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Updated: Aug 8, 2025
Rapid Evaluation of Toxicity of Chemical Compounds Using Zebrafish Embryos
Published on: August 25, 2019
Prediction of zebrafish embryonic developmental toxicity by integrating omics with adverse outcome pathway
Xiao Gou1, Cong Ma1, Huimin Ji1
1State Key Laboratory of Pollution Control & Resource Reuse, School of the Environment, Nanjing University, Nanjing 210023, Jiangsu, China.
Abstract:
New approach methodologies (NAMs), especially omics-based high-throughput bioassays have been developed rapidly, providing rich mechanistic information such as molecular initiation events (MIEs) and (sub)cellular key events (KEs) in adverse outcome pathways (AOPs). However, how to apply the knowledge of MIEs/KEs to predict adverse outcomes (AOs) induced by chemicals represents a new challenge for computational toxicology. Here, an integrated method named ScoreAOP was developed and evaluated to predict chemicals' developmental toxicity for zebrafish embryos by integrating four related AOPs and dose-dependent reduced zebrafish transcriptome (RZT). The rules of ScoreAOP included 1) sensitivity of responsive KEs demonstrated by point of departure of KEs (PODKE), 2) evidence reliability and 3) distance between KEs and AOs. Moreover, eleven chemicals with different modes of action (MoAs) were tested to evaluate ScoreAOP. Results showed that eight of the eleven chemicals caused developmental toxicity at tested concentration in apical tests. All the tested chemicals' developmental defects were predicted using ScoreAOP, whereas eight out of the eleven chemicals predicted by ScoreMIE which was developed to score MIEs disturbed by chemicals based on in vitro bioassays data. Finally, in terms of mechanism explanation, ScoreAOP clustered chemicals with different MoAs while ScoreMIE failed, and ScoreAOP revealed the activation of aryl hydrocarbon receptor (AhR) plays a significant role in dysfunction of cardiovascular system, resulting in zebrafish developmental defects and mortality. In conclusion, ScoreAOP represents a promising approach to apply mechanism information obtained from omics to predict AOs induced by chemicals.
Insights
A new computational toxicology method, ScoreAOP, effectively predicts chemical developmental toxicity in zebrafish embryos using adverse outcome pathways (AOPs) and omics data. ScoreAOP accurately identifies defects and elucidates mechanisms, outperforming methods focused solely on molecular initiation events (MIEs).
Area of Science:
- Computational toxicology
- Omics-based high-throughput bioassays
- Adverse Outcome Pathways (AOPs)
Background:
- New Approach Methodologies (NAMs) provide mechanistic insights (MIEs, KEs) but applying this to predict Adverse Outcomes (AOs) remains challenging.
- Integrating omics data with AOP knowledge is crucial for advancing predictive toxicology.
- Current methods struggle to bridge the gap between molecular events and organism-level toxicity predictions.
Purpose of the Study:
- To develop and evaluate ScoreAOP, an integrated method for predicting chemical developmental toxicity in zebrafish embryos.
- To assess ScoreAOP's ability to utilize AOPs and dose-dependent transcriptome data for toxicity prediction.
- To compare ScoreAOP's performance against ScoreMIE, a method focused on MIEs.
Main Methods:
- ScoreAOP integrates four AOPs and dose-dependent reduced zebrafish transcriptome (RZT) data.
- Key rules for ScoreAOP include sensitivity of key events (PODKE), evidence reliability, and KE-AO distance.
- Eleven chemicals with diverse modes of action were tested to evaluate ScoreAOP's predictive power and mechanistic insights.
Main Results:
- ScoreAOP accurately predicted developmental defects for all eleven tested chemicals.
- Eight of eleven chemicals showed developmental toxicity in apical tests.
- ScoreAOP outperformed ScoreMIE, correctly predicting 11 vs. 8 chemicals, and successfully clustered chemicals by mode of action.
Conclusions:
- ScoreAOP is a promising approach for applying omics-derived mechanistic information to predict chemical-induced Adverse Outcomes (AOs).
- The method provides mechanistic explanations, such as the role of aryl hydrocarbon receptor (AhR) activation in cardiovascular dysfunction leading to developmental defects.
- ScoreAOP advances computational toxicology by bridging molecular events to organism-level toxicity predictions.
