Superfund Research Program

A Novel Mechanism of Ortho-PCB-induced Toxicity: Targeting Nuclear Receptors in Brain of Fish

Project Leader: John J. Stegeman (Woods Hole Oceanographic Institution)
Co-Investigators: Jared V. Goldstone (Woods Hole Oceanographic Institution), Neelakanteswar Aluru (Woods Hole Oceanographic Institution), Makoto Saito (Woods Hole Oceanographic Institution)
Grant Number: P42ES007381
Funding Period: 2017-2021

Project-Specific Links

Final Progress Reports

Year:   2019 

The goal of John Stegeman, Ph.D., and his research team is to understand mechanisms underlying effects in brain, including neurobehavioral effects, of the non-dioxin-like ortho-substituted polychlorinated biphenyls (PCBs). These components of PCB mixtures are neurotoxic, especially to developing animals, but many of the effects and many of the mechanisms are not understood. Scientists involved in the project have found large changes to gene expression caused by ortho-PCBs in fish brain, indicating that there are complex molecular mechanisms that contribute to neurotoxicity. These mechanisms may be mediated by nuclear receptors, and they have characterized in nuclear-receptor “knockout” fish. They have also detailed significant behavioral effects of environmentally common PCB153, PCB138, and PCB95 on zebrafish larvae. Applied doses of PCB153 close to those observed in human samples alter behavior. In addition to increased activity (hyperactivity) during light periods, and decreased activity (hypoactivity) during dark periods, zebrafish larvae exhibit strong changes in their startle-escape responses, taking significantly longer to respond to a loud noise. PCB126, a dioxin-like PCB, does not alter this response. Using genetically engineered zebrafish, immunohistochemistry, and electrical stimulation, which bypasses the sensory system and directly activates escape circuits, the researchers were able to show that cells functionally transmit information downstream of the circuit, and that most morphologies appear normal. Further investigations into the role of neurotransmitters in these effects suggest that both dopaminergic and serotonergic circuits are altered. This study advances understanding of the mechanism of action of ubiquitous environmental contaminants, providing mechanistic insight into a process affecting rapid escape from predators (ecological relevance) and proper neuronal development (human health relevance).