# Pesticide-Mediated Generation of a Toxic Neurotransmitter Metabolite

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2020 · $29,626

## Abstract

PROJECT SUMMARY
Exposure to the organochlorine dieldrin predisposes individuals to Parkinson's Disease (PD); however, the
mechanisms linking exposure to disease and selective loss of dopaminergic cells are unknown. In addition,
dieldrin alone may be insufficient for loss of dopamine (DA) neurons, and neurodegeneration may require an
additional “hit”, such as from genetics. Several animal models have demonstrated that altering DA metabolism
and/or trafficking yields progressive loss of DA neurons; therefore, a genetic variation modifying DA
metabolism may be an additional “hit” that has toxic synergy with pesticide exposure. Cell types other than DA
neurons are thought to be involved in PD, such as glia, and toxic factors released via glial activation are
realized as a critical contributors to disease progression. Both DA neurons and glial cells (e.g., astrocytes)
metabolize DA and other neurotransmitters and generate toxic intermediates such as ROS and aldehydes
(3,4-dihydroxyphenylacetaldehyde, DOPAL), via monoamine oxidase. Based on literature precedent and
preliminary data, we propose DA metabolism and trafficking as a mechanistic target for the pesticide dieldrin
that can produce a build-up of reactive and toxic intermediates such as DOPAL and neuroinflammation. While
the role of DA and its quinone have been explored as a mechanism for neurotoxicity, very little is known about
DOPAL and the role of aldehyde metabolism. DOPAL generation is proposed as a mechanism unifying
pesticide exposure, neuroinflammation and loss of catecholaminergic cells. The goal of this work is to elucidate
mechanisms underlying environmental risk factors for neurodegenerative disease, specifically focusing on the
interaction of the pesticide dieldrin with DArgic and glia and resulting injury to dopaminergic neurons via
reactive intermediates such as DOPAL. In addition, the gene-environment interaction will be explored as
dieldrin alone may be insufficient to cause loss of DA neurons. The central hypothesis is that pesticides such
as dieldrin target DA metabolism and/or trafficking in neurons and glia, yielding reactive aldehyde metabolites
that damage DA neurons and promote neuroinflammatory activation of glial cells. Three Aims will be
completed: 1) Determine the effects of pesticide exposure on the nigro-striatal DA system in transgenic mice
with altered DA metabolism. 2) Determine the contribution of glial-derived reactive DA intermediates to
pesticide-mediated neuronal injury. 3) Identify cellular and molecular targets of reactive intermediates. An
innovative and encompassing approach in vivo and in vitro will be used with a robust genetic strategy of mice
that are deficient or have overexpression of enzymes key to DA metabolism. These Specific Aims will build
upon previous work to address key mechanistic questions regarding critical cellular interactions between
astrocytes and neurons that potentiate dysfunction caused by exposure to pesticides.

## Key facts

- **NIH application ID:** 10089497
- **Project number:** 3R01ES029035-03S1
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** JONATHAN A DOORN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $29,626
- **Award type:** 3
- **Project period:** 2018-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10089497

## Citation

> US National Institutes of Health, RePORTER application 10089497, Pesticide-Mediated Generation of a Toxic Neurotransmitter Metabolite (3R01ES029035-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10089497. Licensed CC0.

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