title: Cholestatic pregnancy is associated with reduced placental 11βHSD2 expression.
abstract: BACKGROUND
  Intrahepatic Cholestasis of Pregnancy (ICP) is associated with an increased risk of fetal morbidity and mortality and is characterised by elevated bile acids in the maternal and fetal compartments. Bile acids have been shown to attenuate renal 11βHSD2 expression and, given the protective role of placental 11βHSD2 in preventing fetal exposure to excessive maternal cortisol, we aimed to establish whether raised serum bile acids in ICP influence placental 11βHSD2 expression.
  
  
  METHODS
  Placental tissue from human and murine cholestatic pregnancy was evaluated for changes in 11βHSD2 mRNA expression compared to uncomplicated pregnancy using quantitative PCR. Parallel in vitro studies were performed using BeWo choriocarcinoma cells to assess the effect of different bile acid species on 11βHSD2 gene expression and whether concurrent UDCA administration can reverse any bile acid induced changes.
  
  
  RESULTS
  Placental 11βHSD2 mRNA expression was reduced in human and murine cholestatic pregnancy. In BeWo cells, treatment with the primary bile acid CDCA resulted in reduced 11βHSD2 gene expression, while treatment with other primary bile acids had no significant effect. Furthermore, the tertiary bile acid UDCA, used in the treatment of ICP did not significantly affect 11βHSD2 mRNA levels either alone, or when co-administered with CDCA.
  
  
  CONCLUSIONS
  Under cholestatic conditions placental 11βHSD2 mRNA is reduced. Studies in BeWo choriocarcinoma cells demonstrated that CDCA is likely to be the specific bile acid that mediates this effect. UDCA, the main bile acid used to treat cholestasis, did not reduce placental 11βHSD2 expression, further supporting its use in the management of ICP.
authors.affiliation: Maternal and Fetal Disease Group, Institute of Reproductive and Developmental Biology, Imperial College London, UK; Division of Obstetric & Consultative Medicine, Women and Infants Hospital, Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: M
authors.initials: M
authors.lastname: Martineau
authors.affiliation: Maternal and Fetal Disease Group, Institute of Reproductive and Developmental Biology, Imperial College London, UK; Women's Health Academic Centre, Kings College London, 2nd Floor Hodgkin Building, Guy's campus, London, UK.
authors.forename: G
authors.initials: G
authors.lastname: Papacleovoulou
authors.affiliation: Maternal and Fetal Disease Group, Institute of Reproductive and Developmental Biology, Imperial College London, UK; Women's Health Academic Centre, Kings College London, 2nd Floor Hodgkin Building, Guy's campus, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Abu-Hayyeh
authors.affiliation: Maternal and Fetal Disease Group, Institute of Reproductive and Developmental Biology, Imperial College London, UK; Women's Health Academic Centre, Kings College London, 2nd Floor Hodgkin Building, Guy's campus, London, UK.
authors.forename: P H
authors.initials: PH
authors.lastname: Dixon
authors.affiliation: Division of Maternal-Fetal Medicine, Women and Infants Hospital, Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: H
authors.initials: H
authors.lastname: Ji
authors.affiliation: Division of Obstetric & Consultative Medicine, Women and Infants Hospital, Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: R
authors.initials: R
authors.lastname: Powrie
authors.affiliation: Division of Obstetric Medicine, Women's Medicine Collaborative, Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: L
authors.initials: L
authors.lastname: Larson
authors.affiliation: Division of Maternal-Fetal Medicine, Women and Infants Hospital, Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: E K
authors.initials: EK
authors.lastname: Chien
authors.affiliation: Maternal and Fetal Disease Group, Institute of Reproductive and Developmental Biology, Imperial College London, UK; Women's Health Academic Centre, Kings College London, 2nd Floor Hodgkin Building, Guy's campus, London, UK. Electronic address: catherine.williamson@ic.ac.uk.
authors.forename: C
authors.initials: C
authors.lastname: Williamson
mesh_terms: D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000096:biosynthesis*; D000818:Animals; D001647:Bile Acids and Salts / Q000097:blood / Q000378:metabolism; D045744:Cell Line, Tumor; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D002780:Cholestasis, Intrahepatic / Q000378:metabolism*; D005260:Female; D006801:Humans; D051379:Mice; D011247:Pregnancy; D011248:Pregnancy Complications / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; D012333:RNA, Messenger; D002635:Chenodeoxycholic Acid; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2
keywords: 11βHSD2; BeWo cells; Bile acid; Cortisol; Intrahepatic cholestasis of pregnancy; Placenta