{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T14:17:07Z","timestamp":1790173027505,"version":"4.1.0"},"reference-count":54,"publisher":"American Society of Hematology","issue":"19","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,11,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Iron disorders are associated with adverse pregnancy outcomes, yet iron homeostatic mechanisms during pregnancy are poorly understood. In humans and rodents, the iron-regulatory hormone hepcidin is profoundly decreased in pregnant mothers, which is thought to ensure adequate iron availability for transfer across placenta. However, the fetal liver also produces hepcidin, which may regulate fetal iron endowment by controlling placental iron export. To determine the relative contribution of maternal vs embryo hepcidin to the control of embryo iron endowment in iron-sufficient or iron-overloaded mice, we generated combinations of mothers and embryos that had or lacked hepcidin. We found that maternal, but not embryonic, hepcidin determined embryo and placental iron endowment in a healthy pregnancy. We further determined that inflammation can counteract pregnancy-dependent suppression of maternal hepcidin. To establish how essential maternal hepcidin suppression is for embryo iron homeostasis, we mimicked the range of maternal hepcidin activity by administering a hepcidin peptide mimetic to pregnant mice. This also allowed us to determine the effect of isolated maternal hepcidin excess on pregnancy, in the absence of other confounding effects of inflammation. Higher doses of hepcidin agonist caused maternal iron restriction and anemia, lower placenta and embryo weight, embryo anemia, and increased embryo mortality. Low agonist doses did not cause maternal anemia but still adversely affected the embryo, causing anemia, tissue iron deficiency (including in the brain), and decreased weight. Our studies demonstrate that suppression of maternal hepcidin during pregnancy is essential for maternal and embryo iron homeostasis and health.<\/jats:p>","DOI":"10.1182\/blood.2020005745","type":"journal-article","created":{"date-parts":[[2020,6,25]],"date-time":"2020-06-25T19:59:41Z","timestamp":1593115181000},"page":"2206-2216","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":61,"title":["Maternal hepcidin determines embryo iron homeostasis in mice"],"prefix":"10.1182","volume":"136","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7397-0815","authenticated-orcid":false,"given":"Veena","family":"Sangkhae","sequence":"first","affiliation":[{"name":"Center for Iron Disorders, Department of Medicine, David Geffen School of Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9393-2442","authenticated-orcid":false,"given":"Allison L.","family":"Fisher","sequence":"additional","affiliation":[{"name":"Center for Iron Disorders, Department of Medicine, David Geffen School of Medicine and"},{"name":"Molecular, Cellular & Integrative Physiology Graduate Program, University of California, Los Angeles, Los Angeles, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristine J.","family":"Chua","sequence":"additional","affiliation":[{"name":"Center for Iron Disorders, Department of Medicine, David Geffen School of Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5574-2779","authenticated-orcid":false,"given":"Piotr","family":"Ruchala","sequence":"additional","affiliation":[{"name":"Center for Iron Disorders, Department of Medicine, David Geffen School of Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2830-5469","authenticated-orcid":false,"given":"Tomas","family":"Ganz","sequence":"additional","affiliation":[{"name":"Center for Iron Disorders, Department of Medicine, David Geffen School of Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3477-2397","authenticated-orcid":false,"given":"Elizabeta","family":"Nemeth","sequence":"additional","affiliation":[{"name":"Center for Iron Disorders, Department of Medicine, David Geffen School of Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"issue":"17","key":"2020110511281572700_B1","doi-asserted-by":"crossref","first-page":"4425","DOI":"10.1182\/blood-2011-01-258467","article-title":"Hepcidin and iron regulation, 10 years