50-A Zebrafish Model to Develop Mitochondrial Targeted Therapeutics for Sodium Fluoroacetate Toxicity
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Research, Professional Development and Education, 2021
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The Society of Critical Care Medicine's Critical Care Congress features internationally renowned faculty and content sessions highlighting the most up-to-date, evidence-based developments in critical care medicine. This is a presentation from the 2021 Critical Care Congress held virtually from January 31-February 12, 2021.

Carly L. Clayman

Introduction/Hypothesis: The pesticide sodium fluoroacetate (SF, Compound 1080) is an established cardiac toxin. Its primary mechanism is inhibition of the tricarboxylic acid cycle, which reduces cellular energy production. Since treatment strategies consist of supportive care to maintain cardiopulmonary function, further therapeutic development is needed. The aim is to develop a high-throughput translational zebrafish model system to advance mitochondrial targeted therapeutic development for acute SF intoxication.

Methods: Zebrafish were randomly assigned to an acute exposure dose of SF dissolved in E3 embryo medium (0, 0.1, 0.25, 0.50, 0.75, or 1.0mM SF) for 24 hours starting at 1 day post fertilization. At the end of exposure, heart rates and respirometry of embryonic zebrafish were assessed. Fish were raised for daily assessments of heart rate and behavioral parameters. DanioVision, a behavioral tracking system, was used to track larval zebrafish swimming activity. Thigmotaxis and reduced exploration upon light stimulus and c-start reflexes in response to a tapping stimulus are assessed as an index of intact neurobehavioral functions along with locomotor function.

Results: SF induced a dose-dependent decrease in oxygen consumption, a measure of mitochondrial function (p<0.0001). Heart rates decreased dose-dependently with exposure to 0.5 to 1.0mM SF (p<0.001) and also recovered dose-dependently. Locomotor activity was impaired, with reduced velocity and distance traveled by fish exposed to low and high doses of SF (p<0.001). Zebrafish exposed to SF maintained responses to light and tapping stimuli, with an intact startle response. Light stimulus response was enhanced in SF-exposed larvae, which decreased time spent in the center of the well and increased directional turning (p<0.001).

Conclusions: We established a high-throughput zebrafish model of SF poisoning showing mitochondrial and cardiac dysfunction and altered neurobehavioral responses as a result of SF exposure. This indicates that zebrafish may be utilized as a model organism for assessing the impact of toxins on mitochondrial, cardiac, and locomotor function. This platform for assessing toxins may be developed by assessing recovery through applying mitochondrial targeted therapeutic cell-permeable succinate prodrugs.


Meta Tag
Content Type Presentation
Knowledge Area Research
Knowledge Area Professional Development and Education
Knowledge Level Advanced
Membership Level Select
Tag Veterinary Medicine
Year 2021
Children's Hospital of Philadelphia
zebrafish model
mitochondrial-targeted therapeutics
sodium fluoroxetate toxicity


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