Phenotypic Anchoring of Gene Expression Changes during Estrogen-Induced Uterine Growth

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 th...

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Bibliographic Details
Published in:Environmental health perspectives 2004-11, Vol.112 (16), p.1589-1606
Main Authors: Moggs, Jonathan G., Tinwell, Helen, Spurway, Tracey, Chang, Hur-Song, Pate, Ian, Lim, Fei Ling, Moore, David J., Soames, Anthony, Stuckey, Ruth, Currie, Richard, Zhu, Tong, Kimber, Ian, Ashby, John, Orphanides, George
Format: Article
Language:English
Subjects:
Animals
Biotechnology industry
Cell growth
DNA Primers
Environmental health
Estradiol - administration & dosage
Estradiol - pharmacology
Estrogens
Female
Gene expression
Gene expression regulation
Gene Expression Regulation, Developmental - drug effects
Genes
Histology
Injections, Subcutaneous
Mice
Mice, Inbred Strains
Organ Size - drug effects
Phenotype
Reverse Transcriptase Polymerase Chain Reaction
RNA
RNA, Messenger - analysis
RNA, Messenger - biosynthesis
Toxicogenomics
Transcriptional regulatory elements
Uterus
Uterus - drug effects
Uterus - growth & development
Uterus - metabolism
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Summary: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$17\beta-estradiol (E_2)$. A multistep analysis method, involving unsupervised hierarchical clustering followed by supervised gene ontology-driven clustering, was used to define the transcriptional program associated with$E_2-induced$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.
ISSN:0091-6765
1552-9924
DOI:10.1289/txg.7345