later","volume":"117","author":"Ganz","year":"2011","journal-title":"Blood"},{"issue":"5704","key":"2020110511281572700_B2","doi-asserted-by":"crossref","first-page":"2090","DOI":"10.1126\/science.1104742","article-title":"Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization","volume":"306","author":"Nemeth","year":"2004","journal-title":"Science"},{"issue":"2-3","key":"2020110511281572700_B3","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1159\/000243791","article-title":"The role of hepcidin in iron metabolism","volume":"122","author":"Nemeth","year":"2009","journal-title":"Acta Haematol"},{"issue":"1","key":"2020110511281572700_B4","doi-asserted-by":"crossref","first-page":"126","DOI":"10.3945\/an.116.013961","article-title":"Regulation of the iron homeostatic hormone hepcidin","volume":"8","author":"Sangkhae","year":"2017","journal-title":"Adv Nutr"},{"issue":"7","key":"2020110511281572700_B5","doi-asserted-by":"crossref","first-page":"2461","DOI":"10.1182\/blood-2002-10-3235","article-title":"Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein","volume":"101","author":"Nemeth","year":"2003","journal-title":"Blood"},{"issue":"9","key":"2020110511281572700_B6","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1172\/JCI200420945","article-title":"IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin","volume":"113","author":"Nemeth","year":"2004","journal-title":"J Clin Invest"},{"issue":"1","key":"2020110511281572700_B7","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1146\/annurev-med-050109-142444","article-title":"Hepcidin and disorders of iron metabolism","volume":"62","author":"Ganz","year":"2011","journal-title":"Annu Rev Med"},{"issue":"1","key":"2020110511281572700_B8","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1111\/j.1753-4887.2012.00550.x","article-title":"Pregnancy and iron homeostasis: an update","volume":"71","author":"Cao","year":"2013","journal-title":"Nutr Rev"},{"issue":"4 suppl","key":"2020110511281572700_B9","doi-asserted-by":"crossref","first-page":"S99","DOI":"10.1177\/15648265030244S106","article-title":"Iron deficiency: global prevalence and consequences","volume":"24","author":"Stoltzfus","year":"2003","journal-title":"Food Nutr Bull"},{"issue":"1","key":"2020110511281572700_B10","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1017\/S0029665113003637","article-title":"Iron deficiency during pregnancy: the consequences for placental function and fetal outcome","volume":"73","author":"McArdle","year":"2014","journal-title":"Proc Nutr Soc"},{"issue":"suppl 1","key":"2020110511281572700_B11","doi-asserted-by":"crossref","first-page":"S43","DOI":"10.1111\/j.1753-4887.2011.00432.x","article-title":"Long-term brain and behavioral consequences of early iron deficiency","volume":"69","author":"Georgieff","year":"2011","journal-title":"Nutr Rev"},{"issue":"4","key":"2020110511281572700_B12","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1093\/ajcn\/78.4.773","article-title":"Iron supplementation during pregnancy, anemia, and birth weight: a randomized controlled trial","volume":"78","author":"Cogswell","year":"2003","journal-title":"Am J Clin Nutr"},{"issue":"5 Pt 1","key":"2020110511281572700_B13","first-page":"741","article-title":"High and low hemoglobin levels during pregnancy: differential risks for preterm birth and small for gestational age","volume":"96","author":"Scanlon","year":"2000","journal-title":"Obstet Gynecol"},{"issue":"2S suppl","key":"2020110511281572700_B14","doi-asserted-by":"crossref","first-page":"443S","DOI":"10.1093\/jn\/130.2.443S","article-title":"Anemia, iron and pregnancy outcome","volume":"130","author":"Scholl","year":"2000","journal-title":"J Nutr"},{"issue":"7","key":"2020110511281572700_B15","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1515\/cclm-2012-0576","article-title":"The iron regulatory hormone hepcidin is decreased in pregnancy: a prospective longitudinal study","volume":"51","author":"van Santen","year":"2013","journal-title":"Clin Chem Lab Med"},{"issue":"2","key":"2020110511281572700_B16","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1172\/JCI127341","article-title":"Effects of maternal iron status on placental and fetal