{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T16:17:08Z","timestamp":1788970628055,"version":"build-2803163510"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T00:00:00Z","timestamp":1782086400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2023YFC2705900"],"award-info":[{"award-number":["2023YFC2705900"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Toxicol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Placental hypoxia and vascular dysfunction are hallmarks of preeclampsia (PE). The Breast Cancer Resistance Protein (BCRP) is critical for maintaining the placental barrier against oxidative stress. We investigated whether the hypoxic microenvironment drives BCRP dysregulation and how this correlates with fetal growth restriction (FGR) in severe preeclampsia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This case-control study enrolled 59 normotensive and 72 preeclamptic pregnancies to compare clinical phenotypes and placental BCRP expression across distinct gestational age subgroups. Mechanistic investigations were conducted using human BeWo trophoblasts under pathological hypoxia (1%O\n                      <jats:sub>2<\/jats:sub>\n                      \u200b). We integrated metabolic profiling (glycolytic shift and JC-1 mitochondrial assays) with rigorous molecular techniques\u2014including Co-immunoprecipitation (Co-IP) and subcellular fractionation\u2014to elucidate the competitive crosstalk between HIF-1\u03b1 and AHR, further validating barrier impairment via Hoechst 33342 functional efflux assays.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Clinically, patients with early-onset preeclampsia (28\u201333\n                      <jats:sup>+6<\/jats:sup>\n                      weeks) exhibited a markedly higher incidence of FGR compared to late-onset or control groups. In these compromised placentas, BCRP expression was significantly suppressed and inversely correlated with the hypoxia marker GLUT1.\n                      <jats:italic>In vitro<\/jats:italic>\n                      assays delineated a \u201cdual-hit\u201d pathological cascade triggered by chronic hypoxia. First, trophoblasts underwent severe metabolic reprogramming characterized by massive glycolytic upregulation and mitochondrial dysfunction. Second, stabilized HIF-1\u03b1 competitively sequestered the obligate co-receptor ARNT, systematically dismantling the AHR\/ARNT transcriptional complex. This specific molecular \u201ccompetitive binding\u201d impaired AHR-mediated protective signaling, resulting in a critical loss of functional BCRP efflux capacity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our study defines a distinct \u201cdual-hit\u201d molecular phenotype in early-onset preeclampsia. Chronic hypoxia not only drives an acute metabolic crisis but also actively dismantles the protective AHR\/BCRP placental barrier via HIF-1\u03b1-mediated ARNT sequestering. This synergistic failure compromises placental xenobiotic detoxification, exacerbates fetal toxicological vulnerability, and fundamentally contributes to the profound severity of FGR.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/ftox.2026.1782187","type":"journal-article","created":{"date-parts":[[2026,6,21]],"date-time":"2026-06-21T22:10:23Z","timestamp":1782079823000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Hypoxia-induced metabolic shifting and AHR\/BCRP axis impairment drive placental dysfunction in early-onset preeclampsia and FGR"],"prefix":"10.3389","volume":"8","author":[{"given":"Jingjing","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxuan","family":"Zhu","sequence":"additional","affiliation":[{"name":"Jining Medical University","place":["Jining, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haixia","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongzhong","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinlai","family":"Meng","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, Shandong, China"]},{"name":"Key Laboratory of Maternal & Fetal Medicine of National Health Commission of China, Shandong Provincial Maternal and Child Healthcare Hospital Affiliated to Qingdao University","place":["Jinan, Shandong, China"]},{"name":"Department of Obstetrics and Gynecology, Shandong Provincial Hospital, Shandong University","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,22]]},"reference":[{"key":"B1","first-page":"1","article-title":"ACOG practice bulletin no. 202: gestational hypertension and preeclampsia","volume":"133","year":"2019","journal-title":"Obstet. Gynecol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1405","DOI":"10.1016\/j.bcp.2013.02.022","article-title":"The circadian clock circuitry and the AHR signaling pathway in physiology and pathology","volume":"85","author":"Anderson","year":"2013","journal-title":"Biochem. Pharmacol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"l2381","DOI":"10.1136\/bmj.l2381","article-title":"Pre-eclampsia: pathophysiology and clinical implications","volume":"366","author":"Burton","year":"2019","journal-title":"BMJ"},{"key":"B4","doi-asserted-by":"publisher","first-page":"S25","DOI":"10.1053\/plac.1999.0522","article-title":"Oxygen and placental development during the first trimester: implications for the pathophysiology of pre-eclampsia","volume":"21","author":"Caniggia","year":"2000","journal-title":"Placenta"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1118","DOI":"10.1124\/jpet.109.160564","article-title":"Transplacental pharmacokinetics of glyburide, rhodamine 123, and BODIPY FL prazosin: effect of drug efflux transporters and lipid solubility","volume":"331","author":"Cygalova","year":"2009","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1308","DOI":"10.1124\/dmd.122.001080","article-title":"Use of traditional and proteomic methods in the assessment of a preclinical model of preeclampsia","volume":"51","author":"Dai","year":"2023","journal-title":"Drug Metab. Dispos."