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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/215983
Developmental toxicity screening in the zebrafish embryo – a metabolomics approach
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[eng] Birth defects occur in about 3-6% of human births worldwide (CDC, 2023). To mitigate the risk to the unborn child, the assessment of embryo-fetal developmental toxicity is an integral part of chemical registration and regulation. This currently requires testing on mammals, which raises ethical concerns, is costly and time-consuming. The zebrafish embryotoxicity test (ZET) has been proposed as an alternative approach to developmental toxicity assessment. However, the ZET is not widely accepted by regulatory authorities as the relevance of morphological findings from zebrafish embryo (ZFE) to humans is questioned. Thus, mechanistic endpoints are included as these are more conserved between vertebrate species and could improve interspecies transferability. Metabolome analysis has proven to be a valuable tool to reveal molecular changes indicative of various toxicity mechanisms. The main objective of this thesis was to evaluate the use of metabolome analysis in ZFE for the assessment of developmental toxicity. Two mechanisms of developmental toxicity, thyroid hormone disruption and antiangiogenesis, were examined through exposure of ZFEs to corresponding model substances. A targeted metabolomics approach measuring pooled ZFEs exposed to 6-propyl-2-thiouracil (PTU) was adopted for the initial study on thyroid hormone disruption. In the second study two specific inhibitors of angiogenesis, SU4312 and sorafenib, and two developmental toxicants, methotrexate, and rotenone, with a presumed antiangiogenic mode of action (MoA) were investigated. An untargeted metabolomics approach was employed to overcome the limitations of the previous study. This enabled the analysis of metabolome changes in the individual embryo and the optimization of metabolite coverage. The initial study demonstrated two main aspects: (i) reproducibility of the metabolome response in ZFE, and (ii) correlations between metabolite changes, the MoA of PTU and developmental toxicity. In the second study, 247 concordant metabolite changes were identified between SU4312, sorafenib, and methotrexate. Among the common changes were references to disturbed metabolic pathways of antiangiogenesis and developmental toxicity. Furthermore, 183 joint effects of methotrexate and rotenone suggested a common MoA related to disturbances in energy metabolism. Both studies support the use of metabolome analysis in ZFE for the assessment of developmental toxicity.
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WILHELMI, Pia rosa maria. Developmental toxicity screening in the zebrafish embryo – a metabolomics approach. [consulta: 3 de desembre de 2025]. [Disponible a: https://hdl.handle.net/2445/215983]