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EPIGENETIC MECHANISM OF THE SYNERGISTIC TUMORIGENIC EFFECT OF ARSENICAND BENZO[A]PYRENE CO-EXPOSURE

Award Number: R01ES028256
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY/ABSTRACT Arsenic and benzo[a]pyrene (BaP) are among the most common environmental pollutants and human exposure to arsenic and BaP mixture is very common. Our knowledge on the effect and mechanism of arsenic and BaP co- exposure is limited. The goal of this study is to determine the mechanism of the effect of arsenic and BaP co- exposure. Epigenetics refers to heritable changes in the pattern of gene expression that are not caused by changes in DNA sequence, but are mediated by DNA methylation, histone posttranslational modifications and noncoding RNAs. Cancer stem cells (CSCs) are cancer cells possessing characteristics of normal stem cells. CSCs or CSC- like cells are considered as cancer initiating cells. While the mechanism of arsenic toxic effect is not clearly defined, it is thought that the toxic effect of BaP mainly depends on its metabolic activation and DNA adduct formation. The reported effects of arsenic on DNA adduct level are controversial, suggesting that other mechanisms may play a key role in the combined effect of arsenic and BaP co-exposure. Our preliminary studies found: (i) Arsenic and BaP co-exposure has a synergistic effect in inducing cell transformation, CSC-like property and lung tumors; (ii) Arsenic and BaP co-exposure has no synergistic effect on BPDE-DNA adduct level. In contrast, the co-exposure shows a synergistic effect in epigenetic deregulations as evidenced by increasing the levels of histone H3K9 methyltransferase SUV39H1 and H3 repressive methylation mark H3K9me2. Moreover, the co-exposure also shows a synergistic effect in reducing the level of suppressor of cytokine signaling 3 (SOCS3) and increasing Akt and Erk1/2 activation; (iii) ShRNA knockdown SUV39H1 reduces H3K9me2 level, increases SOCS3 level, reduces Akt and Erk1/2 activation and soft agar colony formation and CSC-like property; (iv) Stably re-expressing SOCS3 reduces Akt, Erk1/2 activation, soft agar colony formation and CSC-like property; (v) Inhibiting Akt and Erk/1/2 reduces soft agar colony formation and CSC-like property; and (vi) Arsenic and BaP co-exposure significantly increases aryl hydrocarbon receptor (AhR) nuclear localization and siRNA knockdown AhR greatly reduces the level of SUV39H1 in arsenic and BaP co-exposure-transformed cells. Based on our preliminary data, our central hypothesis is: (i) Arsenic and BaP co-exposure up-regulates HMTase SUV39H1 via synergistically activating AhR; (ii) Up-regulation of SUV39H1 leads to SOCS3 down-regulation; and (iii) Down-regulation of SOCS3 causes a stronger Akt and Erk1/2 activation, which enhances cell transformation and CSC-like property thus increasing lung tumorigenesis. Three aims are proposed: Aim 1: Arsenic and BaP co-exposure significantly enhances cell transformation and tumorigenesis by up-regulating HMTase SUV39H1 via synergistically activating AhR. Aim 2: SUV39H1 up-regulation by arsenic and BaP co-exposure enhances cell transformation and tumorigenesis by down-regulating SOCS3 leading to stronger activation of Akt and Erk1/2. Aim 3: Simultaneously inactivating both Akt and Erk1/2 by a natural compound Withaferin A impairs the synergistic effect of arsenic and BaP co- exposure in inducing cell transformation and lung tumorigenesis in mice.


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 = -$123 )
2025	2022	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Environmental Health	000	6	11/12/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$123
														Subtotal = -$123

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Environmental Health	001	6	12/5/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$37,961
2024	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Environmental Health	000	5	12/5/2023	NON-COMPETING CONTINUATION	-$37,961
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = -$2,835 )
2023	2022	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Environmental Health	002	6	5/25/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2023	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Environmental Health	000	5	4/25/2023	NON-COMPETING CONTINUATION	-$304,375
2023	2022	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Environmental Health	001	6	4/26/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$301,540
														Subtotal = -$2,835

Issue Date FY: 2022 ( Subtotal = $362,250 )
2022	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Environmental Health	002	5	5/21/2022	NON-COMPETING CONTINUATION	$362,250
2022	2021	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Environmental Health	001	4	11/7/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$292,699
2022	2020	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Environmental Health	000	3	11/7/2021	NON-COMPETING CONTINUATION	-$292,699
														Subtotal = $362,250

Issue Date FY: 2021 ( Subtotal = $362,250 )
2021	2021	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Environmental Health	001	4	8/26/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$362,250
2021	2020	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Environmental Health	000	3	8/25/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $362,250

Issue Date FY: 2020 ( Subtotal = $344,250 )
2020	2020	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Environmental Health	000	3	6/15/2020	NON-COMPETING CONTINUATION	$344,250
														Subtotal = $344,250

Issue Date FY: 2019 ( Subtotal = $344,250 )
2019	2019	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Environmental Health	000	2	5/16/2019	NON-COMPETING CONTINUATION	$344,250
														Subtotal = $344,250

Issue Date FY: 2018 ( Subtotal = $344,250 )
2018	2018	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Environmental Health	000	1	8/13/2018	NEW	$344,250
2018	2018	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Environmental Health	001	1	8/15/2018	NEW	$0
														Subtotal = $344,250

Grand Total All Awards = $1,754,292

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EPIGENETIC MECHANISM OF THE SYNERGISTIC TUMORIGENIC EFFECT OF ARSENICAND BENZO[A]PYRENE CO-EXPOSURE

Award Number: R01ES028256

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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