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ToxSci Advance Access published online on June 8, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm151
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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

Estrogenic Effects in the Immature Rat Uterus After Dietary Exposure to Ethinylestradiol and Zearalenone Using a Systems Biology Approach

Marjoke Heneweer*, René Houtman{dagger}, Jenneke Poortman*, Maria Groot*, Chris Maliepaard{ddagger},§ and Ad Peijnenburg*

* RIKILT – Institute of Food Safety, Wageningen UR, PO box 230, 6700 AE Wageningen, The Netherlands {dagger} Pamgene International BV, PO box, 1345, 5200 BJ ‘s-Hertogenbosch, The Netherlands {ddagger} Biometris, Wageningen UR, PO box 100, 6700 AC Wageningen, The Netherlands § Current address: Laboratory of plant breeding, Wageningen UR, PO Box 386, 6700 AJ, Wageningen, The Netherlands

Corresponding author: Marjoke Heneweer, Marjoke.Heneweer{at}wur.nl, Phone: +31 317 475599, Fax: +31 317 417717 Express delivery address: Bornsesteeg 45, 6708 PD Wageningen, The Netherlands.

Received May 1, 2007; revision received May 29, 2007; accepted May 29, 2007


  Abstract

Residues of illegally used hormones are regularly detected in animal products, feed or cocktails recovered at farms. In order to better understand the effects of dietary exposure to ethinyl estradiol (EE2, 0.03 - 1 µg/kg bw) and zearalenone (ZEA, 0.03 - 1 mg/kg bw), a immature rat uterotrophic assay was performed and effects were studied at morphological, histological and gene expression levels. Ligand-mediated coregulator recruitment by estrogen receptor {alpha} (ER{alpha}) was studied in vitro. Uterine weight and epithelial cell height were increased dose-dependently after a 3-day oral exposure of rats to the highest tested doses of EE2 or ZEA, respectively. At low doses 0.03 µg/kg EE2 and 0.1 mg/kg ZEA, edema and vacuolization could already be observed in some animals. Exposure to 1 mg/kg ZEA resulted in severe damage of the uterine epithelial layer. Our study suggest similar coregulator recruitment and gene expression patterns for the two estrogenic compounds. Main regulated pathways were remodeling of extracellular matrix, alternative complement activation, cell proliferation and estrogen-mediated calcium signaling. The level of regulation differed between EE2 and ZEA, attributing a much lower estrogenic potency to ZEA than to EE2. A major difference was their ability to recruit coregulator IKBB and induce expression of the matrix metalloproteinase 7 gene (381.4- and 6.9-fold upregulation by EE2 and ZEA, respectively), which plays an important role in the maintenance of the integrity of the epithelial layer of the uterus during proliferation and growth. This observation may explain the observed differences at the histological level.

Key Words: estrogens; DNA microarrays; coregulator peptide recruitment; rat uterus; ethinyl estradiol; zearalenone; systems biology.

Email addresses: Marjoke.Heneweer{at}wur.nl, rhoutman{at}pamgene.com, Jenneke.Poortman{at}wur.nl, Maria.Groot{at}wur.nl, Chris.Maliepaard{at}wur.nl, Ad.Peijnenburg{at}wur.nl


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