title: Testosterone Represses Estrogen Signaling by Upregulating miR-22: A Mechanism for Imbalanced Steroid Hormone Production in Preeclampsia.
abstract: Preeclampsia, a multisystem syndrome occurring during mid- to late gestation in humans, is a leading cause of maternal and perinatal morbidity and mortality. Patients usually present with high circulating testosterone and reduced estradiol production, but the mechanisms remain unclear. Revealing the mechanism that modulating the imbalance of testosterone and estradiol in preeclampsia is of great value in understanding the cause of the disease. The placenta is the predominant source of steroid hormone production during gestation, and we observed markedly increased 17β-HSD3 (17β-hydroxysteroid dehydrogenase 3) levels and downregulated aromatase expression, the key enzymes responsible for synthesis of testosterone and estradiol, respectively, in preeclamptic placentas compared with controls. Furthermore, we found a significant upregulation of microRNA (miR)-22 in preeclamptic placentas. In a trophoblast cell line, JEG-3 cells, testosterone repressed the expression of aromatase and estrogen receptor α and the production of estradiol while promoting miR-22 expression. miR-22 directly targeted and inhibited estrogen receptor α expression while indirectly decreasing aromatase expression and estradiol production by interfering with estrogen receptor α signaling. Furthermore, inhibition of miR-22 expression significantly reversed the inhibitory effect of testosterone on de novo estradiol synthesis in human trophoblastic cells. The findings reveal a mechanism underlying the balanced production of androgen and estrogen modulated by miR-22 in the human placenta and provide new insights into the pathogenesis of preeclampsia from the aspect of endocrine regulation.
authors.affiliation: From the State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China (X.S., Y.L., M.L., H.W., L.M., Y.-x.L., Y.-l. W.); Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China (Y.W., L.Y., Y.Z.); and University of Chinese Academy of Sciences, Beijing, China (Y.L., H.W., L.M., Y.-l. W).
authors.forename: Xuan
authors.initials: X
authors.lastname: Shao
authors.affiliation: From the State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China (X.S., Y.L., M.L., H.W., L.M., Y.-x.L., Y.-l. W.); Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China (Y.W., L.Y., Y.Z.); and University of Chinese Academy of Sciences, Beijing, China (Y.L., H.W., L.M., Y.-l. W).
authors.forename: Yanlei
authors.initials: Y
authors.lastname: Liu
authors.affiliation: From the State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China (X.S., Y.L., M.L., H.W., L.M., Y.-x.L., Y.-l. W.); Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China (Y.W., L.Y., Y.Z.); and University of Chinese Academy of Sciences, Beijing, China (Y.L., H.W., L.M., Y.-l. W).
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.affiliation: From the State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China (X.S., Y.L., M.L., H.W., L.M., Y.-x.L., Y.-l. W.); Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China (Y.W., L.Y., Y.Z.); and University of Chinese Academy of Sciences, Beijing, China (Y.L., H.W., L.M., Y.-l. W).
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Wang
authors.affiliation: From the State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China (X.S., Y.L., M.L., H.W., L.M., Y.-x.L., Y.-l. W.); Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China (Y.W., L.Y., Y.Z.); and University of Chinese Academy of Sciences, Beijing, China (Y.L., H.W., L.M., Y.-l. W).
authors.forename: Liying
authors.initials: L
authors.lastname: Yan
authors.affiliation: From the State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China (X.S., Y.L., M.L., H.W., L.M., Y.-x.L., Y.-l. W.); Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China (Y.W., L.Y., Y.Z.); and University of Chinese Academy of Sciences, Beijing, China (Y.L., H.W., L.M., Y.-l. W).
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: From the State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China (X.S., Y.L., M.L., H.W., L.M., Y.-x.L., Y.-l. W.); Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China (Y.W., L.Y., Y.Z.); and University of Chinese Academy of Sciences, Beijing, China (Y.L., H.W., L.M., Y.-l. W).
authors.forename: Liyang
authors.initials: L
authors.lastname: Ma
authors.affiliation: From the State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China (X.S., Y.L., M.L., H.W., L.M., Y.-x.L., Y.-l. W.); Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China (Y.W., L.Y., Y.Z.); and University of Chinese Academy of Sciences, Beijing, China (Y.L., H.W., L.M., Y.-l. W).
authors.forename: Yu-Xia
authors.initials: YX
authors.lastname: Li
authors.affiliation: From the State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China (X.S., Y.L., M.L., H.W., L.M., Y.-x.L., Y.-l. W.); Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China (Y.W., L.Y., Y.Z.); and University of Chinese Academy of Sciences, Beijing, China (Y.L., H.W., L.M., Y.-l. W).
authors.forename: Yangyu
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: From the State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China (X.S., Y.L., M.L., H.W., L.M., Y.-x.L., Y.-l. W.); Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China (Y.W., L.Y., Y.Z.); and University of Chinese Academy of Sciences, Beijing, China (Y.L., H.W., L.M., Y.-l. W). wangyl@ioz.ac.cn yangaogi@163.com.
authors.forename: Yan-Ling
authors.initials: YL
authors.lastname: Wang
mesh_terms: D001141:Aromatase / Q000096:biosynthesis / Q000187:drug effects; D002460:Cell Line; D004958:Estradiol / Q000096:biosynthesis*; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D006801:Humans; D017403:In Situ Hybridization; D035683:MicroRNAs / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics*; D011225:Pre-Eclampsia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D012313:RNA / Q000235:genetics*; D015398:Signal Transduction; D013739:Testosterone / Q000494:pharmacology*; D014327:Trophoblasts / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation
chemical_list: D004967:Estrogens; C548375:MIRN22 microRNA, human; D035683:MicroRNAs; D013739:Testosterone; D004958:Estradiol; D012313:RNA; D001141:Aromatase
keywords: aromatase; estradiol; estrogen receptor alpha; pre-eclampsia; testosterone