title: Estrogenic effects in the immature rat uterus after dietary exposure to ethinylestradiol and zearalenone using a systems biology approach.
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 microg/kg body weight [bw]) and zearalenone (ZEA, 0.03-1 mg/kg bw), an 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 (ERalpha) 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 microg/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 suggests 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 inhibitor of kappa B beta 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.
authors.affiliation: RIKILT - Institute of Food Safety, Wageningen UR, 6700 AE Wageningen, The Netherlands. Marjoke.Heneweer@wur.nl
authors.forename: Marjoke
authors.initials: M
authors.lastname: Heneweer
authors.forename: René
authors.initials: R
authors.lastname: Houtman
authors.forename: Jenneke
authors.initials: J
authors.lastname: Poortman
authors.forename: Maria
authors.initials: M
authors.lastname: Groot
authors.forename: Chris
authors.initials: C
authors.lastname: Maliepaard
authors.forename: Ad
authors.initials: A
authors.lastname: Peijnenburg
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004717:Endometrium / Q000187:drug effects / Q000473:pathology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000633:toxicity*; D004968:Estrogens, Non-Steroidal / Q000633:toxicity*; D004997:Ethinyl Estradiol / Q000633:toxicity*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D020783:Matrix Metalloproteinase 7 / Q000096:biosynthesis / Q000235:genetics; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation; D014599:Uterus / Q000187:drug effects* / Q000254:growth & development / Q000473:pathology; D015025:Zearalenone / Q000633:toxicity*
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; D004968:Estrogens, Non-Steroidal; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D004997:Ethinyl Estradiol; D015025:Zearalenone; D020783:Matrix Metalloproteinase 7