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Sci."],"published-print":{"date-parts":[[2023,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Gestational hypoxia is a major contributor to fetal growth restriction (FGR) and perinatal morbidity and mortality and has been closely linked to the activation of the unfolded protein response (UPR) in the placenta. Recent studies on adverse pregnancy conditions show differential adaptive responses in pregnancies carrying male or female fetuses. Here, we use an established rat model of hypoxic pregnancy and FGR to test the hypothesis that chronic hypoxia promotes sexually dimorphic activation of the placental UPR. Our data showed that gestational hypoxia increased glucose regulatory protein 78 (GRP78) expression in male placentae, increased activating transcription factor 6 activation (ATF6) in female placentae, and did not induce changes in other UPR markers. In addition, gestational hypoxia reduced fetal weight only in males and ATF6 activation correlated with an increase in the fetal crown-rump-length\/body weight ratio only in females. These results suggest sex-specific divergence in the placental adaptive response to gestational hypoxia, which may account for the sexual dimorphism observed in placental function and pregnancy outcomes in complicated pregnancies.<\/jats:p>\n                <jats:p><jats:bold>Graphical Abstract<\/jats:bold><\/jats:p>","DOI":"10.1007\/s43032-022-01157-w","type":"journal-article","created":{"date-parts":[[2022,12,27]],"date-time":"2022-12-27T16:03:25Z","timestamp":1672157005000},"page":"1994-1997","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Sex-Specific Differences in the Placental Unfolded Protein Response in a Rodent Model of Gestational Hypoxia"],"prefix":"10.1007","volume":"30","author":[{"given":"Wen","family":"Tong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esha","family":"Ganguly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9638-9721","authenticated-orcid":false,"given":"Roberto","family":"Villalobos-Labra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2334-4618","authenticated-orcid":false,"given":"Anita","family":"Quon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8024-4413","authenticated-orcid":false,"given":"Floor","family":"Spaans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1308-1204","authenticated-orcid":false,"given":"Dino A.","family":"Giussani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5559-4905","authenticated-orcid":false,"given":"Sandra T.","family":"Davidge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,12,27]]},"reference":[{"key":"1157_CR1","doi-asserted-by":"publisher","first-page":"401323","DOI":"10.1155\/2010\/401323","volume":"2010","author":"D Hutter","year":"2010","unstructured":"Hutter D, Kingdom J, Jaeggi E. Causes and mechanisms of intrauterine hypoxia and its impact on the fetal cardiovascular system: a review. Int J Pediatr. 2010;2010:401323.","journal-title":"Int J Pediatr"},{"issue":"2","key":"1157_CR2","doi-asserted-by":"publisher","first-page":"e21338","DOI":"10.1096\/fj.202002193R","volume":"35","author":"E Ganguly","year":"2021","unstructured":"Ganguly E, et al. Nanoparticle-encapsulated antioxidant improves placental mitochondrial function in a sexually dimorphic manner in a rat model of prenatal hypoxia. Faseb j. 2021;35(2):e21338.","journal-title":"Faseb j"},{"issue":"Suppl A","key":"1157_CR3","doi-asserted-by":"publisher","first-page":"S43","DOI":"10.1016\/j.placenta.2008.11.003","volume":"30","author":"GJ Burton","year":"2009","unstructured":"Burton GJ, et al. Placental endoplasmic reticulum stress and oxidative stress in the pathophysiology of unexplained intrauterine growth restriction and early onset preeclampsia. Placenta. 2009;30(Suppl A):S43\u20138.","journal-title":"Placenta"},{"issue":"8","key":"1157_CR4","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1038\/s41580-020-0250-z","volume":"21","author":"C Hetz","year":"2020","unstructured":"Hetz C, Zhang K, Kaufman RJ. Mechanisms, regulation and functions of the unfolded protein response. Nat Rev Mol Cell Biol. 2020;21(8):421\u201338.","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"5","key":"1157_CR5","doi-asserted-by":"publisher","first-page":"1970","DOI":"10.1096\/fj.11-190082","volume":"26","author":"HW Yung","year":"2012","unstructured":"Yung HW, et al. Evidence of endoplasmic reticulum stress and protein synthesis inhibition in the placenta of non-native women at high altitude. FASEB J. 2012;26(5):1970\u201381.","journal-title":"FASEB J"},{"key":"1157_CR6","doi-asserted-by":"publisher","unstructured":"Tong W, et al. Chronic hypoxia in ovine pregnancy recapitulates physiological and molecular markers of preeclampsia in the mother, placenta, and offspring. Hypertension. 2022. https:\/\/doi.org\/10.1161\/hypertensionaha.122.19175.","DOI":"10.1161\/hypertensionaha.122.19175"},{"key":"1157_CR7","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/j.placenta.2017.02.004","volume":"51","author":"L Evans","year":"2017","unstructured":"Evans L, Myatt L. Sexual dimorphism in the effect of maternal obesity on antioxidant defense mechanisms in the human placenta. Placenta. 2017;51:64\u20139.","journal-title":"Placenta"},{"issue":"6","key":"1157_CR8","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1095\/biolreprod.113.117259","volume":"90","author":"DW Kim","year":"2014","unstructured":"Kim DW, et al. Obesity during pregnancy disrupts placental morphology, cell proliferation, and inflammation in a sex-specific manner across gestation in the mouse. Biol Reprod. 2014;90(6):130.","journal-title":"Biol Reprod"},{"key":"1157_CR9","doi-asserted-by":"publisher","first-page":"562","DOI":"10.3389\/fphys.2019.00562","volume":"10","author":"E Ganguly","year":"2019","unstructured":"Ganguly E, et al. Sex-specific effects of nanoparticle-encapsulated MitoQ (nMitoQ) delivery to the placenta in a rat model of fetal hypoxia. Front Physiol. 2019;10:562.","journal-title":"Front Physiol"},{"issue":"1663","key":"1157_CR10","doi-asserted-by":"publisher","first-page":"20140074","DOI":"10.1098\/rstb.2014.0074","volume":"370","author":"GE Moore","year":"2015","unstructured":"Moore GE, et al. The role and interaction of imprinted genes in human fetal growth. Philos Trans R Soc Lond B Biol Sci. 2015;370(1663):20140074.","journal-title":"Philos Trans R Soc Lond B Biol Sci"}],"container-title":["Reproductive Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s43032-022-01157-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s43032-022-01157-w\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s43032-022-01157-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,30]],"date-time":"2023-05-30T17:08:27Z","timestamp":1685466507000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s43032-022-01157-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,27]]},"references-count":10,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2023,6]]}},"alternative-id":["1157"],"URL":"https:\/\/doi.org\/10.1007\/s43032-022-01157-w","relation":{},"ISSN":["1933-7191","1933-7205"],"issn-type":[{"value":"1933-7191","type":"print"},{"value":"1933-7205","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,27]]},"assertion":[{"value":"28 August 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 December 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 December 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of Interest"}}]}}