title: Down-regulation of the placental BCRP/ABCG2 transporter in response to hypoxia signaling.
abstract: The BCRP/ABCG2 efflux transporter protects the developing fetus by limiting the transplacental transfer of drugs and chemicals and prevents the apoptosis of trophoblasts. The purpose of this study was to determine whether hypoxia-related signaling alters placental BCRP expression and function in vitro and in human pregnancies.
  
  
  
  Human BeWo choriocarcinoma cells were treated with the hypoxia mimetic, cobalt chloride (CoCl2), or 3% oxygen for 24-48 h. Activation of HIF-1α signaling and regulation of BCRP was assessed using qPCR, ELISA, western blotting and a fluorescent substrate transport assay. In addition, healthy term placentas from high altitude pregnancies with chronic hypoxia were assessed for BCRP expression.
  
  
  
  CoCl2and 3% oxygen increased HIF-1α protein signaling and decreased the mRNA and protein expression of BCRP by 30-75% in BeWo cells. Reduced BCRP expression corresponded with impaired efflux activity during hypoxia as evidenced by accumulation of the substrate Hoechst 33342. A number of transcription factors known to regulate BCRP, including AHR, NRF2 and PPARγ, were also coordinately down-regulated by 3% oxygen in BeWo cells. Moreover, women who gave birth at a high altitude (3100 m) exhibited signs of chronic placental hypoxia, including enhanced protein expression of the HIF-1α target GLUT1, and had reduced BCRP levels in microvillous membranes compared to women at a moderate altitude (1600 m).
  
  
  
  This study provides novel insight into the regulation of the placental BCRP transporter by hypoxia, which may be important for exposure of the fetus to chemicals during early development and in hypoxia-related pregnancy disorders.
authors.affiliation: Rutgers University, Robert Wood Johnson Medical School, Department of Obstetrics, Gynecology and Reproductive Sciences, Maternal-Fetal Medicine Division, 125 Paterson St., New Brunswick, NJ 08091, USA.
authors.forename: Lissa N
authors.initials: LN
authors.lastname: Francois
authors.affiliation: Rutgers University, Ernest Mario School of Pharmacy, Department of Pharmacology and Toxicology, 170 Frelinghuysen Rd., Piscataway, NJ 08854, USA.
authors.forename: Ludwik
authors.initials: L
authors.lastname: Gorczyca
authors.affiliation: China Pharmaceutical University, Gulou, Nanjing, Jiangsu, China.
authors.forename: Jianyao
authors.initials: J
authors.lastname: Du
authors.affiliation: Rutgers University, Ernest Mario School of Pharmacy, Department of Pharmacology and Toxicology, 170 Frelinghuysen Rd., Piscataway, NJ 08854, USA.
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Bircsak
authors.affiliation: Rutgers University, Robert Wood Johnson Medical School, Department of Pediatrics, Division of Neonatology, 1 Robert Wood Johnson Place, New Brunswick, NJ 08903, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Yen
authors.affiliation: Rutgers University, Ernest Mario School of Pharmacy, Department of Pharmacology and Toxicology, 170 Frelinghuysen Rd., Piscataway, NJ 08854, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Wen
authors.affiliation: University of California, Davis, Department of Biochemistry and Molecular Medicine, 2700 Stockton Blvd., Sacramento, CA 95817, USA.
authors.forename: Mei-Juan
authors.initials: MJ
authors.lastname: Tu
authors.affiliation: University of California, Davis, Department of Biochemistry and Molecular Medicine, 2700 Stockton Blvd., Sacramento, CA 95817, USA.
authors.forename: Ai-Ming
authors.initials: AM
authors.lastname: Yu
authors.affiliation: Hackensack University Medical Center, Department of Obstetrics and Gynecology, 30 Prospect Ave, Hackensack, NJ 07601, USA.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Illsley
authors.affiliation: Hackensack University Medical Center, Department of Obstetrics and Gynecology, 30 Prospect Ave, Hackensack, NJ 07601, USA.
authors.forename: Stacy
authors.initials: S
authors.lastname: Zamudio
authors.affiliation: Rutgers University, Ernest Mario School of Pharmacy, Department of Pharmacology and Toxicology, 170 Frelinghuysen Rd., Piscataway, NJ 08854, USA; Environmental and Occupational Health Sciences Institute, 170 Frelinghuysen Rd., Piscataway, NJ 08854, USA; Rutgers Center for Lipid Research, New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, NJ 08901, USA. Electronic address: aleksunes@eohsi.rutgers.edu.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Aleksunes
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003035:Cobalt / Q000494:pharmacology; D015536:Down-Regulation; D005260:Female; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010920:Placenta / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D015398:Signal Transduction / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D051272:Glucose Transporter Type 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; C495677:SLC2A1 protein, human; D042461:Vascular Endothelial Growth Factor A; D003035:Cobalt; C018021:cobaltous chloride
keywords: ABCG2; BCRP; Hypoxia; Placenta; Transporter