# Manganese-Induced Neurotoxic Effects Research in South Africa (MINERS)

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $1

## Abstract

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.

## Key facts

- **NIH application ID:** 10242754
- **Project number:** 5R01ES026891-05
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Brad A Racette
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1
- **Award type:** 5
- **Project period:** 2017-09-01 → 2023-03-24

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242754

## Citation

> US National Institutes of Health, RePORTER application 10242754, Manganese-Induced Neurotoxic Effects Research in South Africa (MINERS) (5R01ES026891-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10242754. Licensed CC0.

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