# Vesicular modulation of dopamine neuron toxicity

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $313,332

## Abstract

Project Abstract
It is widely believed that complex gene-environment interactions underlie the development and progression of
AD. Exposure to synthetic environmental toxicants has been extensively linked to AD. Despite the association
between environmental exposure and AD risk, the mechanisms underlying toxicant-induced neurodegenerative
processes are poorly understood. Using targeted or candidate approaches, epidemiologic studies have identified
compounds strongly associated with dementia and AD. However, new and emerging chemicals are constantly
entering our ecosystem. For these reasons, it is important to take an unbiased approach in determining which
chemicals are associated with disease. Recently, we used unbiased LC and GC-based HRMS to determine
toxicants negatively associated with IQ levels in serum from participants of the Reference Ability Neural Network
(RANN) study. The comprehensive cognitive assessments in RANN assess many of the features associated
with Alzheimer’s disease and related dementias (ADRD). Through this approach, we identified these top 5
compounds: fonofos (organophosphate pesticide), PCB 183 (industrial polychlorinated biphenyl), lindane
(organochlorine pesticide), 1,2-dibromo-3-chloropropane (DBCP) (soil fumigant/nemacide), and cis-permethrin
(pyrethroid pesticide). These compounds represent a multitude of chemical classes, highlighting the importance
of untargeted analysis in identifying possible novel contributors to disease. Despite their seemingly disparate
nature, these data suggest that different chemicals might converge on similar molecular pathways contributing
to cognitive decline. Based on a previous targeted study that demonstrated that a metabolite of the
organochlorine pesticide DDT was elevated in AD patient plasma, we characterized DDT-induced
neurodegenerative outcomes and metabolomic alterations in C. elegans. We found DDT exposure exacerbates
neurodegenerative phenotypes caused by expression of the AD-associated human tau protein, reducing growth,
altering swim behavior, exacerbating protein misfolding, and causing metabolome-wide alterations. Using the
technical toolkit and computational pipelines we already have in place under the parent R01, we seek to
characterize AD-like outcomes in C. elegans exposed to these newly identified compounds. We hypothesize that
exposure to these toxicants will 1) result in AD-like neurodegenerative phenotypes and 2) dysregulate similar
metabolomic pathways. Specific Aim 1: Characterize AD-associated behavioral and pathologic outcomes in C.
elegans expressing AD-related mutant tau exposed to putative cognition-impairing toxicants. Specific Aim 2:
Discover metabolomic pathways altered by putative cognition-impairing toxicants. Successful completion of
these aims will provide molecular characterization of the mechanisms by which environmental toxicants
contribute to neurodegeneration.

## Key facts

- **NIH application ID:** 10498322
- **Project number:** 3R01ES023839-07S1
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** GARY W MILLER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $313,332
- **Award type:** 3
- **Project period:** 2014-11-17 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10498322

## Citation

> US National Institutes of Health, RePORTER application 10498322, Vesicular modulation of dopamine neuron toxicity (3R01ES023839-07S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10498322. Licensed CC0.

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