# Pesticide-Mediated Generation of a Toxic Neurotransmitter Metabolite

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2021 · $309,000

## Abstract

PROJECT SUMMARY. Exposure to the organochlorine dieldrin predisposes individuals to Parkinson's
Disease (PD); however, the mechanisms linking exposure to disease unknown. Dieldrin can disrupt DA
homeostasis but alone may be insufficient for loss of dopamine (DA) neurons, and neurodegeneration may
require an additional “hit”. Several animal models have demonstrated that altering DA homeostasis,
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. Disruption of DA
homeostasis generates toxic intermediates such as ROS and aldehydes (3,4-dihydroxyphenylacetaldehyde,
DOPAL), via monoamine oxidase. Similar to PD, there is evidence that dieldrin is a risk factor for Alzheimer's
Disease (AD). It has been proposed that altered NE homeostasis is linked to the production of toxic species
and cell injury relevant to AD. As with DA, NE is biotransformed via monoamine oxidase to an aldehyde (3,4-
dihydroxyphenylglycolaldehyde, DOPEGAL), which is highly protein reactive and toxic. Early AD
neuropathology occurs in the locus coeruleus (LC), a major site of NE innervation in the brain, and involves
neurofibrillary tangles of the protein Tau, following its cleavage by an asparagine proteinase (AEP). Recent
reports demonstrated that the NE metabolite, DOPEGAL, activates AEP to cleave Tau and induce Tau
aggregation. Modulation of the extracellular matrix (ECM) is thought to be important for AD pathology and may
influence LC dynamics and NE metabolism. We hypothesize NE metabolism/trafficking as a target for dieldrin,
producing elevated levels of DOPEGAL which affects Tau processing and yields Tau aggregation. In addition,
we posit that modulation of ECM as the second “hit” that influences cellular responses to dieldrin. The
proposed work is highly relevant to AD neuropathogenesis and builds upon the previously funded application.
The goal of this supplement is to elucidate mechanisms underlying environmental risk factors for AD,
specifically focusing on the interaction of the pesticide dieldrin with NE metabolism in neurons and the role of
the ECM. The central hypothesis is that dieldrin targets NE metabolism and/or trafficking in neurons, yielding
build-up of reactive metabolites that initiate toxic pathways, such as tau fibrillization, injuring neurons in an
ECM-dependent manner. Two specific aims will be completed: 1) Elucidate the outcomes of pesticide/dieldrin
exposure on noradrenergic cells for production of the toxic species DOPEGAL. 2) Determine the contribution of
the ECM to pesticide- and DOPEGAL-mediated cellular injury. These Specific Aims will build upon previous
work to address key mechanistic questions for AD regarding critical cellular interactions yielding vulnerability of
neurons to pesticides. These innovative studies are significant to identifying key mechanistic targets of
neurotoxic pesticides and to...

## Key facts

- **NIH application ID:** 10288070
- **Project number:** 3R01ES029035-04S1
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** JONATHAN A DOORN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $309,000
- **Award type:** 3
- **Project period:** 2018-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10288070

## Citation

> US National Institutes of Health, RePORTER application 10288070, Pesticide-Mediated Generation of a Toxic Neurotransmitter Metabolite (3R01ES029035-04S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10288070. Licensed CC0.

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