# Project 2: Persisting Neurobehavioral Dysfunction Caused by Interacting Toxicant Exposures During Development: Mechanistic and Treatment Studies with Zebrafish and Rats

> **NIH NIH P42** · DUKE UNIVERSITY · 2022 · $303,145

## Abstract

Abstract
Persisting neurobehavioral toxicity has been shown to result from early developmental exposure to many
different types of toxicants, including polyaromatic hydrocarbons (PAHs) and heavy metals. While the
developmental neurobehavioral toxicity of individual chemicals have been well-studied, their interactions have
not, despite the fact that people are most often exposed to toxicant combinations. Project 1 focuses on
understanding how developmental PAH exposure impacts neurotoxic effects of heavy metals. We will use an
effects-driven mechanistic investigation, working from the persisting neurobehavioral dysfunction caused by
developmental toxicant exposures back to determine the critical mechanisms that caused the neurobehavioral
toxicity. Interactions of two prototypic PAHs (benzo[a]pyrene and fluoranthene) and two heavy metals (lead and
cadmium) producing persisting alterations in locomotor activity, emotional dysfunction and cognitive impairment
will be determined. The mechanistic investigations will range from molecular (DNA methylation) to intracellular
(oxidative stress related to mitochondrial dysfunction) to intercellular (dopamine, serotonin and acetylcholine
neurotransmitter impairments and microglial-mediated changes in inflammatory processes via IL-1β, 6, 10 and
related cytokines). At an organismal level, the importance of behavioral stress response potentiating
neurobehavioral toxicity to PAHs and heavy metals will be determined. Zebrafish will be used as a front-end
model to assess detailed dose-effect interactions of PAH and heavy metal neurotoxicity with isobolographic
characterization, charting interacting dose-effect functions. Rats will be used to determine the character and
mechanisms of persisting neurobehavioral impairment more directly relevant to humans, including sex-selective
effects. Working from this improved mechanistic understanding of the neurobehavioral toxicity, this project will
advance to the study of complex environmental mixtures. Project 2 will determine the efficacy of potential rescue
treatments using antioxidants, methyl donors and anti-inflammatory cytokines during the toxicant exposure.
These will be developed in zebrafish and verified with the rat model. Another important type of toxicant interaction
is sequential exposures. In an exploratory aim we will determine how early exposure to one neurotoxicant could
cause maladaptive development that would impair response to later exposure to another neurotoxicant. This
sequential change in toxicant exposure is important for understanding risks of changing exposures through a
lifetime. Project 2 will collaborate with the other projects, particularly regarding epigenetics (Project 3), oxidative
stress (Projects 3 and 4), behavioral impairments (Projects 1 and 4), complex environmental mixtures (Projects
1, 4, and 5), neurotransmitter analysis (Analytic Chemistry Core), mixture statistical evaluation (Data
Management and Analysis Core), and sharing inform...

## Key facts

- **NIH application ID:** 10353152
- **Project number:** 2P42ES010356-20
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** EDWARD D LEVIN
- **Activity code:** P42 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $303,145
- **Award type:** 2
- **Project period:** 2000-06-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10353152

## Citation

> US National Institutes of Health, RePORTER application 10353152, Project 2: Persisting Neurobehavioral Dysfunction Caused by Interacting Toxicant Exposures During Development: Mechanistic and Treatment Studies with Zebrafish and Rats (2P42ES010356-20). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10353152. Licensed CC0.

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