Concentration-dependent transcriptome of zebrafish embryo for environmental chemical assessment

Mechanistic information is essential to screen and predict the adverse effects of a large number of chemicals during early-life exposure. Concentration-dependent omics can capture the extent of perturbations of biological pathways or processes and provide information on the mechanism of toxicity. However, the application of concentration-dependent transcriptome to assess the developmental toxicity of environmental chemicals is still limited. Here, twelve chemicals representing five different modes of action (MOAs) were tested by the concentration-dependent reduced zebrafish transcriptome approach (CRZT) in combination with a phenotype-based high content screen (PHCS). The responsiveness, sensitivity and mechanistic differentiation of CRZT were validated in comparison with PHCS. First, PHCS identified 10 chemicals with obvious embryotoxicity (LD₅₀ range: 2.11-70.68 μM), while the potencies of the biological pathways perturbed by 12 chemicals (POD_path20 range: 0.002-2.1 μM) were demonstrated by CRZT. Second, although the potency of the transcriptome perturbations was positively correlated with lethality (LD₅₀) (R² = 0.64, P-value < 0.05) for most tested chemicals, BbF was non-embryotoxic but was the most potent on the perturbance of biological pathways. Finally, the profiles of the perturbed biological processes and the transcriptome potency (POD_path20) captured by CRZT could effectively classify most chemicals corresponding to their known MOAs. In summary, CRZT could significantly improve testing the developmental toxicity of environmental chemicals.