Superfund Research Program
Persisting Neurobehavioral Dysfunction Caused by Interacting Toxicant Exposures During Development: Mechanistic and Treatment Studies with Zebrafish and Rats
Project Leader: Edward D. Levin
Grant Number: P42ES010356
Funding Period: 2022-2027
- Project Summary
Project Summary (2022-2027)
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.
In this project, the researchers 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 determined. The mechanistic investigations 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-1ß, 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 are 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 are 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 advances the study of complex environmental mixtures.
This project also works to determine the efficacy of potential rescue treatments using antioxidants, methyl donors and anti-inflammatory cytokines during the toxicant exposure. These are developed in zebrafish and verified with the rat model. Another important type of toxicant interaction is sequential exposures. In an exploratory aim, the team determines 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.
This project collaborates with the other projects, particularly regarding epigenetics (Mitochondrial and Cellular Mechanisms of Neurotoxicity of Superfund Chemical Co-exposures project), oxidative stress (Mitochondrial and Cellular Mechanisms of Neurotoxicity of Superfund Chemical Co-exposures and Neurobehavioral and Bioenergetic Consequences of Evolving Resistance to Polycyclic Aromatic Hydrocarbons in a Multi-stressor Environment projects), behavioral impairments (Prenatal Exposures to PAHs and Metals in an Impacted Community: Assessing Neurodevelopment Impacts and Tracing Metal Sources and Neurobehavioral and Bioenergetic Consequences of Evolving Resistance to Polycyclic Aromatic Hydrocarbons in a Multi-stressor Environment projects), complex environmental mixtures (Prenatal Exposures to PAHs and Metals in an Impacted Community: Assessing Neurodevelopment Impacts and Tracing Metal Sources, Neurobehavioral and Bioenergetic Consequences of Evolving Resistance to Polycyclic Aromatic Hydrocarbons in a Multi-stressor Environment, and Microencapsulation Delivery Vehicles for the Implementation of Precision Bioremediation at PAH-Contaminated Superfund Sites projects), neurotransmitter analysis (Analytical Chemistry Core), mixture statistical evaluation (Data Management and Analysis Core), and sharing information with the broader community (Community Engagement Core) to enhance understanding of real world neurotoxic risks to toxicant mixtures and develop treatments to reduce adverse neurobehavioral toxicity.