Temporal- and dose-dependent hepatic gene expression changes in immature ovariectomized mice following exposure to ethynyl estradiol

被引:28
作者
Boverhof, DR
Fertuck, KC
Burgoon, LD
Eckel, JE
Gennings, C
Zacharewski, TR [1 ]
机构
[1] Michigan State Univ, Natl Food Safety & Toxicol Ctr, Dept Biochem & Mol Biol, E Lansing, MI 48824 USA
[2] Michigan State Univ, Natl Food Safety & Toxicol Ctr, Dept Pharmacol & Toxicol, E Lansing, MI 48824 USA
[3] Michigan State Univ, Inst Environm Toxicol, E Lansing, MI 48824 USA
[4] Virginia Commonwealth Univ, Dept Biostat, Richmond, VA 23298 USA
关键词
D O I
10.1093/carcin/bgh114
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 mug/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 mug/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 mug/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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页码:1277 / 1291
页数:15
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