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Developmental and Neurodevelopmental Toxicity Profiles of Human Neuroactive Drugs in Zebrafish Larvae
Citation:
Waalkes, M., D. Hunter, K. Jarema, AND S. Padilla. Developmental and Neurodevelopmental Toxicity Profiles of Human Neuroactive Drugs in Zebrafish Larvae. SETAC, Minneapolis, MN, November 12 - 16, 2017.
Impact/Purpose:
The Environmental Protection Agency is screening chemicals to prioritize them for toxicity potential. An important facet of that screen is the larval zebrafish developmental assay combined with behavioral assessment, which is a measure of brain development. Zebrafish embryos were treated during development with one of four human neuroactive drugs to see if they were toxic to the developing animal and also toxic to the developing nervous system. Our data indicate that developmental toxicity potency does not necessarily predict neurodevelopmental potency, and that multiple mechanisms of action are represented, given that the two developmentally neurotoxic chemicals are thought to target different neurotransmitter pathways.
Description:
The Environmental Protection Agency is screening chemicals to prioritize them for toxicity potential. An important facet of that screen is the larval zebrafish developmental assay combined with behavioral assessment, which measures zebrafish locomotor activity in response to changes in light intensity. Zebrafish embryos were treated during development with one of four neuroactive drugs: cocaine (monoamine reuptake inhibitor), diazepam (modulates GABA transmission), fluoxetine (serotonin reuptake inhibitor) or haloperidol (antipsychotic). Developmental toxicity was assessed using death and dysmorphology as endpoints; neurodevelopmental toxicity was assessed using a locomotor behavior test at 6 days post fertilization (dpf). Specifically, embryos/larvae were treated with half-log concentrations (0.004 to 120 µM) of each drug on 0 and 3 dpf. Following 24 hour depuration, developmental and neurodevelopmental outcomes were evaluated in 6 dpf zebrafish. Dysmorphic or dead zebrafish were not included in the behavioral analysis. Results revealed that cocaine was the only chemical which was not developmentally toxic; haloperidol had a developmental Lowest Observed Adverse Effect Level (LOAEL) of 4 µM, whereas the LOAEL for diazepam or fluoxetine was 40 µM. Only animals treated with diazepam or fluoxetine during development presented with developmental neurotoxicity (i.e., changes in locomotor behavior) with a LOAEL of 1.2 µM in both cases. These data indicate that zebrafish developmental toxicity potency does not necessarily predict neurodevelopmental potency, and that multiple mechanisms of action appear to be targeted, given that the two developmentally neurotoxic chemicals are thought to target different neurotransmitter pathways. This abstract may not necessarily reflect official Agency policy.