Carcinogenesis Advance Access originally published online on February 19, 2004
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Carcinogenesis, Vol. 25, No. 7, 1277-1291,
July 2004
Carcinogenesis vol.25 no.7 © Oxford University Press 2004; all rights reserved.
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Temporal- and dose-dependent hepatic gene expression changes in immature ovariectomized mice following exposure to ethynyl estradiol
1 Department of Biochemistry and Molecular Biology, 2 Department of Pharmacology and Toxicology, National Food Safety and Toxicology Center and 3 Institute for Environmental Toxicology, Michigan State University, East Lansing, MI 48824, USA and 4 Department of Biostatistics, Virginia Commonwealth University, Richmond, VA 23298, USA
5 To whom correspondence should be addressed Email: tzachare{at}msu.edu
Temporal- and dose-dependent changes in hepatic gene expression were examined in immature ovariectomized C57BL/6 mice gavaged with ethynyl estradiol (EE), an orally active estrogen. For temporal analysis, mice were gavaged every 24 h for 3 days with 100 µg/kg EE or vehicle and liver samples were collected at 2, 4, 8, 12, 24 and 72 h. Gene expression was monitored using custom cDNA microarrays containing 3067 genes/ESTs of which 393 exhibited a change at one or more time points. Functional gene annotation extracted from public databases associated temporal gene expression changes with growth and proliferation, cytoskeletal and extracellular matrix responses, microtubule-based processes, oxidative metabolism and stress, and lipid metabolism and transport. In the dose–response study, hepatic samples were collected 24 h following treatment with 0, 0.1, 1, 10, 100 or 250 µg/kg EE. Thirty-nine of the 79 genes identified as differentially regulated at 24 h in the time course study exhibited a dose–response relationship with an average ED50 value of 47 ± 3.5 µg/kg. Comparative analysis indicated that many of the identified temporal and dose-dependent hepatic responses are similar to EE-induced uterine responses reported in the literature and in a companion study using the same animals. Results from these studies confirm that the liver is a highly estrogen responsive tissue that exhibits a number of common responses shared with the uterus as well as distinct estrogen-mediated profiles. These data will further aid in the elucidation of the mechanisms of action of estrogens in the liver as well as in other classical and non-classical estrogen responsive tissues.
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