Katayama Seiichi, Ashizawa Koji, Gohma Hiroshi, Fukuhara Tadahiro, Narumi Kazunori, Tsuzuki Yasuhiro, Tatemoto Hideki, Nakada Tadashi, Nagai Kenji
Kashima Laboratory, Mitsubishi Chemical Safety Institute Ltd., 14 Sunayama, Kamisu, Ibaraki 314-0255, Japan.
Toxicol Appl Pharmacol. 2006 Dec 15;217(3):375-83. doi: 10.1016/j.taap.2006.10.003. Epub 2006 Oct 6.
The objective of this study was to investigate the effects of estrogen receptor (ER) agonists and an ER antagonist on the expression of Hedgehog genes (Indian hedgehog: Ihh; Desert hedgehog: Dhh) and Hedgehog target genes (Patched 1: Ptc1; glioma-associated oncogene homolog 1: Gli1; chicken ovalbumin upstream promoter transcription factor II: Coup-TfII) in the rat uterus. Immature female rats were administered once with 17alpha-ethynyl estradiol (EE, an ER agonist), propyl pyrazole triole (PPT, an ERalpha-selective agonist), diarylpropionitrile (DPN, an ERbeta-selective agonist), or ICI 182,780 (an ER antagonist). Expression of mRNA for Ihh, Dhh, and Ptc1 was dose-dependently downregulated by EE in the uterus of immature rats, mediated by ER as confirmed by coadministration of ICI 182,780. The mRNA expression levels of Ptc1, Gli1, and Coup-TfII were simultaneously downregulated during the period in which the mRNA expression levels of Ihh and Dhh were downregulated in the uterus after administration of EE. PPT downregulated the transcription of Ihh, Dhh, Ptc1, Gli1, and Coup-TfII, indicating that expression of these genes was regulated by the ERalpha-dependent pathway. DPN also downregulated the transcription of Ihh and Dhh, although the effect was weaker than that of PPT, indicating that the regulation of uterine Ihh and Dhh transcription was also affected by the ERbeta-dependent pathway. These results suggest that the expression of Hedgehog genes (Ihh, Dhh) and Hedgehog target genes (Ptc1, Gli1, Coup-TfII) is affected by estrogenic stimuli in the uterus of immature female rats.
本研究的目的是探讨雌激素受体（ER）激动剂和ER拮抗剂对大鼠子宫中刺猬基因（印度刺猬因子：Ihh；沙漠刺猬因子：Dhh）以及刺猬靶基因（patched 1：Ptc1；胶质瘤相关癌基因同源物1：Gli1；鸡卵清蛋白上游启动子转录因子II：Coup-TfII）表达的影响。对未成熟雌性大鼠一次性给予17α-乙炔雌二醇（EE，一种ER激动剂）、丙基吡唑三醇（PPT，一种ERα选择性激动剂）、二芳基丙腈（DPN，一种ERβ选择性激动剂）或ICI 182,780（一种ER拮抗剂）。ICI 182,780共同给药证实，EE在未成熟大鼠子宫中剂量依赖性地下调Ihh、Dhh和Ptc1的mRNA表达，其由ER介导。在给予EE后，子宫中Ihh和Dhh的mRNA表达水平下调期间，Ptc1、Gli1和Coup-TfII的mRNA表达水平同时下调。PPT下调Ihh、Dhh、Ptc1、Gli1和Coup-TfII的转录，表明这些基因的表达受ERα依赖性途径调控。DPN也下调Ihh和Dhh的转录，尽管其作用比PPT弱，表明子宫Ihh和Dhh转录的调控也受ERβ依赖性途径影响。这些结果表明，刺猬基因（Ihh、Dhh）和刺猬靶基因（Ptc1,、Gli1、Coup-TfII）的表达受未成熟雌性大鼠子宫中雌激素刺激的影响。
