Reduced Zebrafish Transcriptome Atlas toward Understanding Environmental Neurotoxicants

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 (AgNO3, 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.