# Cholinergic and Monoaminergic Mechanisms of Persistent Neurobehavioral Toxicity

> **NIH NIH P42** · DUKE UNIVERSITY · 2020 · $497,287

## Abstract

Cognitive dysfunction is one of the most prevalent persisting adverse effects reported in epidemiological
studies of environmental toxicant exposure. Cognitive as well as emotional dysfunction have been found in
children after developmental exposure to a wide variety of toxicants including pesticides, heavy metals and
polycyclic and polyhalogenated hydrocarbons. Cognitive and emotional impairment are also seen in
experimental animal models of developmental neurotoxic exposures, showing the cause-and-effect
relationships between developmental toxicant exposure and persisting deficits in learning, memory, attention
and anxiety. In our previous research in the Duke University Superfund Research Center (DUSRC) we have
demonstrated the adverse effects of organophosphate (OP) pesticide exposures and persisting cognitive as
well as emotional effects in rat models. These have been found to be related to OP induced disruptions of the
transmitter systems acetylcholine (ACh) as well as the monoamines, dopamine (DA) and serotonin (5HT).
These neurotransmitter systems have been shown in a wide variety of studies to play important roles in the
neural bases of cognitive and emotional function. In the next phase of research with rats, we will determine
how disruptions of ACh, DA and 5HT across different toxicant classes can impair cognitive and emotional
function. We hypothesize that the persisting impacts of pesticides, flame retardants and polycyclic
hydrocarbons on cognitive and emotional function involve an adverse outcome pathway converging on this
neurotransmitter triad. Pharmacological challenges will determine causative relationships between ACh, DA
and 5HT disruption and behavioral impairments. The neurochemical and pharmacological studies will inform
our innovative development of therapeutic treatments of persistent cognitive and emotional deficits, directly
helping people who have cognitive and emotional dysfunction due to early life neurotoxic exposure. We will
complement the classic rat model with the innovative higher throughput zebrafish neurobehavioral model. We
will determine conserved neurobehavioral pathways for the neurotoxic induction of cognitive and emotional
impairment across toxicant classes. Showing that the ACh, DA and 5HT triad is conserved in the zebrafish
model will establish a higher-throughput model to expand the number of chemical exposures that can be
evaluated and related to mechanistic changes that underlie behavioral dysfunction. Understanding the
neurotransmitter involvement in neurotoxicant induced cognitive and emotional dysfunction will not only
provide a common basis for understanding the functional impairments caused by diverse toxicants, it also
provides a basis for devising effective therapeutics for neurotoxic damage. This will bring generalized
advances to the understanding of neurobehavioral toxicology based on underlying synaptic mechanisms rather
than on the behavioral effects of individual chemicals. This multi-...

## Key facts

- **NIH application ID:** 9942436
- **Project number:** 5P42ES010356-18
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** EDWARD D LEVIN
- **Activity code:** P42 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $497,287
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9942436

## Citation

> US National Institutes of Health, RePORTER application 9942436, Cholinergic and Monoaminergic Mechanisms of Persistent Neurobehavioral Toxicity (5P42ES010356-18). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9942436. Licensed CC0.

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