title: Effect of oxygen on multidrug resistance in the first trimester human placenta.
abstract: BACKGROUND
  The multidrug resistance proteins, P-glycoprotein (P-gp, encoded by the ABCB1 gene) and breast cancer resistance protein (BCRP, encoded by ABCG2) are highly expressed in the first trimester placenta. These transporters protect the fetus from exposure to maternally derived toxins and xenobiotics. Since oxygen is a regulator of multidrug resistance in various tissues, we hypothesized that changes in oxygen tension alter placental ABCB1/P-gp and ABCG2/BCRP expression in the first trimester.
  
  
  METHODS
  Placental specimens were collected from first (n = 7), second (n = 5) and term pregnancies (n = 5). First trimester placental villous explants were incubated (24 or 48 h) in different oxygen tension (3-20%). ABCB1, ABCG2 and VEGFA mRNA expression levels were assessed by RT-PCR and protein was localized by IHC.
  
  
  RESULTS
  ABCB1 is expressed most highly in the first trimester placenta (p < 0.05), whereas ABCG2 expression does not change significantly over pregnancy. P-gp and BCRP staining is present in the syncytiotrophoblast and in cytotrophoblasts. ABCG2 mRNA is increased in hyperoxic (20%) conditions after 48 h (p < 0.05). In contrast, hypoxia (3%) did not change ABCB1 mRNA expression but significantly increased VEGFA mRNA (p < 0.05). Hypoxia resulted in increased BCRP staining in cytotrophoblasts and in the microvillous membrane of the syncytium. Whereas, hypoxia resulted in increased P-gp staining in proliferating cytotrophoblasts.
  
  
  CONCLUSIONS
  We conclude that placental multidrug resistance expression, specifically ABCG2, is regulated by oxygen tension in the first trimester. It is possible that changes in placental oxygen supply are capable of altering fetal drug exposure especially during early pregnancy.
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Lye
authors.forename: E
authors.initials: E
authors.lastname: Bloise
authors.forename: C
authors.initials: C
authors.lastname: Dunk
authors.forename: M
authors.initials: M
authors.lastname: Javam
authors.forename: W
authors.initials: W
authors.lastname: Gibb
authors.forename: S J
authors.initials: SJ
authors.lastname: Lye
authors.forename: S G
authors.initials: SG
authors.lastname: Matthews
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia; D018432:Drug Resistance, Multiple; D005260:Female; D018507:Gene Expression Regulation, Developmental; D015726:Giant Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D010920:Placenta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010929:Placentation; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D011262:Pregnancy Trimester, Second; D011263:Pregnancy Trimester, Third; D012333:RNA, Messenger / Q000378:metabolism; D014015:Tissue Banks; D046509:Tissue Culture Techniques; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
chemical_list: C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins; D012333:RNA, Messenger; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D010100:Oxygen
keywords: BCRP; First-trimester placenta; Hyperoxia; Hypoxia; Multidrug resistance; P-glycoprotein