Naila Abid, Joan Embola and Zoe Tryfonos contributed equally to this study.Abbreviations: 8 Br-cAMP, 8-Bromo adenosine-3', 5'-cyclic monophosphate; BSA, bovine serum albumin; cAMP, adenosine-3', 5'-cyclic monophosphate; DAB, 3,3′-diaminobenzidine; DP44mT, di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone; Epac, exchange proteins directly activated by cAMP; FCS, fetal calf serum; GSK-3β, glycogen synthase kinase-3β; hCG, human chorionic gonadotrophin; HIF, hypoxia-Inducible factor; HRE, hypoxia response element; IGF, insulin-like growth factor; IGFBP4, insulin-like growth factor binding protein; mTOR, mammalian target of rapamycin; mTORC, mammalian target of rapamycin complex; NDRG-1, N-myc downstream-regulated gene 1; NHS, National Health Service; PAPP-A, pregnancy-associated plasma protein-A; PBS, phosphate-buffered saline; PBST, phosphate-buffered saline with tween; PI 3 -Kinase, phosphatidylinositol-3 kinase; PKA, protein kinase A; SGK-1, serum and glucocorticoid-induced kinase-1; STC-1, stanniocalcin-1; TBS, tris-buffered saline; TBST, tris-buffered saline with tween. AbstractStanniocalcin-1 (STC-1) is a multi-functional glycosylated peptide present in the plasma of healthy women postpartum and increased further in pregnancies complicated by preeclampsia. Although the STC-1 gene is expressed by the placenta what regulates its secretion and from which cells at the feto-maternal interface is unknown.Here, we demonstrate for the first time that the syncytiotrophoblast and cytotrophoblast are a major site of STC-1 protein expression in first trimester placental tissue. Further, in response to low oxygen, first trimester chorionic villous tissue from pregnancies at increased risk of developing preeclampsia secreted significantly more STC-1 than normal tissue under the same conditions. Using the human trophoblast cell line BeWo we have shown that low oxygen increased the secretion of STC-1 but it required co-stimulation with the Adenosine-3', 5'-cyclic monophosphate (cAMP) analogue, 8-Bromo adenosine-3', 5'-cyclic monophosphate cAMP to reach significance. Inhibition of Hypoxia inducible factor 2α (HIF-2α) and the Phosphatidylinositol-3 kinase (PI 3 -Kinase)/AKT/Serum and glucocorticoid-induced kinase-1(SGK-1) pathway resulted in significant inhibition of STC-1 secretion. As both low oxygen and cAMP are known to play a central role in placental function, their regulation of STC-1 points to a potentially important role in the maintenance of a normal healthy pregnancy and we would hypothesize that it may act to protect against prolonged placental hypoxia seen in preeclampsia. K E Y W O R D Sfirst trimester, hypoxia, placenta, stanniocalcin-1, trophoblasts