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

Project Leaders

Goals and Importance of Research

There is ample evidence linking early developmental exposures to various individual environmental contaminants, and neurobehavioral impacts later in life. However, people are not exposed to a single chemical in isolation, but to mixtures. This study will look at multiple potential mechanisms for neurobehavioral impacts by using zebrafish and rats. Zebrafish will help assess varying contaminant doses and mixtures, while rats will be used to study key impacts that are more directly relatable to humans. The study of these mechanisms and their specific neurobehavioral effects can improve understanding of risk and help to develop treatments that limit health impacts.

Summary

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 back from the persisting neurobehavioral dysfunction 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 include:

  • molecular (DNA methylation)
  • intracellular (oxidative stress related to mitochondrial dysfunction)
  • 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.

Project Aims

  1. With zebrafish, determine mutually potentiating neurobehavioral toxicity of interacting developmental exposures to heavy metal and PAHs toxicants and complex mixtures.
  2. Determine in rats mutually potentiating effects of developmental interacting exposures to heavy metals and PAHs in producing lifelong locomotor, emotional and cognitive dysfunction and mechanisms for these effects.
  3. Develop therapeutic treatments to prevent neurobehavioral toxicity.
  4. Exploratory Aim: Determine adverse effects of sequential exposures to different toxicants