Pure and Applied Chemistry

Abstract: Genomics can be applied in toxicology as a means of identifying modes of action, for generating hypotheses on the relationships of gene activity and toxicity, and for better characterizing the nature of dose-response relationships at low doses. This paper provides examples from our research on endocrine active compounds that illustrate each of these applications. We have determined that agents that bind estrogen receptors produce a characteristic transcript profile in estrogen-responsive tissues of the fetal and juvenile rat. The transcript profile is diagnostic of the mechanism of action. The transcripts that are up- or down-regulated by estrogens belong to a number of functional groups, such as growth factors, pro-apoptotic factors, transcription factors, and steroid metabolizing enzymes. There are a number of testable hypotheses that can be generated from these data regarding the relationships between changes in these genes and developmental or physiological responses to estrogens. We have determined that the sensitivity of gene expression changes is high, making it possible to define the shape of the dose-response curve at dose levels of estrogen several orders of magnitude below those that cause a physiological response (in this case, a uterotrophic response). The shape of the dose response is monotonic: both the number of genes changed and the intensity of the up- or down-regulation decreases with decreasing dose.