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Manganese-Induced Neurotoxic Effects Research in South Africa

Award Number: R01ES026891
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: 03/25/2023
PERIOD OF PERFORMANCE END DATE: 08/31/2024

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Manganese-Induced Neurotoxic Effects Research in South Africa - Abstract Manganese (Mn) is an established neurotoxicant that affects motor and cognitive brain pathways. This proposal builds on a growing body of Mn neurotoxicity research generated by our investigative team and others. Despite these important contributions to studying the health effects of Mn exposure in vivo, defining the associated neuropathology is essential to understand mechanisms of injury and to characterize dose- response relations that will inform regulatory policy. These types of studies are extremely challenging due to the difficulty in acquiring human brain tissue and quantifying lifetime exposure to Mn in the same subjects. Over the last seven years, we have developed a collaboration with the University of the Witwatersrand in Johannesburg, South Africa using the only population-wide, occupational autopsy program in the world. Through this collaboration we have conducted novel preliminary Mn neuropathology studies that support the aims in this proposal. Our data suggest that chronic, low-level Mn exposure in these mines is associated with lower neuronal density and higher microglial/astrocyte ratios in the caudate and putamen, indicating that Mn exposure may cause astrocytic dysfunction which in turn induces a pro-inflammatory neurotoxic state in the corpus striatum (caudate, putamen, globus pallidus), driven by the activation of microglia. Astrocytic dysfunction is likely attributable, in part, to dysregulation of several key mitochondrial proteins induced by Mn exposure. However, our preliminary studies also suggest that Mn mineworkers, with high MRI signal intensity on T1 MRI, have similar corpus striatal tissue Mn concentrations, but possibly lower Fe concentrations, than non-Mn mineworkers. In this proposal, we will follow-up on these preliminary data by collecting brains from deceased Mn mineworkers with contemporaneous Mn exposures and appropriately matched non-Mn mineworkers. We will use unbiased stereologic methods to quantify neurons, astrocytes, and microglia in the caudate, putamen, globus pallidus, substantia nigra pars compacta (SNpc), and olfactory bulbs in both groups of workers and investigate the overall and dose-response associations between these counts and cumulative Mn exposure. We will also use immunofluorescence microscopy to quantify targeted astrocytic mitochondrial proteins and inductively coupled plasma-mass spectrometry to compare corpus striatal Mn and Fe concentrations between groups. This highly innovative study will provide a rare opportunity to advance the field of Mn neurotoxicity by investigating the neuropathologic effects of chronic Mn exposure.


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 = $0 )
2025	2021	DIGNITY HEALTH	350 W THOMAS RD	PHOENIX	AZ	85013	MARICOPA	USA	Environmental Health	000	6	2/25/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = -$149,767 )
2024	2021	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Environmental Health	001	5	9/27/2024	NON-COMPETING CONTINUATION	-$1
2024	2020	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Environmental Health	000	4	9/27/2024	NON-COMPETING CONTINUATION	-$149,766
														Subtotal = -$149,767

Issue Date FY: 2023 ( Subtotal = $87,321 )
2023	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Environmental Health	000	5	3/23/2023	NON-COMPETING CONTINUATION	-$536,635
2023	2021	DIGNITY HEALTH	185 BERRY ST STE 200	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Environmental Health	002	6	8/24/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2023	2021	DIGNITY HEALTH	185 BERRY ST STE 300	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Environmental Health	001	6	3/24/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$623,956
														Subtotal = $87,321

Issue Date FY: 2021 ( Subtotal = $536,636 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Environmental Health	000	5	8/27/2021	NON-COMPETING CONTINUATION	$536,636
														Subtotal = $536,636

Issue Date FY: 2020 ( Subtotal = $557,321 )
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Environmental Health	000	4	8/20/2020	NON-COMPETING CONTINUATION	$557,321
														Subtotal = $557,321

Issue Date FY: 2019 ( Subtotal = $560,790 )
2019	2019	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Environmental Health	000	3	8/16/2019	NON-COMPETING CONTINUATION	$560,790
														Subtotal = $560,790

Issue Date FY: 2018 ( Subtotal = $949,827 )
2018	2018	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Environmental Health	001	2	8/31/2018	SUPPLEMENT FOR EXPANSION	$386,475
2018	2018	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Environmental Health	000	2	8/22/2018	NON-COMPETING CONTINUATION	$563,352
														Subtotal = $949,827

Issue Date FY: 2017 ( Subtotal = $588,636 )
2017	2017	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Environmental Health	000	1	8/8/2017	NEW	$588,636
														Subtotal = $588,636

Grand Total All Awards = $3,130,764

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Manganese-Induced Neurotoxic Effects Research in South Africa

Award Number: R01ES026891

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: 03/25/2023

PERIOD OF PERFORMANCE END DATE: 08/31/2024

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