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Γ Agonists on Estradiol-Induced Proliferation and Hyperplasia Fo 229 Effects of peroxisome proliferator activated receptors- and - agonists on estradiol-induced proliferation and hyperplasia formation in the mouse uterus A G Gunin, A D Bitter, A B Demakov, E N Vasilieva and N V Suslonova Department of Obstetrics and Gynecology, Medical School, Chuvash State University, P.O. Box 86, Cheboksary 428034, Russia (Requests for offprints should be addressed to A G Gunin; Email: [email protected]) Abstract It is suggested that the action of peroxisome proliferator- animals treated with estradiol and rosiglitazone for 30 days, activated receptors (PPARs) cross-talks with estrogen uterine mass was increased, abnormal uterine glands and signaling in the uterus. However, it is not known how atypical endometrial hyperplasia were found more often PPAR agonists affect estrogen-dependent processes in and levels of estrogen receptors- and -catenin were the uterus, especially proliferation and morphogenetic decreased. In animals treated with estradiol and fenofibrate changes. The effects of agonists of PPAR- and - on for 30 days, uterine mass was decreased, most of the proliferative and morphogenetic reactions in the uterus uterine glands had a normal structure, no cases of atypical under short- and long-term estrogen treatments were hyperplasia were diagnosed, proliferative activity was therefore examined. Ovariectomized mice were treated declined and the levels of estrogen receptors- and with estradiol dipropionate (4 µg/100 g, s.c., once a week) -catenin were markedly higher. Treatment with rosi- or vehicle and rosiglitazone (PPAR- agonist) or fenofi- glitazone or fenofibrate did not affect the serum estradiol brate (PPAR- agonist) or with no additional treatment level in the mice which received estradiol together with for 2 days or for 30 days. Treatment with estradiol and PPAR agonists for 30 days. Thus, rosiglitazone exerted the PPAR agonists for 2 days did not affect uterine mass. In proliferative and morphogenetic effects of estradiol, but mice treated with estradiol and rosiglitazone for 2 days, fenofibrate had the opposite effect. The actions of rosi- proliferation was enhanced and levels of estrogen glitazone and fenofibrate are associated with changes in the receptors- and -catenin were decreased in all uterine expression of estrogen receptors- and -catenin in the tissues. Treatment with estradiol and fenofibrate for 2 days uterus. had the opposite effects on the parameters tested. In Journal of Endocrinology (2004) 182, 229–239 Introduction thousands of cases of endometrial cancer are registered each year in all countries. Thus, new aspects of estrogen Estrogen hormones induce powerful proliferation and action in the uterus or new steps in estrogen signaling must changes in the structure of tissues in the uterus (Martin be discovered to achieve more effective prevention and et al. 1973, Bigsby 2002). The culmination of these treatment of estrogen-dependent diseases. estrogen-induced changes in proliferation and morpho- Peroxisome proliferator-activated receptors (PPARs) genesis is the formation of cancer in the endometrium and compounds acting on these receptors have a variety of (Emons et al. 2000, Akhmedkhanov et al. 2001). Endo- powerful effects in the organism (Elangbam et al. 2001, metrial cancer can be easily induced in laboratory rodents Shearer & Hoekstra 2003). There are three types of by treatment with estrogens (Akhmedkhanov et al. 2001). PPAR, , and (Shearer & Hoekstra 2003). PPAR- The incidence of this pathology in women is more often and PPAR- have been documented in the uterus when increased estrogen levels or unopposed treatment (Houston et al. 2003). It is also interesting that in the past with estrogen hormones are present (Deligdisch 2000). In some shared steps, mostly indirect and controversial, addition, it is now absolutely clear that endometrial cancer between estrogen signaling and PPAR have been found. is an estrogen-dependent disease. In spite of some progress There are some works documenting interactions in our understanding of the interactions between estro- between PPAR- and estrogen signaling or uterine physi- gen and the uterus and in estrogen hormone signaling, ology. It has been shown that activation of PPAR- Journal of Endocrinology (2004) 182, 229–239 Online version via http://www.endocrinology.org 0022–0795/04/0182–229 2004 Society for Endocrinology Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 05:05:07PM via free access 230 A G GUNIN and others · PPAR agonists affect estradiol action Table 1 Experimental design and treatments Treatments and their prolongation (days) Estradiol Rosiglitazone Fenofibrate No. of Estradiol vehicle (PPAR- agonist) (PPAR- agonist) animals Group no. 12 2 7 22 2 7 32 7 4225 52 25 62 5 73030 14 830 3014 930 14 10 30 30 5 11 30 30 5 12 30 5 inhibits the growth of uterine leiomyoma, which is also an Materials and Methods estrogen-dependent disease (Houston et al. 2003). It was supposed that this inhibitory action was mediated by the Animals