# Neuroinflammation and developmental vulnerability to manganese toxicity

> **NIH NIH R01** · COLORADO STATE UNIVERSITY · 2020 · $330,700

## Abstract

Project Summary
The nigro-striatal dopamine system in the basal ganglia is highly sensitive to damage from environmental
neurotoxins. Exposure to elevated levels of the essential element manganese (Mn) causes neuronal
injury to this brain region, as well as cortical and subcortical structures. The results of this neurotoxicity
represent a continuum of neurological effects ranging from cognitive and behavioral impairment in
children exposed to Mn in drinking water, to Mn-induced parkinsonism (manganism) from high-dose
occupational exposure in adults. However, it is not clear how early life exposures to Mn might increase
susceptibility to other neurotoxic challenges throughout life. Pesticides such as rotenone that affect
mitochondrial function are amongst the environmental neurotoxins thought to amplify the effects of heavy
metals such as Mn to increase risk for neurodegenerative disease. The capacity of Mn to sensitize neural
tissue to damage from pesticide exposure may involve persistent inflammatory changes in glial cells. Mn-
induced expression of neuroinflammatory genes in glial cells is regulated by the transcription factor,
Nuclear Factor Kappa B (NF-κB), which promotes neuronal injury. However, the signaling mechanisms
between microglia and astrocytes that regulate this damaging glial phenotype are not well understood.
Lack of this information hinders scientific and medical progress in understanding key signaling pathways
that may render individuals more susceptible to neurological disease following combined exposures to
environmental neurotoxins, including Mn and pesticides. To address this question, we postulate that Mn
exposure during development stimulates NF-κB-dependent inflammatory signaling between microglia
and astrocytes, resulting in persistent glial activation that enhances susceptibility to neurotoxic injury
during aging. This hypothesis will tested in three Specific Aims that will 1) Determine how manganese
exposure during juvenile development promotes inflammatory activation of glial cells and modulates the
effects of rotenone on neuronal injury during aging, 2) Identify critical inflammatory signaling pathways in
microglia that modulate the effects of manganese and rotenone on neurological injury, and 3)
Characterize the intercellular signaling factors between microglia and astrocytes that mediate neuronal
injury during exposure to manganese and rotenone. To accomplish these Specific Aims, we will use
unique microglia-specific NF-κB knockout mice generated in our laboratory in a `two-hit' model to
determine how juvenile exposure to Mn alters glial activation and susceptibility to neurotoxic injury during
aging following exposure to the environmental pesticide, rotenone, a systemic mitochondrial complex I
inhibitor. It is our expectation that use of this powerful transgenic model will enable the determination of
specific molecular signaling events underlying NF-κB-dependent activation of neuroinflammatory genes
in glial cell...

## Key facts

- **NIH application ID:** 9937706
- **Project number:** 5R01ES021656-08
- **Recipient organization:** COLORADO STATE UNIVERSITY
- **Principal Investigator:** RONALD TJALKENS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $330,700
- **Award type:** 5
- **Project period:** 2018-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9937706

## Citation

> US National Institutes of Health, RePORTER application 9937706, Neuroinflammation and developmental vulnerability to manganese toxicity (5R01ES021656-08). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9937706. Licensed CC0.

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