Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Flusilazole dose response in zebrafish embryo

ABSTRACT: The zebrafish embryotoxicity test (ZET) is considered as a useful alternative model in predictive toxicology. Currently, morphological assessment of the embryo is the main readout for this assay. However, implementation of transcriptomics may help to detect more subtle effects which may increase the sensitivity and predictability of the test. Most transcriptomics studies to date have used only a single toxicant concentration, generally selected based on the sensitivity of the classical morphological endpoint. However, effects on morphology and gene expression are dependent on compound concentration, which consequently may influence prediction of developmental toxicity. In this study, we tested a concentration-response of flusilazole in the ZET. At 24 hours post fertilization, microarray analysis revealed a number of processes to be regulated in a concentration-dependent way. We identified development related processes, retinol metabolism and transcription, as well as processes corresponding to the anti-fungal mechanism of action, steroid biosynthesis and fatty acid metabolism, to be differentially regulated. Retinol metabolism and transcription were already significantly altered at concentrations that were not inducing morphological effects. Differential expression of genes related to steroid biosynthesis and fatty acid metabolism showed a concentration-response similar to morphology. An increase in concentration was also positively associated with an increase in magnitude of expression for each individual gene. Our study shows that transcriptomics analysis in the ZET is a more sensitive readout of compound-induced effects than morphological assessment. However, the interpretation of differential gene expression in terms of predicting morphological effects is not straightforward and requires further study.

ORGANISM(S): Danio rerio

SUBMITTER: Tessa Pronk

PROVIDER: E-MTAB-832 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Concentration-response analysis of differential gene expression in the zebrafish embryotoxicity test following flusilazole exposure.

Hermsen Sanne A B SA Pronk Tessa E TE van den Brandhof Evert-Jan EJ van der Ven Leo T M LT Piersma Aldert H AH

Toxicological sciences : an official journal of the Society of Toxicology 20120229 1

The zebrafish embryotoxicity test (ZET) is considered a promising alternative model in predictive toxicology. Currently, morphological assessment of the embryo is the main readout for this assay. However, implementation of transcriptomics may help to detect more subtle effects, which may increase the sensitivity and predictability of the test. In this study, we tested a concentration response of flusilazole in the ZET. After exposure for 24 h postfertilization, microarray analysis revealed a num ...[more]

PMID: 22382673

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Project description:Within the regulatory framework on the approval of new substances, the assessment of immunotoxic modes of action (MoA) is currently not covered. This is not least due to the lack of standardized methods and reliable validated biomarkers for immunotoxic effects. The experimental set up was designed to analyze the compound-specific response of zebrafish embryos to two immunomodulative reference substances, clobetasol propionate (CP, CAS 25122-46-7) and imiquimod (IMQ, CAS 99011-02-6), on the global level of gene expression. The obtained results were used to (i) identify potential biomarker candidates for the assessment of immunotoxic MoAs, (ii) identify compound-specific molecular signatures, (iii) evaluate the reliability of data acquisition using OMICs-coupled approaches and (iv) to assess the suitability of the zebrafish embryo as an alternative model for the human-representative investigation of psoriatic effects. For this, the transcriptomic profiles of embryos were bioinformatically analysed subsequent to an CP-induced immunosuppression in absence or presence of an IMQ-induced immune challenge, i.e. the simulation of a resting and an activated immune system. In a modified version of the zebrafish embryo toxicity test (OECD 236), 15 fertilized eggs were exposed to either CP (250 nM) or to IMQ (4000 nM) or to a combination of both under semi static conditions. Exposure to CP started at 2 hours post fertilization (hpf) until 72 hpf. Exposure to IMQ started at 48 hpf until 72 hpf. Untreated embryos reared in medium without CP nor IMQ dissolved was used as a negative control. All conditions comprised three biological replicates. Medium was exchanged on a daily basis by renewing half its volume. Occurrence of morphological changes and indicators of lethality as described in the OECD test guideline 236 were examined microscopically on a daily basis. At 72 hpf, all larvae were pooled for each sample for RNA extraction using a NucleoSpin RNA/Protein kit (Macherey-Nagel) following the manufacturer’s protocol. RNA quality was assessed with a 2100 Bioanalyzer system (Agilent) before coding RNA was purified (PolyA selection with TruSeq RNA Library Prep Kit v2) and sequenced on an Illumina NovaSeq 6000 System (Illumina) in 150 bp paired-end mode, producing a minimum of 30 million reads per sample. Adapter sequences were removed with trimmomatic and sequences were aligned to the Danio rerio reference genome GRCz11 with STAR. Counting of feature mapped reads was performed through featureCounts. Library gene count tables were then merged to a single count matrix as input for differential gene expression analysis with DESeq2.

Dataset Information

Flusilazole dose response in zebrafish embryo

Publications

Concentration-response analysis of differential gene expression in the zebrafish embryotoxicity test following flusilazole exposure.

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