title: The effect of 17α-ethynylestradiol induced intrahepatic cholestasis of pregnancy on placental P-glycoprotein in mice: Implications in the individualized transplacental digoxin treatment for fetal heart failure.
abstract: Placental P-glycoprotein (P-gp) plays a significant role in controlling transplacental digoxin transfer rate. Investigations on P-gp regulation in placenta of women with different pregnant pathological states are of great significance to individualized transplacental digoxin treatment for fetal heart failure (FHF). This study aimed to explore the effect of 17α-ethynylestradiol induced intrahepatic cholestasis of pregnancy (ICP) on placental P-gp in mice.
  
  
  
  ICP model in mice was induced by subcutaneous injection of 17α-ethynylestradiol dissolved in propylene glycol once daily from E12.5 to E16.5. Maternal plasma ALT, AST, TB, DBIL, γ-GT, LDH, ALP and TBA concentrations were measured. HE staining was applied for observation of maternal liver cells degeneration, necrosis and intrahepatic cholestasis. Placental Abcb1a/Abcb1b/HIF-1α mRNA and P-gp/HIF-1α protein expression were determined by real-time quantitative PCR and western-blot. Maternal plasma and fetal-unit digoxin concentrations were detected by a commercial kit assay.
  
  
  
  The ICP group showed higher levels of maternal plasma ALT, AST, TB, DBIL, γ-GT, LDH, ALP and TBA concentrations, reduction in fetal survival rates, lower placental and fetal weights, and typical liver cells degeneration, necrosis and intrahepatic cholestasis. The placental Abcb1a mRNA and P-gp expression of ICP group were significantly elevated, while transplacental digoxin transfer rates were significantly decreased. Both placental HIF-1α mRNA and protein expression was significantly elevated in the ICP group, and there was a positive correlation between Abcb1a mRNA and HIF-1α mRNA.
  
  
  
  17α-ethynylestradiol induced ICP could up-regulate placental P-gp expression and reduce transplacental digoxin transfer rate in mice, which might be partly associated with higher expression of HIF-1α.
authors.affiliation: Department of Pediatric Cardiology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China; The Cardiac Development and Early Intervention Unit, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China; West China Medical School of Sichuan University, Chengdu, Sichuan, China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Wang
authors.affiliation: The Cardiac Development and Early Intervention Unit, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pediatric Cardiology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China; The Cardiac Development and Early Intervention Unit, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China; West China Medical School of Sichuan University, Chengdu, Sichuan, China.
authors.forename: Yalan
authors.initials: Y
authors.lastname: Zhan
authors.affiliation: West China Medical School of Sichuan University, Chengdu, Sichuan, China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Luo
authors.affiliation: Department of Pediatric Cardiology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China; The Cardiac Development and Early Intervention Unit, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Yifei
authors.initials: Y
authors.lastname: Li
authors.affiliation: The Cardiac Development and Early Intervention Unit, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Dajian
authors.initials: D
authors.lastname: Qiu
authors.affiliation: Department of Pediatric, Chengdu Women's & Children's Central Hospital, Chengdu, Sichuan, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Dezhi
authors.initials: D
authors.lastname: Mu
authors.affiliation: Department of Pediatric Cardiology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China; The Cardiac Development and Early Intervention Unit, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Duan
authors.affiliation: Department of Pediatric Cardiology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China; The Cardiac Development and Early Intervention Unit, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China. Electronic address: kaiyuzhou313@163.com.
authors.forename: Kaiyu
authors.initials: K
authors.lastname: Zhou
authors.affiliation: Department of Pediatric Cardiology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China; The Cardiac Development and Early Intervention Unit, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China. Electronic address: nathan_hua@126.com.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Hua
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D002780:Cholestasis, Intrahepatic / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D004077:Digoxin / Q000627:therapeutic use*; D004997:Ethinyl Estradiol; D005260:Female; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D010920:Placenta / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D011248:Pregnancy Complications / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004997:Ethinyl Estradiol; D004077:Digoxin
keywords: Digoxin; Fetal heart failure; HIF-1α; Intrahepatic cholestasis of pregnancy; P-glycoprotein; Placenta