iron homeostasis","volume":"130","author":"Sangkhae","year":"2019","journal-title":"J Clin Invest"},{"issue":"5","key":"2020110511281572700_B17","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1136\/gut.2003.031153","article-title":"Changes in the expression of intestinal iron transport and hepatic regulatory molecules explain the enhanced iron absorption associated with pregnancy in the rat","volume":"53","author":"Millard","year":"2004","journal-title":"Gut"},{"issue":"2","key":"2020110511281572700_B18","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1002\/ajh.25341","article-title":"Iron homeostasis in pregnancy and spontaneous abortion","volume":"94","author":"Guo","year":"2019","journal-title":"Am J Hematol"},{"issue":"4","key":"2020110511281572700_B19","doi-asserted-by":"crossref","first-page":"1402","DOI":"10.1182\/blood-2006-02-003376","article-title":"Targeted disruption of the hepcidin 1 gene results in severe hemochromatosis","volume":"108","author":"Lesbordes-Brion","year":"2006","journal-title":"Blood"},{"issue":"1","key":"2020110511281572700_B20","doi-asserted-by":"crossref","first-page":"33","DOI":"10.3945\/jn.111.145961","article-title":"Maternal hepcidin is associated with placental transfer of iron derived from dietary heme and nonheme sources","volume":"142","author":"Young","year":"2012","journal-title":"J Nutr"},{"issue":"suppl 1","key":"2020110511281572700_B21","doi-asserted-by":"crossref","first-page":"S11","DOI":"10.1016\/S0020-7292(11)60005-2","article-title":"Anemia and pregnancy: a link to maternal chronic diseases","volume":"115","author":"Gangopadhyay","year":"2011","journal-title":"Int J Gynaecol Obstet"},{"issue":"4","key":"2020110511281572700_B22","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1111\/j.1600-0609.2010.01479.x","article-title":"Maternal serum hepcidin is low at term and independent of cord blood iron status","volume":"85","author":"Rehu","year":"2010","journal-title":"Eur J Haematol"},{"issue":"11","key":"2020110511281572700_B23","doi-asserted-by":"crossref","first-page":"1620","DOI":"10.1111\/j.1447-0756.2011.01586.x","article-title":"Serum maternal hepcidin levels 3 days after delivery are higher compared to those measured at parturition","volume":"37","author":"Gyarmati","year":"2011","journal-title":"J Obstet Gynaecol Res"},{"issue":"1","key":"2020110511281572700_B24","doi-asserted-by":"crossref","first-page":"75","DOI":"10.3109\/14767058.2013.804054","article-title":"Hepcidin, iron status, and inflammation variables among healthy pregnant women in the Turkish population","volume":"27","author":"Simavli","year":"2014","journal-title":"J Matern Fetal Neonatal Med"},{"issue":"3","key":"2020110511281572700_B25","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1093\/jn\/nxx052","article-title":"Anemia of inflammation during human pregnancy does not affect newborn iron endowment","volume":"148","author":"Abioye","year":"2018","journal-title":"J Nutr"},{"issue":"4","key":"2020110511281572700_B26","doi-asserted-by":"crossref","first-page":"E975","DOI":"10.3390\/nu12040975","article-title":"Erythropoiesis and red cell indices undergo adjustments during pregnancy in response to maternal body size but not inflammation","volume":"12","author":"Vega-S\u00e1nchez","year":"2020","journal-title":"Nutrients"},{"issue":"8","key":"2020110511281572700_B27","doi-asserted-by":"crossref","first-page":"E1000","DOI":"10.3390\/nu10081000","article-title":"Relationships between maternal obesity and maternal and neonatal iron status","volume":"10","author":"Flynn","year":"2018","journal-title":"Nutrients"},{"issue":"6","key":"2020110511281572700_B28","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1093\/jn\/nxaa065","article-title":"Prepregnancy obesity is not associated with iron utilization during the third trimester","volume":"150","author":"Koenig","year":"2020","journal-title":"J Nutr"},{"issue":"3","key":"2020110511281572700_B29","doi-asserted-by":"crossref","first-page":"E693","DOI":"10.3390\/nu11030693","article-title":"Obesity is associated with changes in iron nutrition status and its homeostatic regulation in