title: Dexamethasone stimulates placental system A transport and trophoblast differentiation in term villous explants.
abstract: Synthetic glucocorticoids (GCs) are given to women with threatened preterm labour but their administration has been linked to reduced infant birthweight. The underlying mechanisms are unknown, but impaired placental development and/or function has been implicated. The activity of the system A amino acid transporter is decreased in placentas from pregnancies complicated by fetal growth restriction. Whether GCs adversely affect placental amino acid transport is unknown. The objective of this study was to determine the regulatory effects of GCs on system A transport using a human in vitro placental explant model. Term explants (n=7) were treated with dexamethasone (DEX 10(-8)M or 10(-6)M) or vehicle for 48 h. System A activity was measured by the uptake of (14)C-N-methylated aminoisobutyric acid by explants. Explants were also processed for electron microscopy (EM), immunohistochemistry, and qRT-PCR. Lactate dehydrogenase (LDH), human chorionic gonadotropin (hCG) and human placental lactogen (hPL) release into the culture medium was measured. DEX (10(-6)M) stimulated system A activity compared to vehicle (p<0.05). System A transporter proteins were localized to the newly regenerating syncytiotrophoblast layer, but mRNA levels were unchanged with DEX treatment. DEX did not adversely affect explant viability as determined by reduced LDH release (p<0.05). DEX treatment was associated with morphological (accelerated apical microvilli formation, nuclear maturation, and increased cell organelle number) and functional (elevated hCG secretion, increased 11beta-HSD2 mRNA expression and reduced cytotrophoblast proliferation (p<0.05 for all)) markers of syncytiotrophoblast differentiation. These findings suggest that DEX stimulates system A activity and promotes syncytiotrophoblast differentiation and maturation.
authors.affiliation: Department of Physiology, University of Toronto, Toronto, ON, Canada. m.audette@utoronto.ca
authors.forename: M C
authors.initials: MC
authors.lastname: Audette
authors.forename: S L
authors.initials: SL
authors.lastname: Greenwood
authors.forename: C P
authors.initials: CP
authors.lastname: Sibley
authors.forename: C J P
authors.initials: CJ
authors.lastname: Jones
authors.forename: J R G
authors.initials: JR
authors.lastname: Challis
authors.forename: S G
authors.initials: SG
authors.lastname: Matthews
authors.forename: R L
authors.initials: RL
authors.lastname: Jones
mesh_terms: D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000235:genetics / Q000378:metabolism; D026924:Amino Acid Transport System A / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D006063:Chorionic Gonadotropin / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D015686:Gene Products, env / Q000235:genetics / Q000378:metabolism; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D019394:Ki-67 Antigen / Q000378:metabolism; D010920:Placenta / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects; D047929:Term Birth; D013997:Time Factors; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
chemical_list: D026924:Amino Acid Transport System A; D006063:Chorionic Gonadotropin; D015686:Gene Products, env; D005938:Glucocorticoids; D019394:Ki-67 Antigen; D011257:Pregnancy Proteins; D020033:Protein Isoforms; C405335:syncytin; D003907:Dexamethasone; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; C468387:HSD11B2 protein, human