},{"key":"B7","doi-asserted-by":"publisher","first-page":"884","DOI":"10.3390\/pharmaceutics16070884","article-title":"Altered expression of BCRP impacts fetal accumulation of rosuvastatin in a rat model of preeclampsia","volume":"16","author":"Dai","year":"2024","journal-title":"Pharmaceutics"},{"key":"B8","doi-asserted-by":"publisher","first-page":"710","DOI":"10.20517\/cdr.2019.31","article-title":"Recent advances in the search of BCRP- and dual P-gp\/BCRP-based multidrug resistance modulators","volume":"2","author":"Dei","year":"2019","journal-title":"Cancer Drug Resist"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1754","DOI":"10.1093\/carcin\/bgi139","article-title":"Identification of BCRP as transporter of Benzo[a]pyrene conjugates metabolically formed in Caco-2 cells and its induction by Ah-receptor agonists","volume":"26","author":"Ebert","year":"2005","journal-title":"Carcinogenesis"},{"key":"B10","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1016\/j.rbre.2016.07.008","article-title":"Role of HIF-1\u03b1 signaling pathway in osteoarthritis: a systematic review","volume":"57","author":"Fern\u00e1ndez-Torres","year":"2017","journal-title":"Rev. Bras. Reumatol. Engl. Ed."},{"key":"B11","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.placenta.2017.01.125","article-title":"Down-regulation of the placental BCRP\/ABCG2 transporter in response to hypoxia signaling","volume":"51","author":"Francois","year":"2017","journal-title":"Placenta"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1268","DOI":"10.1016\/s0046-8177(87)80412-4","article-title":"Ras p21 expression in the progression of breast cancer","volume":"18","author":"Fromowitz","year":"1987","journal-title":"Hum. Pathol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1669","DOI":"10.1126\/science.277.5332.1669","article-title":"Regulation of human placental development by oxygen tension","volume":"277","author":"Genbacev","year":"1997","journal-title":"Science"},{"key":"B14","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1186\/s12964-023-01058-8","article-title":"When AHR signaling pathways meet viral infections","volume":"21","author":"Hu","year":"2023","journal-title":"Cell Commun. Signal"},{"key":"B15","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1095\/biolreprod.106.051557","article-title":"Dynamic HIF1A regulation during human placental development","volume":"75","author":"Ietta","year":"2006","journal-title":"Biol. Reprod."},{"key":"B16","doi-asserted-by":"publisher","first-page":"597","DOI":"10.3724\/abbs.2024022","article-title":"AHR signaling pathway mediates mitochondrial oxidative phosphorylation which leads to cytarabine resistance","volume":"56","author":"Jia","year":"2024","journal-title":"Acta Biochim. Biophys. Sin. (Shanghai)"},{"key":"B17","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1042\/BST20130002","article-title":"Epigenetic regulation of placental endocrine lineages and complications of pregnancy","volume":"41","author":"John","year":"2013","journal-title":"Biochem. Soc. Trans."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1521","DOI":"10.4155\/fmc.15.83","article-title":"Design of inhibitors of BCRP\/ABCG2","volume":"7","author":"Juvale","year":"2015","journal-title":"Future Med. Chem."},{"key":"B19","doi-asserted-by":"publisher","first-page":"580","DOI":"10.1111\/cts.12742","article-title":"Role of elevated SFLT-1 on the regulation of placental transporters in women with pre-eclampsia","volume":"13","author":"Kojovic","year":"2020","journal-title":"Clin. Transl. Sci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1095\/biolreprod.112.099861","article-title":"The pathophysiology of preeclampsia involves altered levels of angiogenic factors promoted by hypoxia and autoantibody-mediated mechanisms","volume":"87","author":"Laresgoiti-Servitje","year":"2012","journal-title":"Biol. Reprod."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.biopen.2018.05.001","article-title":"AhR signaling pathways and regulatory functions","volume":"7","author":"Larigot","year":"2018","journal-title":"Biochim. Open"},{"key":"B22","doi-asserted-by":"publisher","first-page":"817","DOI":"10.1016\/j.placenta.2013.05.010","article-title":"Effect of oxygen on multidrug resistance in the first trimester human placenta","volume":"34","author":"Lye","year":"2013","journal-title":"Placenta"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1150","DOI":"10.3390\/cells8101150","article-title":"Breast cancer resistance protein (BCRP\/ABCG2) inhibits extra villous trophoblast migration: the impact of bacterial and viral infection","volume":"8","author":"Lye","year":"2019","journal-title":"Cells"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1244","DOI":"10.1007\/s11095-008-9537-z","article-title":"BCRP\/ABCG2 in the placenta: expression, function and regulation","volume":"25","author":"Mao","year":"2008","journal-title":"Pharm. Res."