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Applications of zebrafish embryo models to predict developmental toxicity for agrochemical product development

ABSTRACT: Development of safe crop protection products is a complex process that traditionally relies on intensive animal use for hazard identification. Methods that capture toxicity at early stages of agrochemical discovery programs enable a more efficient and sustainable product development pipeline. Here we have explored whether the zebrafish model can be leveraged to identify mammalian-relevant toxicity. We used transgenic zebrafish to assess developmental toxicity following exposures to known mammalian teratogens, and captured larval morphological malformations, including bone and vascular perturbations. We further applied toxicogenomics to identify common biomarker signatures of teratogen exposure. The results show that the larval malformation assay predicted teratogenicity with 82.35% accuracy, 87.50% specificity, and 77.78% sensitivity. Slightly lower accuracy was obtained with the vascular and bone assays. A set of 20 biomarkers were identified that efficiently segregated teratogenic chemicals from non-teratogens. In conclusion, zebrafish are valuable, robust, and cost-effective models for toxicity testing at early stages of product development.

ORGANISM(S): Danio rerio

PROVIDER: GSE254415 | GEO | 2024/03/31

REPOSITORIES: GEO

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Project description:Congenital malformations are a prevalent cause of infant mortality in the United States and their induction has been linked to a variety of factors, including exposure to teratogens. However, the molecular mechanisms of teratogenicity are not fully understood. MicroRNAs are an important group of small, non-coding RNAs that regulate mRNA expression. MicroRNA roles in early embryonic development are well established, and their disruption during development can cause abnormalities. We hypothesized that developmental exposure to teratogens such as valproic acid alters microRNA expression profiles in developing embryos. Valproic acid is an anticonvulsant and mood-stabilizing drug used to treat epilepsy, bipolar disorder and migraines. To examine the effects of valproic acid on microRNA expression during development, we used zebrafish embryos as a model vertebrate developmental system. Zebrafish embryos were continuously exposed to valproic acid (1 mM) or vehicle control (ethanol) starting from 4 hours post-fertilization (hpf) and sampled at 48 and 96 hpf to determine the miRNA expression profiles prior to and after the onset of developmental defects. At 96 hpf, 95% of the larvae showed skeletal deformities, abnormal swimming behavior, and pericardial effusion. Microarray expression profiling was done using Agilent zebrafish miRNA microarrays. Microarray results revealed changes in miRNA expression at both the time points. Thirteen miRNAs were differentially expressed at 48 hpf and 22 miRNAs were altered at 96 hpf. Among them, six miRNAs (miR-16a, 18c, 122, 132, 457b, and 724) were common to both time points. Bioinformatic target prediction and examination of published literature revealed that these miRNAs target several genes involved in the normal functioning of the central nervous system. These results suggest that the teratogenic effects of valproic acid could involve altered miRNA expression. Small RNA profiles were deteremined in valproic acid exposed zebrafish embryos using Agilent miRNA microarrays

Project description:The heavy use of pesticides in intensive agricultural areas often leads to the contamination of neighbouring mosquito larvae breeding sites. Such exposure to complex agrochemical mixtures can affect the tolerance of mosquitoes larvae to insecticides. The objective of this study was to determine whether agrochemical pollutants found in Anopheline larval breeding sites can affect the tolerance of adults to Fludora® Fusion, a novel vector control insecticide formulation combining two insecticides with distinct modes of action. An. gambiae larvae were exposed to a sub-lethal dose of a mixture of agrochemical pesticides representative of a region with an intense agricultural activity in Ivory Coast. Comparative bioassays with Fludora® Fusion and its two insecticide component (deltamethrine and clothianidin) were carried out between adult mosquitoes exposed or not to the agrochemicals at the larval stage. A transcriptomic analysis through RNA sequencing was subsequently performed in larvae and adults in order to highlight the molecular mechanisms underlying the phenotypic changes observed. Bioessais revealed a significant increased tolerance of adult females to clothianidin (2.5-fold) and Fludora® Fusion (2.2-fold) following larval exposure to agrochemicals. No significant increased tolerance to deltamethrin was observed suggesting that pesticide exposure affects the efficacy of the Fludora® Fusion mixture mainly through mechanisms acting on clothianidin tolerance. Transcriptomic analysis revealed the potential of agrochemicals to induce various resistance mechanisms including cuticle proteins, detoxifications activities and altered insecticide sequestration. These results suggest that though Fludora® Fusion has a good potential for vector control, its efficacy may be locally affected by the ecological context. The present study also suggests that, although the complex interactions between the use of agrochemicals and vector control insecticides are difficult to decipher in the field, they still must be considered in the frame of insecticide resistance management programmes.

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Applications of zebrafish embryo models to predict developmental toxicity for agrochemical product development

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