: 2013 ( Subtotal = $327,250 )
2013	2013	HEALTH RESEARCH, INC - ALBANY DIVISION	1 UNIVERSITY PLACE	RENSSELAER	NY	12144	RENSSELAER	USA	Environmental Health	000	1	8/20/2013	NEW	$327,250
														Subtotal = $327,250

Grand Total All Awards = $5,759,185

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Metabolic Mechanisms of Naphthalene Toxicity in Lung

Award Number: R01ES020867

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: 08/20/2013

PERIOD OF PERFORMANCE END DATE: 11/30/2029

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