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Jonathan G. Moggs,¹ Helen Tinwell,¹ Tracey Spurway,¹ Hur-Song Chang,²* Ian Pate,¹ Fei Ling Lim,¹ David J. Moore,¹ Anthony Soames,¹ Ruth Stuckey,¹ Richard Currie,¹ Tong Zhu,² Ian Kimber,¹ John Ashby,¹ and George Orphanides¹

¹Syngenta Central Toxicology Laboratory, Alderley Park, Cheshire, United Kingdom; ²Syngenta Biotechnology Inc., Research Triangle Park, North Carolina, USA

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 17ß-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. Key words: estrogen, gene expression, microarray, phenotypic anchoring, uterus. Environ Health Perspect 112:1589-1606 (2004) . doi:10.1289/txg.7345 available via http://dx.doi.org/ [Online 7 October 2004]

Address correspondence to G. Orphanides, Syngenta CTL, Alderley Park, Cheshire, SK10 4TJ, UK. Telephone: 44-1625-510803. Fax: 44-1625-585715. E-mail: george.orphanides@syngenta.com

*Present address: Diversa Corporation, 4955 Directors Place, San Diego, CA 92121 USA.

Supplemental data is available online (http://ehp.niehs.nih.gov/txg/members/ 2004/7345/supplemental.pdf)

We thank M.G. Parker, D.G. Deavall, N. Wallis, and T. Barlow for critical comments on the manuscript ; P. Lefevre and J. Odum for technical assistance ; and I. Kupershmidt and E. Hunter (Silicon Genetics) for advice on statistical analysis of microarray data.

This work was partially supported by the UK Food Standards Agency.

The authors declare they have no competing financial interests.

Received 22 June 2004 ; accepted 7 October 2004.