title: Phenotypic anchoring of gene expression changes during estrogen-induced uterine growth.
abstract: 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 (E2). 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.
authors.affiliation: Syngenta Central Toxicology Laboratory, Alderley Park, Cheshire SK10 4TJ, UK.
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Moggs
authors.forename: Helen
authors.initials: H
authors.lastname: Tinwell
authors.forename: Tracey
authors.initials: T
authors.lastname: Spurway
authors.forename: Hur-Song
authors.initials: HS
authors.lastname: Chang
authors.forename: Ian
authors.initials: I
authors.lastname: Pate
authors.forename: Fei Ling
authors.initials: FL
authors.lastname: Lim
authors.forename: David J
authors.initials: DJ
authors.lastname: Moore
authors.forename: Anthony
authors.initials: A
authors.lastname: Soames
authors.forename: Ruth
authors.initials: R
authors.lastname: Stuckey
authors.forename: Richard
authors.initials: R
authors.lastname: Currie
authors.forename: Tong
authors.initials: T
authors.lastname: Zhu
authors.forename: Ian
authors.initials: I
authors.lastname: Kimber
authors.forename: John
authors.initials: J
authors.lastname: Ashby
authors.forename: George
authors.initials: G
authors.lastname: Orphanides
mesh_terms: D000818:Animals; D017931:DNA Primers; D004958:Estradiol / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D007279:Injections, Subcutaneous; D051379:Mice; D008815:Mice, Inbred Strains; D009929:Organ Size / Q000187:drug effects; D010641:Phenotype; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014599:Uterus / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism
chemical_list: D017931:DNA Primers; D012333:RNA, Messenger; D004958:Estradiol