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Duke University

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Superfund Research Program

Cholinergic and Monoaminergic Mechanisms of Persistent Neurobehavioral Toxicity

Project Leader: Edward D. Levin
Co-Investigators: Theodore A. Slotkin (Duke University Medical Center), Frederic J. Seidler
Grant Number: P42ES010356
Funding Period: 2017-2022

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Project Summary (2017-2022)

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 previous research at the Duke University Superfund Research Program (SRP) Center, the researchers demonstrated adverse effects of organophosphate (OP) pesticide exposures and persisting cognitive and emotional effects in rat models. Their research found these effects were related to OP-induced disruptions of the transmitter systems acetylcholine (ACh) and 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 current studies in rats, the researchers are determining how disruptions of ACh, DA, and 5HT across different toxicant classes can impair cognitive and emotional function. The researchers hypothesize that the persisting impacts of pesticides, flame retardants, and polycyclic aromatic 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 in rats will inform their innovative development of therapeutic treatments of persistent cognitive and emotional deficits, with the potential to directly help people who have cognitive and emotional dysfunction due to early life neurotoxic exposure.

The Duke SRP Center researchers complement the classic rat model with the innovative higher throughput zebrafish neurobehavioral model. They are determining 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-component, biologically-based investigation progresses beyond classic adverse outcome pathways to an adverse outcome interacting systems approach.

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