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Arsenic, GATA-1, and Hematotoxicity

Award Number: R01ES029369
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: 04/01/2018
PERIOD OF PERFORMANCE END DATE: 09/30/2024

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Arsenic, GATA-1, and Hematotoxicity - Project Summary Arsenic exposure is associated with various acute and chronic health effects. The World Health Organization (WHO) estimates that over 200 million people worldwide are chronically exposed to arsenic in drinking water at concentrations above the WHO safety standard. Emerging evidence from epidemiological studies in multiple countries indicate a strong link between environmental arsenic exposure and increased incidence of anemia, suggesting that arsenic is a human hematotoxicant. However, little is known about how arsenic causes hematotoxicity and how this adverse effect of arsenic can be prevented. Research from our labs demonstrates that: i) Analysis of blood collected from a group of people in Bangladesh exposed to a wide range of arsenic in their drinking water revealed positive effects of arsenic exposure on hematological indicators of anemia; ii) Hematology analysis of blood from mice treated 60 days via drinking water with environmentally relevant concentrations of sodium arsenite (As+3) showed significant alterations in measures of hemoglobin as well as impaired bone marrow erythropoiesis; iii) More intriguingly, our preliminary study revealed that GATA-1, a key transcription factor that mediates both the development and function of red blood cells, is a sensitive molecular target for arsenic interaction. We found that As+3 could replace zinc in the zinc finger moiety of GATA-1 at low non-cytotoxic concentrations, resulting in loss of zinc and protein function. Based on our compelling experimental evidence, we hypothesize that exposure to environmentally relevant concentrations of arsenic causes anemia through inhibiting GATA-1 function by disrupting its zinc finger domain. In Aim 1, we will utilize a variety of cell biology and biochemical methods to definitively examine the impact of As+3 exposure on the process of red blood cell production. These findings will establish what specific steps in the lineage of RBC production that arsenic exposure affects, and how arsenic interrupts these steps. Aim 2 will investigate As+3 interaction with GATA-1 and the functional consequences of this interaction. The experiments are designed to reveal the specific mechanisms by which As+3 interacts with GATA-1 to disrupt its function in cells. In Aim 3, we will validate GATA-1 as a sensitive target in vivo, and test the hypothesis that zinc supplement can prevent arsenic-induced hematotoxicity. The outcomes from our vigorously designed studies are expected to provide novel insights in our understanding of mechanisms underlying increased incidents of anemia in populations exposed to arsenic, thus filling a critical gap in our knowledge of arsenic-induced anemia. Importantly, our study will provide a solid foundation for a clear mechanistic understanding of how supplemental zinc reduces arsenic-induced anemia, and provide the proof of principle for the potential of zinc supplements to prevent arsenic-induced anemia. If validated, supplemental zinc could represent a low cost and easily implemented strategy to prevent anima in arsenic exposed populations.


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 = -$470 )
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	2/27/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$470
														Subtotal = -$470

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	000	6	5/27/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$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	6/3/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $17,700 )
2023	2022	UNIVERSITY OF NEW MEXICO	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	004	5	8/25/2023	NON-COMPETING CONTINUATION	-$4,369
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	005	6	8/25/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$9,599
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	1/12/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$352,908
2023	2022	UNIVERSITY OF NEW MEXICO	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	000	5	1/10/2023	NON-COMPETING CONTINUATION	-$335,208
2023	2022	UNIVERSITY OF NEW MEXICO	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	002	5	5/15/2023	NON-COMPETING CONTINUATION	-$1,298
2023	2021	UNIVERSITY OF NEW MEXICO	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	003	4	8/25/2023	NON-COMPETING CONTINUATION	-$3,932
														Subtotal = $17,700

Issue Date FY: 2022 ( Subtotal = $340,875 )
2022	2022	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	000	5	3/28/2022	NON-COMPETING CONTINUATION	$340,875
														Subtotal = $340,875

Issue Date FY: 2021 ( Subtotal = $340,875 )
2021	2021	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	001	4	5/4/2021	NON-COMPETING CONTINUATION	$340,875
2021	2020	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	000	3	4/2/2021	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $340,875

Issue Date FY: 2020 ( Subtotal = $438,108 )
2020	2020	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	000	3	3/23/2020	NON-COMPETING CONTINUATION	$340,875
2020	2020	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	001	3	5/14/2020	SUPPLEMENT FOR EXPANSION	$97,233
														Subtotal = $438,108

Issue Date FY: 2019 ( Subtotal = $340,875 )
2019	2019	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	000	2	4/1/2019	NON-COMPETING CONTINUATION	$340,875
														Subtotal = $340,875

Issue Date FY: 2018 ( Subtotal = $340,875 )
2018	2018	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Environmental Health	000	1	3/5/2018	NEW	$340,875
														Subtotal = $340,875

Grand Total All Awards = $1,818,838

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Arsenic, GATA-1, and Hematotoxicity

Award Number: R01ES029369

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: 04/01/2018

PERIOD OF PERFORMANCE END DATE: 09/30/2024

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