Human exposure to mixtures of chemicals is ubiquitous, but regulation has long focused on single compounds. (1) Today investigators are interested in predicting the effects of chemical mixtures based on known toxicities from single compounds. (2) A recent study in Environmental Health Perspectives (3) found toxicogenomic predictions to be accurate even when mixture components belonged to different chemical classes or differed in their pharmacological mode of action (MOA).
"High-throughput technology allows us to measure the molecular effects of many chemicals at once, but appropriate experimental designs are key for predicting mixture effects," says Wibke Busch, a toxicologist at the Helmholtz Centre for Environmental Research in Leipzig, Germany, and the paper's senior author. "The goal of our proof-of-concept study was to test how well we can predict genomewide mixture effects from time-resolved dose-response curves for single chemicals [developed in an earlier study (4)]."
In earlier research, (4) the authors developed whole-transcriptome time-resolved dose-response curves for three compounds found in many aquatic environments (5): two drugs with the same molecular target and MOA in fish (diclofenac, naproxen) and one herbicide with an unknown and presumably dissimilar MOA in fish (diuron). In the new study, the team exposed zebrafish embryos to mixtures of the three chemicals and analyzed whole-transcriptome responses-in other words, the entire range of gene expression.
To reduce the complexity of analyzing the responses of more than 20,000 gene transcripts, the researchers used a 60 * 60 grid onto which they had mapped all zebrafish transcripts--a "toxico-genomic universe"--in their earlier study. (4) The grid's 3,600 nodes depict groups of genes in the same anatomical site or with similar functions. Thus, the map is a visual display of whole-transcriptome gene expression "fingerprints" of certain conditions or chemicals to which zebrafish embryos are exposed. The researchers...