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.
Highlights
The aim of our study is to test whether these developmental neurotoxicity (DNT) effects can be reproduced in the zebrafish embryos, thereby assessing whether this zebrafish (Danio rerio) embryo (ZFE) model can have a role in DNT screening for psychoactive pharmaceuticals acting on the development of the central nervous system (CNS) [13,14]
A quantitative evaluation objectively supported the graphic estimation by comparing the relative potency factor (RPF)-Confidence interval (CI) calculated with and without mixture (Table 4)
Our study provides a new approach method characterized by a defined behavioural phenotype
Summary
Introduction published maps and institutional affilLicensee MDPI, Basel, Switzerland.Attribution (CC BY) license (https://creativecommons.org/licenses/by/ 4.0/).Embryonal and foetal development of the central nervous system is complex and occurs in strictly controlled timeframes, involving many different processes at the molecular, cellular, and tissue levels, such as cell proliferation, differentiation, migration, axon guidance, and network formation [1,2]. Perturbation of these processes by genetic and environmental factors, such as chemical exposure, might cause neurodevelopmental disorders, including attention-deficit/hyperactivity disorder (ADHD), autism, learning disabilities, Int. J. Environ. Res. Public Health 2021, 18, 6717. https://doi.org/10.3390/ijerph18136717 https://www.mdpi.com/journal/ijerph
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