pregnancy","volume":"11","author":"Flores-Quijano","year":"2019","journal-title":"Nutrients"},{"issue":"18","key":"2020110511281572700_B30","doi-asserted-by":"crossref","first-page":"2388","DOI":"10.1080\/14767058.2017.1344209","article-title":"Mitochondrial content and hepcidin are increased in obese pregnant mothers","volume":"31","author":"Anelli","year":"2018","journal-title":"J Matern Fetal Neonatal Med"},{"issue":"5","key":"2020110511281572700_B31","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1177\/1933719115607976","article-title":"Prepregnancy body mass index and gestational weight gain have no negative impact on maternal or neonatal iron status","volume":"23","author":"Cao","year":"2016","journal-title":"Reprod Sci"},{"issue":"4","key":"2020110511281572700_B32","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1038\/ijo.2015.3","article-title":"The impact of maternal obesity on iron status, placental transferrin receptor expression and hepcidin expression in human pregnancy","volume":"39","author":"Garcia-Valdes","year":"2015","journal-title":"Int J Obes"},{"issue":"7","key":"2020110511281572700_B33","doi-asserted-by":"crossref","first-page":"4596","DOI":"10.1073\/pnas.072632499","article-title":"Severe iron deficiency anemia in transgenic mice expressing liver hepcidin","volume":"99","author":"Nicolas","year":"2002","journal-title":"Proc Natl Acad Sci USA"},{"issue":"12","key":"2020110511281572700_B34","doi-asserted-by":"crossref","first-page":"4880","DOI":"10.1172\/JCI57693","article-title":"Minihepcidins are rationally designed small peptides that mimic hepcidin activity in mice and may be useful for the treatment of iron overload","volume":"121","author":"Preza","year":"2011","journal-title":"J Clin Invest"},{"issue":"18","key":"2020110511281572700_B35","doi-asserted-by":"crossref","first-page":"3829","DOI":"10.1182\/blood-2012-07-440743","article-title":"Minihepcidins prevent iron overload in a hepcidin-deficient mouse model of severe hemochromatosis","volume":"120","author":"Ramos","year":"2012","journal-title":"Blood"},{"issue":"8","key":"2020110511281572700_B36","doi-asserted-by":"crossref","first-page":"3062","DOI":"10.3390\/nu6083062","article-title":"Hepcidin and iron homeostasis during pregnancy","volume":"6","author":"Koenig","year":"2014","journal-title":"Nutrients"},{"issue":"5","key":"2020110511281572700_B37","doi-asserted-by":"crossref","first-page":"e12816","DOI":"10.1111\/aji.12816","article-title":"Lipopolysaccharide-induced maternal inflammation induces direct placental injury without alteration in placental blood flow and induces a secondary fetal intestinal injury that persists into adulthood","volume":"79","author":"Fricke","year":"2018","journal-title":"Am J Reprod Immunol"},{"issue":"1","key":"2020110511281572700_B38","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.chom.2014.12.001","article-title":"Hepcidin-induced hypoferremia is a critical host defense mechanism against the siderophilic bacterium Vibrio vulnificus","volume":"17","author":"Arezes","year":"2015","journal-title":"Cell Host Microbe"},{"issue":"5","key":"2020110511281572700_B39","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1016\/j.cmet.2015.09.006","article-title":"Ironing out ferroportin","volume":"22","author":"Drakesmith","year":"2015","journal-title":"Cell Metab"},{"issue":"5","key":"2020110511281572700_B40","doi-asserted-by":"crossref","first-page":"R151","DOI":"10.1530\/REP-13-0232","article-title":"Influence of infection during pregnancy on fetal development","volume":"146","author":"Adams Waldorf","year":"2013","journal-title":"Reproduction"},{"issue":"1","key":"2020110511281572700_B41","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1189\/jlb.3MR0615-272RR","article-title":"Inflammation and preterm birth","volume":"99","author":"Cappelletti","year":"2016","journal-title":"J Leukoc Biol"},{"issue":"4","key":"2020110511281572700_B42","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1016\/j.bmcl.2014.12.094","article-title":"Thiol-derivatized minihepcidins retain biological activity","volume":"25","author":"Fung","year":"2015","journal-title":"Bioorg Med Chem Lett"},{"issue":"8","key":"2020110511281572700_B43","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1182\/blood-2017-05-786590","article-title":"Structure-function