PUBLICATION
Developmental Neurotoxicity of Environmentally Relevant Pharmaceuticals and Mixtures Thereof in a Zebrafish Embryo Behavioural Test
- Authors
- Atzei, A., Jense, I., Zwart, E.P., Legradi, J., Venhuis, B.J., van der Ven, L.T.M., Heusinkveld, H.J., Hessel, E.V.S.
- ID
- ZDB-PUB-210703-26
- Date
- 2021
- Source
- International Journal of Environmental Research and Public Health 18(13): (Journal)
- Registered Authors
- Keywords
- alternative to in vivo test, chemical mixtures, developmental neurotoxicity (DNT), environmental and human risk assessment, psychopharmaceuticals, zebrafish embryo behavioural test
- MeSH Terms
-
- Animals
- Behavior Rating Scale
- Embryo, Nonmammalian
- Humans
- Neurotoxicity Syndromes*/etiology
- Pharmaceutical Preparations*
- Water Pollutants, Chemical*
- Zebrafish
- PubMed
- 34206423 Full text @ Int. J. Environ. Res. Public Health
Citation
Atzei, A., Jense, I., Zwart, E.P., Legradi, J., Venhuis, B.J., van der Ven, L.T.M., Heusinkveld, H.J., Hessel, E.V.S. (2021) Developmental Neurotoxicity of Environmentally Relevant Pharmaceuticals and Mixtures Thereof in a Zebrafish Embryo Behavioural Test. International Journal of Environmental Research and Public Health. 18(13):.
Abstract
Humans are exposed daily to complex mixtures of chemical substances via food intake, inhalation, and dermal contact. Developmental neurotoxicity is an understudied area and entails one of the most complex areas in toxicology. Animal studies for developmental neurotoxicity (DNT) are hardly performed in the context of regular hazard studies, as they are costly and time consuming and provide only limited information as to human relevance. There is a need for a combination of in vitro and in silico tests for the assessment of chemically induced DNT in humans. The zebrafish (Danio rerio) embryo (ZFE) provides a powerful model to study DNT because it shows fast neurodevelopment with a large resemblance to the higher vertebrate, including the human system. One of the suitable readouts for DNT testing in the zebrafish is neurobehaviour (stimulus-provoked locomotion) since this provides integrated information on the functionality and status of the entire nervous system of the embryo. In the current study, environmentally relevant pharmaceuticals and their mixtures were investigated using the zebrafish light-dark transition test. Zebrafish embryos were exposed to three neuroactive compounds of concern, carbamazepine (CBZ), fluoxetine (FLX), and venlafaxine (VNX), as well as their main metabolites, carbamazepine 10,11-epoxide (CBZ 10,11E), norfluoxetine (norFLX), and desvenlafaxine (desVNX). All the studied compounds, except CBZ 10,11E, dose-dependently inhibited zebrafish locomotor activity, providing a distinct behavioural phenotype. Mixture experiments with these pharmaceuticals identified that dose addition was confirmed for all the studied binary mixtures (CBZ-FLX, CBZ-VNX, and VNX-FLX), thereby supporting the zebrafish embryo as a model for studying the cumulative effect of chemical mixtures in DNT. This study shows that pharmaceuticals and a mixture thereof affect locomotor activity in zebrafish. The test is directly applicable in environmental risk assessment; however, further studies are required to assess the relevance of these findings for developmental neurotoxicity in humans.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping