Reduced Zebrafish Transcriptome Atlas toward Understanding Environmental Neurotoxicants

摘要

Transcriptomic approaches monitoring gene responses at genome-scale are increasingly used in toxicological research and help to clarify the molecular mechanisms of adverse effects caused by environmental toxicants. However, their applications for chemical assessment are hampered due to high expenses required and more importantly the lack of in-depth data mining and mechanistic perspectives. Here, we described a reduced transcriptome atlas (RTA) approach which integrates transcriptomic data sets and a comprehensive panel of genes generated to represent neurogenesis and the early neuronal development of zebrafish, to determine the potential neurodevelopmental toxicities of environmental chemicals. Transcriptomic data sets of 74 chemicals and 736 related gene expression profiles were integrated resulting in 135 exposure signatures. Chemical prioritization demonstrated four sets of hits to be neurotoxic: neuro-active chemicals (representatively, Valproic acid, VPA and Carbamazepine, CAR), xenoestrogens (Bisphenol A, BPA; Genistein, GEN; 17-α ethinylestradiol, EE2), microcystins (cyanopeptolin, CP1020; microcystin-LR, MCLR) and heavy metals (AgNO_(3), AgNPs). The enriched biological pathways and processes were distinct among the four sets, while the overlapping functional enrichments were observed within each set, for example, over 25% differentially expressed genes and four of top five KEGG pathways were shared between VPA and CAR. Furthermore, gene expression index (GEI) analysis demonstrated that a gene panel with 300 genes was sufficient to effectively characterize and cluster chemicals and therefore offer an efficient and cost-effective tool for the prioritization of neurotoxicants. Thus, the RTA approach provides novel insights into the understanding of the in-depth molecular mechanisms of environmental neurotoxicants and can be used as an indication for potential adverse outcomes.