Developmental Neurotoxicity of Environmentally Relevant Pharmaceuticals and Mixtures Thereof in a Zebrafish Embryo Behavioural Test
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...
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doaj-e3af5133c55b4ba7aaca2ba7cbd4bcd62021-07-15T15:34:09ZengMDPI AGInternational Journal of Environmental Research and Public Health1661-78271660-46012021-06-01186717671710.3390/ijerph18136717Developmental Neurotoxicity of Environmentally Relevant Pharmaceuticals and Mixtures Thereof in a Zebrafish Embryo Behavioural TestAlessandro Atzei0Ingrid Jense1Edwin P. Zwart2Jessica Legradi3Bastiaan J. Venhuis4Leo T.M. van der Ven5Harm J. Heusinkveld6Ellen V.S. Hessel7National Institute for Public Health and the Environment (RIVM), 3721 AB Bilthoven, The NetherlandsNational Institute for Public Health and the Environment (RIVM), 3721 AB Bilthoven, The NetherlandsNational Institute for Public Health and the Environment (RIVM), 3721 AB Bilthoven, The NetherlandsEnvironment & Health, VU University Amsterdam, 1081 HV Amsterdam, The NetherlandsNational Institute for Public Health and the Environment (RIVM), 3721 AB Bilthoven, The NetherlandsNational Institute for Public Health and the Environment (RIVM), 3721 AB Bilthoven, The NetherlandsNational Institute for Public Health and the Environment (RIVM), 3721 AB Bilthoven, The NetherlandsNational Institute for Public Health and the Environment (RIVM), 3721 AB Bilthoven, The NetherlandsHumans 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 (<i>Danio rerio</i>) 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.https://www.mdpi.com/1660-4601/18/13/6717developmental neurotoxicity (DNT)psychopharmaceuticalsalternative to in vivo testzebrafish embryo behavioural testchemical mixturesenvironmental and human risk assessment |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Alessandro Atzei Ingrid Jense Edwin P. Zwart Jessica Legradi Bastiaan J. Venhuis Leo T.M. van der Ven Harm J. Heusinkveld Ellen V.S. Hessel |
spellingShingle |
Alessandro Atzei Ingrid Jense Edwin P. Zwart Jessica Legradi Bastiaan J. Venhuis Leo T.M. van der Ven Harm J. Heusinkveld Ellen V.S. Hessel Developmental Neurotoxicity of Environmentally Relevant Pharmaceuticals and Mixtures Thereof in a Zebrafish Embryo Behavioural Test International Journal of Environmental Research and Public Health developmental neurotoxicity (DNT) psychopharmaceuticals alternative to in vivo test zebrafish embryo behavioural test chemical mixtures environmental and human risk assessment |
author_facet |
Alessandro Atzei Ingrid Jense Edwin P. Zwart Jessica Legradi Bastiaan J. Venhuis Leo T.M. van der Ven Harm J. Heusinkveld Ellen V.S. Hessel |
author_sort |
Alessandro Atzei |
title |
Developmental Neurotoxicity of Environmentally Relevant Pharmaceuticals and Mixtures Thereof in a Zebrafish Embryo Behavioural Test |
title_short |
Developmental Neurotoxicity of Environmentally Relevant Pharmaceuticals and Mixtures Thereof in a Zebrafish Embryo Behavioural Test |
title_full |
Developmental Neurotoxicity of Environmentally Relevant Pharmaceuticals and Mixtures Thereof in a Zebrafish Embryo Behavioural Test |
title_fullStr |
Developmental Neurotoxicity of Environmentally Relevant Pharmaceuticals and Mixtures Thereof in a Zebrafish Embryo Behavioural Test |
title_full_unstemmed |
Developmental Neurotoxicity of Environmentally Relevant Pharmaceuticals and Mixtures Thereof in a Zebrafish Embryo Behavioural Test |
title_sort |
developmental neurotoxicity of environmentally relevant pharmaceuticals and mixtures thereof in a zebrafish embryo behavioural test |
publisher |
MDPI AG |
series |
International Journal of Environmental Research and Public Health |
issn |
1661-7827 1660-4601 |
publishDate |
2021-06-01 |
description |
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 (<i>Danio rerio</i>) 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. |
topic |
developmental neurotoxicity (DNT) psychopharmaceuticals alternative to in vivo test zebrafish embryo behavioural test chemical mixtures environmental and human risk assessment |
url |
https://www.mdpi.com/1660-4601/18/13/6717 |
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