PUBLICATION
Head skeleton malformations in zebrafish (Danio rerio) to assess adverse effects of mixtures of compounds
- Authors
- Staal, Y.C.M., Meijer, J., van der Kris, R.J.C., de Bruijn, A.C., Boersma, A.Y., Gremmer, E.R., Zwart, E.P., Beekhof, P.K., Slob, W., van der Ven, L.T.M.
- ID
- ZDB-PUB-181006-5
- Date
- 2018
- Source
- Archives of toxicology 92(12): 3549-3564 (Journal)
- Registered Authors
- van der Ven, Leo
- Keywords
- Craniofacial malformations, Cumulative assessment groups, Head skeleton, Mixture toxicology, Zebrafish embryos
- MeSH Terms
-
- Animals
- Bone Development/drug effects*
- Craniofacial Abnormalities/chemically induced
- Dose-Response Relationship, Drug
- Embryo, Nonmammalian/drug effects*
- Embryonic Development/drug effects*
- Risk Assessment/methods
- Skull/abnormalities
- Skull/drug effects
- Skull/embryology
- Toxicity Tests/methods*
- Zebrafish
- PubMed
- 30288550 Full text @ Arch. Toxicol.
Citation
Staal, Y.C.M., Meijer, J., van der Kris, R.J.C., de Bruijn, A.C., Boersma, A.Y., Gremmer, E.R., Zwart, E.P., Beekhof, P.K., Slob, W., van der Ven, L.T.M. (2018) Head skeleton malformations in zebrafish (Danio rerio) to assess adverse effects of mixtures of compounds. Archives of toxicology. 92(12):3549-3564.
Abstract
The EU-EuroMix project adopted the strategy of the European Food Safety Authority (EFSA) for cumulative risk assessment, which limits the number of chemicals to consider in a mixture to those that induce a specific toxicological phenotype. These so-called cumulative assessment groups (CAGs) are refined at several levels, including the target organ and specific phenotype. Here, we explore the zebrafish embryo as a test model for quantitative evaluation in one such CAG, skeletal malformations, through exposure to test compounds 0-120 hpf and alcian blue cartilage staining at 120 hpf, focusing on the head skeleton. Reference compounds cyproconazole, flusilazole, metam, and thiram induced distinctive phenotypes in the head skeleton between the triazoles and dithiocarbamates. Of many evaluated parameters, the Meckel's-palatoquadrate (M-PQ) angle was selected for further assessment, based on the best combination of a small confidence interval, an intermediate maximal effect size and a gentle slope of the dose-response curve with cyproconazole and metam. Additional test compounds included in the CAG skeletal malformations database were tested for M-PQ effects, and this set was supplemented with compounds associated with craniofacial malformations or cleft palate to accommodate otherwise organized databases. This additional set included hexaconazole, all-trans-retinoic acid, AM580, CD3254, maneb, pyrimethanil, imidacloprid, pirimiphos-methyl, 2,4-dinitrophenol, 5-fluorouracil, 17alpha-ethynylestradiol (EE2), ethanol, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), PCB 126, methylmercury, boric acid, and MEHP. Most of these compounds produced a dose-response for M-PQ effects. Application of the assay in mixture testing was provided by combined exposure to cyproconazole and TCDD through the isobole method, supporting that in this case the combined effect can be modeled through concentration addition.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping