{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,9]],"date-time":"2026-11-09T21:08:17Z","timestamp":1794258497483,"version":"4.9.0"},"reference-count":58,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2022,5,31]],"date-time":"2022-05-31T00:00:00Z","timestamp":1653955200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82173559"],"award-info":[{"award-number":["82173559"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2022,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Epidemiological and animal experimental studies suggest an association between gestational cholestasis and intrauterine growth restriction (IUGR). Here, we explored the mechanism through which gestational cholestasis induced IUGR. To establish gestational cholestasis model, pregnant mice were subcutaneously injected with 17\u03b1\u2010Ethynylestradiol (E2) on gestational day 13 (GD13)\u2013GD17. Some pregnant mice were intraperitoneally injected with 4\u03bc8C on GD13\u2013GD17. The results found that the apoptosis of trophoblast cells was elevated in placentas of mice with gestational cholestasis and in deoxycholic acid (DCA)\u2010treated human trophoblast cell lines and primary mouse trophoblast cells. Correspondingly, the levels of placental cleaved caspase\u20103 and Bax were increased, while placental Bcl2\u00a0level was decreased in mice with gestational cholestasis and in DCA\u2010treated trophoblast cells. Further analysis found that placental IRE1\u03b1 pathway was activated in mice with gestational cholestasis and in DCA\u2010treated trophoblast cells. Interestingly, 4\u03bc8C, an IRE1\u03b1 RNase inhibitor, significantly inhibited caspase\u20103 activity and apoptosis of trophoblast cells in vivo and in vitro. Importantly, 4\u03bc8C rescued gestational cholestasis\u2010induced placental insufficiency and IUGR. Furthermore, a case\u2013control study demonstrated that placental IRE1\u03b1 and caspase\u20103 pathways were activated in cholestasis cases. Our results provide evidence that gestational cholestasis induces placental insufficiency and IUGR may be via triggering IRE1\u03b1\u2010mediated apoptosis of placental trophoblast cells.<\/jats:p>","DOI":"10.1096\/fj.202101844rr","type":"journal-article","created":{"date-parts":[[2022,5,31]],"date-time":"2022-05-31T10:58:58Z","timestamp":1653994738000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Gestational cholestasis induced intrauterine growth restriction through triggering IRE1\u03b1\u2010mediated apoptosis of placental trophoblast cells"],"prefix":"10.1096","volume":"36","author":[{"given":"Xing\u2010Xing","family":"Gao","sequence":"first","affiliation":[{"name":"School of Basic Medical Sciences Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Lin","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei\u2010Ying","family":"Jiang","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng\u2010Ying","family":"Ye","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuan\u2010Xiang","family":"Hu","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7344-4436","authenticated-orcid":false,"given":"Yuan\u2010Hua","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences Anhui Medical University  Hefei China"},{"name":"Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes Anhui Medical University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,5,31]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2018.12.023"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajogmf.2019.02.005"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-25744-7"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2021.8608"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202000985RR"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature19806"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-018-4694-z"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.15.2049"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-73378-5"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2015.03.010"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.26444"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0040-1717076"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)31877-4"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms9186"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2020.11.038"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-66138-y"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/7419249"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-020-0372-6"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2014.02.033"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1080\/14767058.2019.1636371"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12916-020-01869-3"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsbmb.2020.105733"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-020-02791-5"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/2746521"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2016.07.019"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3266"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1159\/000443039"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2017.06.017"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2020.00098"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2013.183"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20130295"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1601331"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10495-011-0633-x"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1115623109"},{"key":"e_1_2_10_36_1","article-title":"Isolation of primary mouse trophoblast cells and trophoblast invasion assay","volume":"59","author":"Pennington KA","year":"2012","journal-title":"J Vis Exp"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.31494"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1111\/liv.14800"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI68927"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1097\/GRF.0000000000000495"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-2007-1007357"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(00)80139-7"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27171"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1053\/jhep.2002.33327"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2021.04.006"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2017.11.577"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1002\/uog.20103"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2020.00051"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-00269-1"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-021-03030-2"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0083281"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1111\/1471-0528.15926"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj3560481"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00092.2011"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.11-190082"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2013.12.008"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0903775106"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.55865"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2020.06.031"}],"container-title":["The FASEB Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.202101844RR","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1096\/fj.202101844RR","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.202101844RR","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T17:10:26Z","timestamp":1761671426000},"score":1,"resource":{"primary":{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/10.1096\/fj.202101844RR"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,31]]},"references-count":58,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2022,7]]}},"alternative-id":["10.1096\/fj.202101844RR"],"URL":"https:\/\/doi.org\/10.1096\/fj.202101844rr","archive":["Portico"],"relation":{},"ISSN":["0892-6638","1530-6860"],"issn-type":[{"value":"0892-6638","type":"print"},{"value":"1530-6860","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,31]]},"assertion":[{"value":"2021-12-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-05-23","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-05-31","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e22388"}}