},{"key":"B25","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1208\/s12248-014-9668-6","article-title":"Role of the breast cancer resistance protein (BCRP\/ABCG2) in drug transport--an update","volume":"17","author":"Mao","year":"2015","journal-title":"AAPS J."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1000","DOI":"10.1124\/dmd.111.038166","article-title":"ATP-Binding cassette transporter expression in human placenta as a function of pregnancy condition","volume":"39","author":"Mason","year":"2011","journal-title":"Drug Metab. Dispos."},{"key":"B27","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1016\/j.placenta.2011.05.006","article-title":"First-trimester placental protein 13, PAPP-A, uterine artery doppler and maternal characteristics in the prediction of pre-eclampsia","volume":"32","author":"Odibo","year":"2011","journal-title":"Placenta"},{"key":"B28","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/ijgo.12802","article-title":"The international Federation of gynecology and obstetrics (FIGO) initiative on pre-eclampsia: a pragmatic guide for first-trimester screening and prevention","volume":"145","author":"Poon","year":"2019","journal-title":"Int. J. Gynaecol. Obstet."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1094","DOI":"10.1161\/CIRCRESAHA.118.313276","article-title":"Preeclampsia: pathophysiology, challenges, and perspectives","volume":"124","author":"Rana","year":"2019","journal-title":"Circ. Res."},{"key":"B30","doi-asserted-by":"publisher","first-page":"e20250008","DOI":"10.62958\/j.cjap.2025.008","article-title":"Natural flavonoids as anticancer agents: targeting the HIF-1\u03b1 signaling pathway","volume":"41","author":"Shinde","year":"2025","journal-title":"Zhongguo Ying Yong Sheng Li Xue Za Zhi"},{"key":"B31","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1124\/jpet.106.105023","article-title":"Expression and transport activity of breast cancer resistance protein (Bcrp\/Abcg2) in dually perfused rat placenta and HRP-1 cell line","volume":"319","author":"Staud","year":"2006","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"B32","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1007\/s11060-017-2730-3","article-title":"Overexpression of aryl hydrocarbon receptor (AHR) signalling pathway in human meningioma","volume":"137","author":"Talari","year":"2018","journal-title":"J. Neurooncol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1124\/mol.110.065078","article-title":"Aryl hydrocarbon receptor is a transcriptional activator of the human breast cancer resistance protein (BCRP\/ABCG2)","volume":"78","author":"Tan","year":"2010","journal-title":"Mol. Pharmacol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"181","DOI":"10.4132\/jptm.2015.02.25","article-title":"Galectins: double-Edged swords in the cross-roads of pregnancy complications and female reproductive tract inflammation and neoplasia","volume":"49","author":"Than","year":"2015","journal-title":"J. Pathol. Transl. Med."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1754","DOI":"10.1016\/j.bcp.2010.08.016","article-title":"A novel xenobiotic responsive element regulated by aryl hydrocarbon receptor is involved in the induction of BCRP\/ABCG2 in LS174T cells","volume":"80","author":"Tompkins","year":"2010","journal-title":"Biochem. Pharmacol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1016\/j.cbi.2014.05.001","article-title":"Regulatory crosstalk and interference between the xenobiotic and hypoxia sensing pathways at the AhR-ARNT-HIF1\u03b1 signaling node","volume":"218","author":"Vorrink","year":"2014","journal-title":"Chem. Biol. Interact."},{"key":"B37","doi-asserted-by":"publisher","first-page":"732","DOI":"10.1016\/j.placenta.2014.06.372","article-title":"Expression of hypoxia-regulated genes and glycometabolic genes in placenta from patients with intrahepatic cholestasis of pregnancy","volume":"35","author":"Wei","year":"2014","journal-title":"Placenta"},{"key":"B38","doi-asserted-by":"publisher","first-page":"1569","DOI":"10.4155\/fmc-2023-0169","article-title":"Novel 4-aminoquinoline analogs targeting the HIF-1\u03b1 signaling pathway","volume":"15","author":"Wu","year":"2023","journal-title":"Future Med. Chem."},{"key":"B39","doi-asserted-by":"publisher","first-page":"9675","DOI":"10.3390\/ijms22189675","article-title":"The impact of hypoxia in early pregnancy on placental cells","volume":"22","author":"Zhao","year":"2021","journal-title":"Int. J. Mol. Sci."}],"updated-by":[{"DOI":"10.3389\/ftox.2026.1953267","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000}}],"container-title":["Frontiers in Toxicology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/ftox.2026.1782187\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T15:40:17Z","timestamp":1788968417000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/ftox.2026.1782187\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,22]]},"references-count":39,"alternative-id":["10.3389\/ftox.2026.1782187"],"URL":"https:\/\/doi.org\/10.3389\/ftox.2026.1782187","relation":{},"ISSN":["2673-3080"],"issn-type":[{"value":"2673-3080","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,22]]},"article-number":"1782187"}}