analysis of ferroportin defines the binding site and an alternative mechanism of action of hepcidin","volume":"131","author":"Aschemeyer","year":"2018","journal-title":"Blood"},{"issue":"7","key":"2020110511281572700_B44","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1038\/35080570","article-title":"Placental development: lessons from mouse mutants","volume":"2","author":"Rossant","year":"2001","journal-title":"Nat Rev Genet"},{"issue":"suppl 6","key":"2020110511281572700_B45","doi-asserted-by":"crossref","first-page":"1567S","DOI":"10.3945\/ajcn.117.155812","article-title":"Iron homeostasis during pregnancy","volume":"106","author":"Fisher","year":"2017","journal-title":"Am J Clin Nutr"},{"issue":"3","key":"2020110511281572700_B46","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1182\/blood-2014-01-551150","article-title":"Matriptase-2 is essential for hepcidin repression during fetal life and postnatal development in mice to maintain iron homeostasis","volume":"124","author":"Willemetz","year":"2014","journal-title":"Blood"},{"issue":"6","key":"2020110511281572700_B47","doi-asserted-by":"crossref","first-page":"2539","DOI":"10.1182\/blood-2008-04-149773","article-title":"Membrane-bound serine protease matriptase-2 (Tmprss6) is an essential regulator of iron homeostasis","volume":"112","author":"Folgueras","year":"2008","journal-title":"Blood"},{"issue":"4","key":"2020110511281572700_B48","doi-asserted-by":"crossref","first-page":"135321","DOI":"10.1172\/jci.insight.135321","article-title":"Fetal and amniotic fluid iron homeostasis in healthy and complicated murine, macaque, and human pregnancy","volume":"5","author":"Fisher","year":"2020","journal-title":"JCI Insight"},{"issue":"3","key":"2020110511281572700_B49","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1038\/jp.2012.81","article-title":"Obesity during pregnancy and fetal iron status: is Hepcidin the link?","volume":"33","author":"Dao","year":"2013","journal-title":"J Perinatol"},{"issue":"11","key":"2020110511281572700_B50","doi-asserted-by":"crossref","first-page":"2111","DOI":"10.3889\/oamjms.2018.471","article-title":"The levels of hepcidin and erythropoietin in pregnant women with anemia of various geneses","volume":"6","author":"Vazenmiller","year":"2018","journal-title":"Open Access Maced J Med Sci"},{"issue":"14","key":"2020110511281572700_B51","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1055\/s-0036-1582397","article-title":"Inflammation in complicated pregnancy and its outcome","volume":"33","author":"Kalagiri","year":"2016","journal-title":"Am J Perinatol"},{"issue":"5879","key":"2020110511281572700_B52","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1126\/science.1157121","article-title":"The serine protease TMPRSS6 is required to sense iron deficiency","volume":"320","author":"Du","year":"2008","journal-title":"Science"},{"issue":"2","key":"2020110511281572700_B53","doi-asserted-by":"crossref","first-page":"e0028","DOI":"10.5041\/RMMJ.10305","article-title":"Maternal inflammation, fetal brain implications and suggested neuroprotection: a summary of 10 years of research in animal models","volume":"8","author":"Ginsberg","year":"2017","journal-title":"Rambam Maimonides Med J"},{"issue":"3","key":"2020110511281572700_B54","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.spen.2006.08.004","article-title":"Iron deficiency and brain development","volume":"13","author":"Lozoff","year":"2006","journal-title":"Semin Pediatr Neurol"}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/136\/19\/2206\/1780405\/bloodbld2020005745.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/136\/19\/2206\/1780405\/bloodbld2020005745.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,11,5]],"date-time":"2020-11-05T16:30:46Z","timestamp":1604593846000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/136\/19\/2206\/461131\/Maternal-hepcidin-determines-embryo-iron"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,5]]},"references-count":54,"journal-issue":{"issue":"19","published-print":{"date-parts":[[2020,11,5]]}},"URL":"https:\/\/doi.org\/10.1182\/blood.2020005745","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,5]]}}}