title: Acute Effects of Viral Exposure on P-Glycoprotein Function in the Mouse Fetal Blood-Brain Barrier.
abstract: OBJECTIVE
  Viral infection during pregnancy is known to affect the fetal brain. The toll-like receptor (TLR)-3 is a pattern recognition receptor activated by viruses known to elicit adverse fetal neurological outcomes. The P-glycoprotein (P-gp) efflux transporter protects the developing fetus by limiting the transfer of substrates across both the placenta and the fetal blood-brain barrier (BBB). As such, inhibition of P-gp at these blood-barrier sites may result in increased exposure of the developing fetus to environmental toxins and xenobiotics present in the maternal circulation. We hypothesized that viral exposure during pregnancy would impair P-gp function in the placenta and in the developing BBB. Here we investigated whether the TLR-3 ligand, polyinosinic:polycytidylic acid (PolyI:C), increased accumulation of one P-gp substrate in the fetus and in the developing fetal brain.
  
  
  METHODS
  Pregnant C57BL/6 mice (GD15.5) were injected (i.p.) with PolyI:C (5 mg/kg or 10 mg/kg) or vehicle (saline). [3H]digoxin (P-gp substrate) was injected (i.v.) 3 or 23h post-treatment and animals were euthanized 1h later. Maternal plasma, 'fetal-units' (fetal membranes, amniotic fluid and whole fetus), and fetal brains were collected.
  
  
  RESULTS
  PolyI:C exposure (4h) significantly elevated maternal plasma IL-6 (P<0.001) and increased [3H]digoxin accumulation in the fetal brain (P<0.05). In contrast, 24h after PolyI:C exposure, no effect on IL-6 or fetal brain accumulation of P-gp substrate was observed.
  
  
  CONCLUSIONS
  Viral infection modeled by PolyI:C causes acute increases in fetal brain accumulation of P-gp substrates and by doing so, may increase fetal brain exposure to xenobiotics and environmental toxins present in the maternal circulation.
authors.forename: Enrrico
authors.initials: E
authors.lastname: Bloise
authors.forename: Sophie
authors.initials: S
authors.lastname: Petropoulos
authors.forename: Majid
authors.initials: M
authors.lastname: Iqbal
authors.forename: Alisa
authors.initials: A
authors.lastname: Kostaki
authors.forename: Tania Maria
authors.initials: TM
authors.lastname: Ortiga-Carvalho
authors.forename: William
authors.initials: W
authors.lastname: Gibb
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Matthews
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D004077:Digoxin / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005333:Fetus / Q000098:blood supply / Q000378:metabolism*; D015870:Gene Expression; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D008431:Maternal-Fetal Exchange; D051379:Mice; D008810:Mice, Inbred C57BL; D010920:Placenta / Q000378:metabolism; D011070:Poly I-C / Q000008:administration & dosage*; D011247:Pregnancy; D014316:Tritium; D014777:Virus Diseases / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D015850:Interleukin-6; C577686:interleukin-6, mouse; D014316:Tritium; D004077:Digoxin; D011070:Poly I-C
keywords: Blood-brain barrier (BBB); P-glycoprotein (P-gp); Placenta; Polyinosinic:polycytidylic acid (PolyI:C); Toll-like receptor 3 (TLR-3)