Phenotypic anchoring of gene expression changes during estrogen-induced uterine growth

Jonathan G. Moggs, Helen Tinwell, Tracey Spurway, Hur Song Chang, Ian Pate, Fei Ling Lim, David J. Moore, Anthony Soames, Ruth Stuckey, Richard Currie, Tong Zhu, Ian Kimber, John Ashby, George Orphanides

    Research output: Contribution to journalArticlepeer-review


    A major challenge in the emerging field of toxicogenomics is to define the relationships between chemically induced changes in gene expression and alterations in conventional toxicologic parameters such as clinical chemistry and histopathology. We have explored these relationships in detail using the rodent uterotrophic assay as a model system. Gene expression levels, uterine weights, and histologic parameters were analyzed 1, 2, 4, 8, 24, 48, and 72 hr after exposure to the reference physiologic estrogen 17β-estradiol (E 2). A multistep analysis method, involving unsupervised hierarchical clustering followed by supervised gene ontology-driven clustering, was used to define the transcriptional program associated with E2-induced uterine growth and to identify groups of genes that may drive specific histologic changes in the uterus. This revealed that uterine growth and maturation are preceded and accompanied by a complex, multistage molecular program. The program begins with the induction of genes involved in transcriptional regulation and signal transduction and is followed, sequentially, by the regulation of genes involved in protein biosynthesis, cell proliferation, and epithelial cell differentiation. Furthermore, we have identified genes with common molecular functions that may drive fluid uptake, coordinated cell division, and remodeling of luminal epithelial cells. These data define the mechanism by which an estrogen induces organ growth and tissue maturation, and demonstrate that comparison of temporal changes in gene expression and conventional toxicology end points can facilitate the phenotypic anchoring of toxicogenomic data.
    Original languageEnglish
    Pages (from-to)1589-1606
    Number of pages17
    JournalEnvironmental Health Perspectives
    Issue number16
    Publication statusPublished - Nov 2004


    • Estrogen
    • Gene expression
    • Microarray
    • Phenotypic anchoring
    • Uterus


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