Zebrafish Whole-Adult-Organism Chemogenomics for Large-Scale Predictive and Discovery Chemical Biology

The ability to perform large-scale, expression-based chemogenomics on whole adult organisms, as in invertebrate models (worm and fly), is highly desirable for a vertebrate model but its feasibility and potential has not been demonstrated. We performed expression-based chemogenomics on the whole adult organism of a vertebrate model, the zebrafish, and demonstrated its potential for large-scale predictive and discovery chemical biology. Focusing on two classes of compounds with wide implications to human health, polycyclic (halogenated) aromatic hydrocarbons [P(H)AHs] and estrogenic compounds (ECs), we generated robust prediction models that can discriminate compounds of the same class from those of different classes in two large independent experiments. The robust expression signatures led to the identification of biomarkers for potent aryl hydrocarbon receptor (AHR) and estrogen receptor (ER) agonists, respectively, and were validated in multiple targeted tissues. Knowledge-based data mining of human homologs of zebrafish genes revealed highly conserved chemical-induced biological responses/effects, health risks, and novel biological insights associated with AHR and ER that could be inferred to humans. Thus, our study presents an effective, high-throughput strategy of capturing molecular snapshots of chemical-induced biological states of a whole adult vertebrate that provides information on biomarkers of effects, deregulated signaling pathways, and possible affected biological functions, perturbed physiological systems, and increased health risks. These findings place zebrafish in a strategic position to bridge the wide gap between cell-based and rodent models in chemogenomics research and applications, especially in preclinical drug discovery and toxicology.Author Summary: To understand chemical-induced biological responses/effects, it is important to have large-scale and rapid capacity to investigate gene expression changes caused by chemical compounds at genome-wide scale in an adult vertebrate model; this capability is essential for drug development and toxicology. Small aquarium fish with vast genomic resources, such as zebrafish, will probably be the only vertebrate models that allow for cost-effective, large-scale, genome-wide determination of gene expression net changes in the entire adult organism in response to a chemical compound. Presently, such a whole adult organism approach is only feasible in invertebrate models such as the worm and fly, and not in rodent models, hence the usefulness of such an approach has not been demonstrated in a vertebrate. By using two classes of chemicals with wide implications to human health, we showed that capturing net changes of gene expression at a genome-wide scale in an entire adult zebrafish is useful for predicting toxicity and chemical classes, for discovering biomarkers and major signaling pathways, as well as for inferring human health risk and new biological insights. Our study provides a new approach for genome-wide investigation of chemical-induced biological responses/effects in a whole adult vertebrate that can benefit the drug discovery process and chemical toxicity testing for environmental health risk inference.