# Mechanisms of chlorpyrifos-mediated programmed cell death in primary neurons

> **NIH NIH F31** · DARTMOUTH COLLEGE · 2020 · $36,679

## Abstract

Abstract
Debilitating age-related neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease,
are characterized by progressive neuronal loss. Although a percentage of these cases can be attributed to
genetic mutations, the majority arise from unknown causes. Exposure to environmental toxicants, such as
pesticides, heavy metals, and industrial solvents, is strongly associated with an increased risk of developing
neurodegenerative diseases. Despite this growing body of epidemiologic evidence, the molecular basis for this
increased risk resulting from environmental exposure remains poorly characterized. Delineating the molecular
mechanisms by which environmental toxicant exposure translates to neuronal cell death is anticipated to
improve our understanding of the initiation and progression of neurologic disorders and inform the
development of new treatments. Chlorpyrifos (CPF) is a widely-used, commercially available blood-brain-
barrier permeant organophosphate pesticide that is widely-accepted to act through inhibition of
acetylcholinesterase (AChE). Exposure to CPF is associated with increased risk of developing multiple age-
related neurodegenerative diseases but discrepancies exist related to mechanisms of toxicity underlying CPF
exposure. For example, experimental evidence suggests that AChE inhibition is neuroprotective; and
moreover, CPF toxicity is readily observed in cells that are not known to express AChE. This disconnect
underscores the importance of characterizing alternative mechanisms of CPF-induced neuronal cell death. We
have characterized CPF-induced neuronal cell death utilizing cultured primary neurons. Transcriptomic and
ontologic analyses identified the pro-apoptotic mediator Bbc3 (aka Puma) and the p53 pathway as significantly
enriched following CPF exposure compared to controls. Several studies have identified CPF-induced neuronal
stress and programmed cell death in cell and animal models, but it is unknown whether activation of the p53-
Bbc3 signaling axis is required for programmed cell death in neurons or if inhibition of Bbc3 activity is
neuroprotective in CPF-exposed neurons. Here we describe a rigorous research and training plan designed to
test the hypothesis that CPF exposure leads to the activation of a Bbc3-dependent cellular death program, an
induction of molecular machinery independent of CPF's inhibitory action on AChE. These mechanistic studies
will provide experimental evidence to support epidemiologic findings related to CPF and prevalent neurologic
disorders as well as a platform for further analysis of the impact of disease-associated pesticides on the brain.

## Key facts

- **NIH application ID:** 10148547
- **Project number:** 5F31ES030982-02
- **Recipient organization:** DARTMOUTH COLLEGE
- **Principal Investigator:** Faith L Anderson
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $36,679
- **Award type:** 5
- **Project period:** 2019-09-20 → 2021-05-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10148547

## Citation

> US National Institutes of Health, RePORTER application 10148547, Mechanisms of chlorpyrifos-mediated programmed cell death in primary neurons (5F31ES030982-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10148547. Licensed CC0.

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