title: Impact of bacterial and viral challenge on multidrug resistance in first- and third-trimester human placenta.
abstract: The ABC transporters P-glycoprotein (P-gp, official gene symbol ABCB1) and breast cancer resistance protein (BCRP, official gene symbol ABCG2) protect the conceptus from exposure to toxins and xenobiotics present in the maternal circulation. Viral or bacterial challenges alter expression of placental multidrug transporters in rodents. We hypothesized that exposure to lipopolysaccharide (LPS, bacterial antigen) and polyinosinic-polycytidylic acid (poly(I:C), viral antigen) would decrease P-gp and BCRP in the human placenta. Placental explants from first and third trimesters were challenged with 0.1 to 10 μg/mL LPS or 1 to 50 μg/mL poly(I:C) for 4 or 24 hours; mRNA levels, protein expression, and localization were assessed by quantitative real-time PCR, Western blot analysis, and immunohistochemistry, respectively. Toll-like receptor (TLR)-3 and TLR-4 mRNA expression increased from the first to third trimester (P < 0.01), and the receptors localized to cytotrophoblasts in the first trimester and to syncytiotrophoblasts in the third trimester. LPS exposure in first-trimester explants decreased (P < 0.001) ABCB1 and ABCG2 mRNA and protein levels. In contrast, poly(I:C) decreased (P < 0.05) ABCB1, TLR-3, and TLR-4 mRNA levels in the third trimester but not first trimester. LPS and poly(I:C) treatments increased (P < 0.01) IL-8 and chemokine ligand 2. Results suggest that bacterial infections likely alter exposure of the conceptus to toxins and drugs during early pregnancy, whereas viral infections may disrupt fetal protection in later stages of pregnancy.
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Phetcharawan
authors.initials: P
authors.lastname: Lye
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Laboratory of Translational Endocrinology, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Enrrico
authors.initials: E
authors.lastname: Bloise
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Javam
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada; Department of Obstetrics and Gynecology, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: William
authors.initials: W
authors.lastname: Gibb
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Department of Obstetrics and Gynecology, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Lye
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Department of Obstetrics and Gynecology, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. Electronic address: stephen.matthews@utoronto.ca.
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*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D018432:Drug Resistance, Multiple / Q000502:physiology; D005260:Female; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010920:Placenta / Q000187:drug effects* / Q000378:metabolism*; D011070:Poly I-C / Q000494:pharmacology; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D011263:Pregnancy Trimester, Third; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D020813:Receptor, trkB; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D014327:Trophoblasts / Q000378:metabolism
chemical_list: C116614:ABCG2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D011505:Protein-Tyrosine Kinases; D020813:Receptor, trkB; C000591259:tropomyosin-related kinase-B, human; D011070:Poly I-C