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Effects of HFE H63D on Brain Mn Accumulation and Neurotoxicity

Award Number: F30ES030607
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 05/01/2019
PERIOD OF PERFORMANCE END DATE: 05/31/2024

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Effects of HFE H63D on Brain Mn Accumulation and Neurotoxicity - PROJECT SUMMARY/ABSTRACT Manganese (Mn) is an essential cofactor for many cellular processes, but at elevated concentrations is known to exert neurotoxic effects on the brain. To date, population-based studies of Mn-exposed children and welders have consistently shown that chronic Mn exposure (X) is associated with deficits in motor and neurobehavioral outcomes (Y). Additionally, magnetic resonance imaging (MRI) has shown that both Mn exposure and outcomes are associated with brain Mn accumulation (M). While these associations have raised interest in the development of imaging-based safety guidelines, it is presently unknown as to how brain Mn accumulation may mediate the relationship between Mn exposure and motor and neurobehavior outcomes (X→M→Y). This lack of understanding has led some to attempt complex, high-dimensional data analyses to deconvolve the underlying relationships governing neurotoxicity in Mn-exposed individuals. However, few so far have accounted for common genetic variants that are likely to have significant moderating effects. Importantly, Mn levels are known to be influenced by iron (Fe) levels and the expression of Fe-regulatory proteins. Chemically similar, Mn and Fe move between intra- and extracellular compartments through shared transport mechanisms. The human hemochromatosis protein (HFE) is an Fe-regulatory protein that negatively regulates mechanisms facilitating Mn entry into the brain. The HFE histidine-to-aspartate substitution at position 63 (H63D) is a commonly carried gene variant that results in HFE partial loss-of-function. Thus, the central hypothesis of this fellowship application is that HFE H63D moderates the relationships between welding, brain Mn accumulation, and neurobehavioral and motor outcomes. In doing so, H63D may moderate the neurotoxic effects of prolonged Mn exposure. Uncovering these effects is of particular


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 = -$10,784 )
2025	2024	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Environmental Health	001	5	3/25/2025	NON-COMPETING CONTINUATION	-$11,971
2025	2024	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Environmental Health	000	5	2/13/2025	NON-COMPETING CONTINUATION	$1,187
														Subtotal = -$10,784

Issue Date FY: 2024 ( Subtotal = $29,244 )
2024	2024	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Environmental Health	001	5	5/10/2024	NON-COMPETING CONTINUATION	-$23,450
2024	2024	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Environmental Health	000	5	2/28/2024	NON-COMPETING CONTINUATION	$52,694
														Subtotal = $29,244

Issue Date FY: 2023 ( Subtotal = $52,694 )
2023	2023	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Environmental Health	000	4	2/22/2023	NON-COMPETING CONTINUATION	$52,694
														Subtotal = $52,694

Issue Date FY: 2022 ( Subtotal = $33,607 )
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Environmental Health	000	3	2/18/2022	NON-COMPETING CONTINUATION	$32,891
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Environmental Health	001	3	6/1/2022	NON-COMPETING CONTINUATION	$716
														Subtotal = $33,607

Issue Date FY: 2021 ( Subtotal = $32,781 )
2021	2021	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Environmental Health	000	2	3/1/2021	NON-COMPETING CONTINUATION	$32,781
														Subtotal = $32,781

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2019	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY DR C1607	HERSHEY	PA	17033	DAUPHIN	USA	Environmental Health	000	1	11/11/2019	NEW	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $31,655 )
2019	2019	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY DR C1607	HERSHEY	PA	17033	DAUPHIN	USA	Environmental Health	001	1	4/17/2019	NEW	$0
2019	2019	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY DR C1607	HERSHEY	PA	17033	DAUPHIN	USA	Environmental Health	002	1	5/17/2019	NEW	$0
2019	2019	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY DR C1607	HERSHEY	PA	17033	DAUPHIN	USA	Environmental Health	000	1	4/17/2019	NEW	$31,655
														Subtotal = $31,655

Grand Total All Awards = $169,197

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Effects of HFE H63D on Brain Mn Accumulation and Neurotoxicity

Award Number: F30ES030607

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 05/01/2019

PERIOD OF PERFORMANCE END DATE: 05/31/2024

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