negative influence of PPAR- on estrogen receptor sign- All procedures were performed in accordance with the aling (Houston et al. 2003). It was found that PPAR- UFAW Handbook on the Care and Management of ligands stimulate secretion of some cytokines (interleukin Laboratory Animals and with the Chuvash State (IL)-1, IL-6, colony stimulation factor-1 (CSF-1)) by University rules for work with laboratory animals. White endometrial cells (Wanichkul et al. 2003). There is also an non-linear female mice (20·330·33 g; meanS.E.M.)of observation showing that PPAR- ligands reduce chemo- 3 months of age were used. Animals were obtained from kine production in human endometrial stromal cells (Pritts the Animal Department of Chuvash State University et al. 2002). Some reports indicate that PPAR- could (Cheboksary, Russia) and were housed with free access to mediate the expression of estrogen target genes and could water and food. Mice were ovariectomized 2 weeks before levels (Keller attenuate estrogen receptors and cyclin D1 the experiments were started. All surgical procedures et al. 1995, Wang & Kilgore 2002, Houston et al. 2003, were performed under anesthesia with ketamine and Qin et al. 2003). It has also been shown that PPAR- diazepam (75 mg/kg, 0·12 mg/kg respectively, i.p.; coactivator-1 potently enhances the activity of estrogen Gedeon-Richter, Budapest, Hungary). receptor- (Kressler et al. 2002). Estradiol treatment was demonstrated to inhibit the ligand-stimulated trans- activation of PPAR- in breast cancer cells (Wang & Kilgore 2002). Treatment There are also only a few data which show interactions Ovariectomized mice were divided into several groups between PPAR- and estrogen-dependent events in the according to treatment, as follows and as shown in Table 1. uterus. PPAR- agonists have been shown to possess The first group of mice (n=7) was treated with a uterotrophic action, which is also synergized with the single s.c. injection of estradiol dipropionate in olive oil uterotrophic effect of estradiol (Chandra et al. 1982). (Minmedprom, Rostov-Don, Russia) at a dose of 4 µg/ However, other researchers have documented no effect 100 g body mass and allowed to drink tap water with (Ashby et al. 1997). 0·005% (w/v) rosiglitazone (Avandia; GlaxoSmithKline, Thus, there is some evidence that PPARs can alter the Brentford, Essex, UK) for 2 days. The second group of intracellular estrogen signaling pathway. Hence, it can mice (n=7) was treated with a single injection of estradiol be suggested that PPARs can affect estrogen-dependent and fed mouse chow with 0·2% (w/w) fenofibrate (Sigma processes, such as proliferation and morphogenetic shifts, Chemical Co., St Louis, MO, USA) for 2 days. The third in the uterus. However, there are no data on this problem. group of animals (n=7) was treated with a single injection Therefore, the effects of agonists of PPAR- and - on of estradiol with no additional treatment for 2 days. The proliferative and morphogenetic reactions in the uterus fourth (n=5), fifth (n=5) and sixth (n=5) groups received under short- and long-term estrogen treatment were a single injection of estradiol vehicle and rosiglitazone or examined in this work. fenofibrate, or with no additional treatment respectively Journal of Endocrinology (2004) 182, 229–239 www.endocrinology.org Downloaded from Bioscientifica.com at 09/28/2021 05:05:07PM via free access PPAR agonists affect estradiol action · A G GUNIN and others 231 for 2 days. The seventh group of mice (n=14) was treated sections stained with iron hematoxylin. BrdU was with injections of estradiol once a week and drank water detected immunohistochemically. Sections were hydrated with 0·005% rosiglitazone for 30 days. The eighth group and put in 4 M HCl for 20 min. Slides were then placed (n=14) received injections of estradiol once a week and in 0·05% (w/v) trypsin in Tris-buffered saline (TBS), pH was fed mouse chow with 0·2% fenofibrate for 30 days. 7·2–7·6 for 20 min. The sections were rinsed (310 min) The ninth group of mice (n=14) was treated with estradiol in TBS. Non-specific binding was blocked with the avidin once a week with no additional treatment for 30 days. and biotin blocking solutions (Vector Laboratories, The tenth (n=5), eleventh (n=5) and twelfth groups Burlingame, CA, USA) for 30 min each. Tissues were (n=5) received injections of the estradiol vehicle and then incubated overnight with anti-BrdU mouse rosiglitazone or fenofibrate, or with no additional treat- monoclonal antibody conjugated with biotin (Caltag ments respectively for 30 days. Laboratories, Burlingame, CA, USA) diluted 1:50 in TBS The uteri were removed 48 h after the last estradiol or with 1% (v/v) blocking solution (Immunotech, Marseille, vehicle injection. All animals were injected i.p. with France) and 0·1% (v/v) Triton X-100. After being rinsed bromodeoxyuridine (BrdU; 5 mg/100 g body mass; in TBS (320 min), sections were incubated for 1 h Sigma) dissolved in saline 2 h before the tissues were with streptavidin conjugated with alkaline phosphatase removed.
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