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Title
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Advancing the Zebrafish Embryo Developmental Toxicity Assay (ZEDTA) towards a sensitive screening assay
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Author
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Abstract
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| Within Europe, new approach methodologies (NAMs) for toxicity assessment of xenobiotics become very important. Several pharmaceutical, (agro)chemical and cosmetic companies are currently using zebrafish embryo assays as an alternative for animal testing to screen new compounds for developmental toxicity. The zebrafish embryo assay is considered to be very promising, as it is the only non-animal assay that allows assessment of a vertebrate model during the main organogenesis period with a relatively high accuracy. However, it still suffers from some limitations. Inter- and intra-laboratory discordances in teratogenicity classification of identical compounds, as well as false negative and false positive results are reported for known mammalian teratogens and non-teratogens, respectively. In view of human safety, false negative results are more critical than false positive results, as teratogens may be missed. Causes for these false negative results include: inter-species differences in mode of action, issues with compound uptake, the limited biotransformation capacity and the limited number of morphological endpoints in zebrafish embryo assays. Therefore, the aim of this doctoral thesis was to further standardize and optimize the Zebrafish Embryo Developmental Toxicity Assay (ZEDTA) in order to increase the sensitivity of this screening assay, and as such better predict birth defects caused by drugs during the first trimester of pregnancy. To do so, we: 1) developed a standardized ZEDTA protocol that can be extended with a metabolic activation system, 2) determined the maximal concentration of DMSO that can be safely used as a solvent in the ZEDTA, 3) investigated whether the sensitivity of the ZEDTA could be increased by including a skeletal staining method, and 4) investigated whether anti-epileptic drugs that require bioactivation to exert their teratogenic potential are biotransformed by non-CYP enzymes in zebrafish embryos and young larvae, and whether these metabolites cause developmental toxicity. |
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Language
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English
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Publication
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Antwerp
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University of Antwerp, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, Department of Veterinary Sciences
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2024
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ISBN
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978-90-5728-845-6
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DOI
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10.63028/10067/2060960151162165141
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Volume/pages
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218 p.
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Note
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Van Cruchten, Steven [Supervisor]
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Foubert, Kenn [Supervisor]
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Full text (open access)
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