Phenotypic anchoring: linking cause and effect.

Toxicogenomics combines genetics, transcriptomics (genomic-scale mRNA expression), proteomics (celland tissuewide protein expression), metabonomics (metabolite profiling), and bioinformatics with conventional toxicology in an effort to understand the role of gene–environment interactions in disease. Central to the research strategy of the National Center for Toxicogenomics (NCT) at the NIEHS is the fundamental concept of “phenotypic anchoring,” in which studies are designed to relate specific alterations in gene expression profiles to specific adverse effects of environmental stresses defined by conventional parameters of toxicity such as clinical chemistry and histopathology. The Toxicology/Pathology (Tox/Path) Working Group of the NCT performs experiments designed to gain insight into mechanisms of toxicity, to establish signatures of effects, and to link the patterns of altered gene expression to specific parameters of well-defined indices of toxicity. Such proof-of-principle experiments can lead to specific applications of genomics, proteomics, and metabonomics technologies to toxicology. The group’s overall approach is guided by the fact that processes of injury and repair are highly conserved across many species. For example, necrosis, apoptosis, and DNA repair have been studied effectively in nonmammalian and nonprimate systems because there is such a high degree of conservation of the various genes involved in fundamental aspects of these effects. However, chemicals exert their adverse effects over dose and time, and there are modifier genes in various species or strains that can affect the action of a chemical through metabolism or during some of the basic processes of injury and repair. Studies are therefore designed to cover a full range of dose-related effects—from pharmacologic, to beneficial, to irreversibly toxic. The Tox/Path researchers anticipate that these studies will enable them to both identify biomarkers of specific toxicity (by studying well-defined toxic end points) and apply these biomarkers at earlier times and lower doses in a predictive manner.