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Omics approaches can monitor responses and alterations of biological pathways at genome-scale, which are useful to predict potential adverse effects by environmental toxicants. However, high throughput application of transcriptoinics in chemical assessment is limited due to the high cost and lack of "standardized" toxicogenomic methods. Here, a reduced-zebrafish transcriptome (RZT) approach was developed to represent the whole transcriptome and to profile bioactivity of chemical and environmental mixtures in zebrafish embryo. RZT gene set of 1637 zebrafish Entrez genes was designed to cover a wide range of biological processes, and to faithfully capture gene-level and pathway level changes by toxicants compared with the whole transcriptome. Concentration response modeling was used to calculate the effect concentrations (ECs) of DEGs and corresponding molecular pathways. To validate the RZT approach, quantitative analysis of gene expression by RNA-ampliseq technology was used to identify differentially expressed genes (DEGs) at 32 hpf following exposure to seven serial dilutions of reference chemical BPA (10-10E(-5)mu M) or each of four water samples ranging from wastewater to drinking water (relative enrichment factors 10-6.4 X 10(-4)). The RZT-ampliseq-embryo approach was both sensitive and able to identify a wide spectrum of biological activities associated with BPA exposure. Water quality was benchmarked based on the sensitivity distribution curve of biological pathways detected using RZT-ampliseq-embryo. Finally, the most sensitive biological pathways were identified, including those linked with adverse reproductive outcomes, genotoxicity and development outcomes. RZT-ampliseq-embryo approach provides an efficient and cost-effective tool to prioritize toxicants based on responsiveness of biological pathways.