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ToxSci Advance Access originally published online on March 9, 2007
Toxicological Sciences 2007 97(2):467-490; doi:10.1093/toxsci/kfm046
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Uterine Temporal Response to Acute Exposure to 17{alpha}-Ethinyl Estradiol in the Immature Rat

Jorge M. Naciff1, Gary J. Overmann, Suzanne M. Torontali, Gregory J. Carr, Zubin S. Khambatta, Jay P. Tiesman, Brian D. Richardson and George P. Daston

The Procter and Gamble Company, Miami Valley Innovation Center, Cincinnati, Ohio 45253

1 To whom correspondence should be addressed at The Procter and Gamble Company, Miami Valley Innovation Center, PO Box 538707 #805, Cincinnati, OH 45253-8707. Fax: (513) 627-0323. E-mail: naciff.jm{at}pg.com.

Received January 19, 2007; accepted February 20, 2007


  Abstract

The rat uterus responds to acute estrogen treatment with a series of well-characterized physiological responses; however, the gene expression changes required to elicit these responses have not been fully characterized. In order to understand early events induced by estrogen exposure in vivo, we evaluated the temporal gene expression in the uterus of the immature rat after a single dose of 17{alpha}-ethinyl estradiol (EE) by microarray analysis, evaluating the expression of 15,923 genes. Immature 20-day-old rats were exposed to a single dose of EE (10 µg/kg), and the effects on uterine histology, weight, and gene expression were determined after 1, 2, 8, 24, 48, 72, and 96 h. EE induced changes in the expression of 3867 genes, at least at one time point (p ≤ 0.0001), and at least 1.5-fold (up- or downregulated). Specifically, the expression of 8, 116, 3030, 2076, 381, 445, and 125 genes was modified at 1, 2, 8, 24, 48, 72, or 96 h after exposure to EE, respectively (p ≤ 0.0001, t-test). At the tissue and organ level, a clear uterotrophic response was elicited by EE after only 8 h, reaching a maximum after 24 h and remaining detectable even after 96 h of exposure. The uterine phenotypic changes were induced by sequential changes in the transcriptional status of a large number of genes, in a program that involves multiple molecular pathways. Using the Gene Ontology to better understand the temporal response to estrogen exposure, we determined that the earliest changes were in the expression of genes whose products are involved in transcriptional regulation and signal transduction, followed by genes implicated in protein synthesis, energy utilization, solute transport, cell proliferation and differentiation, tissue remodeling, and immunological responses among other pathways. The compendium of genes here presented represents a comprehensive compilation of estrogen-responsive genes involved in the uterotrophic response.

Key Words: estrogens; microarray; female reproductive tract; temporal gene expression; uterotrophic response.


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