title: In utero exposure to venlafaxine, a serotonin-norepinephrine reuptake inhibitor, increases cardiac anomalies and alters placental and heart serotonin signaling in the rat.
abstract: BACKGROUND
  Human studies are inconsistent with respect to an association between treatment with selective serotonin and serotonin-norepinephrine reuptake inhibitors (SSRI/SNRIs) and an increase in the incidence of congenital heart defects. Here we tested the hypothesis that in utero exposure to venlafaxine, a highly prescribed SNRI, increases the incidence of fetal heart defects and alters placental and fetal heart serotonin signaling in the rat.
  
  
  METHODS
  Timed-pregnant Sprague Dawley rats were gavaged daily with venlafaxine hydrochloride (0, 3, 10, 30, or 100 mg/kg/day) from gestation day 8 to 20. On gestation day 21, fetuses were examined for external and internal malformations; placentas and fetal hearts were collected for the analysis of gene expression.
  
  
  RESULTS
  Venlafaxine had no effect on the number of live fetuses, fetal body weights, or external morphology in the absence of maternal toxicity. However, venlafaxine significantly increased the placental index (fetal body/placental weight ratio) and the incidence of fetal cardiac anomalies. Venlafaxine exposure decreased placental expression of the serotonin transporter (SERT/Slc6a4) at the transcript and protein levels. In contrast, venlafaxine increased SERT expression in the hearts of female, but not male, fetuses. Expression of the serotonin 2B receptor (5-HT2B/Htr2b) and of fibroblast growth factor 8 was induced in fetal hearts.
  
  
  CONCLUSIONS
  In utero venlafaxine exposure altered the placental index and induced fetal cardiac anomalies in rats. We propose that the increased incidence of cardiac anomalies is mediated through alterations in serotonin signaling in the placenta and fetal heart. Birth Defects Research (Part A), 2016. © 2016 Wiley Periodicals, Inc. Birth Defects Research (Part A) 106:1044-1055, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: INRS-Institut Armand-Frappier, Laval, QC, Canada.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Laurent
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
authors.forename: Chunwei
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
authors.forename: Sheila R
authors.initials: SR
authors.lastname: Ernest
authors.affiliation: Faculty of Pharmacy, University of Montreal, and Research Center, CHU Sainte-Justine, Montreal, QC, Canada.
authors.forename: Anick
authors.initials: A
authors.lastname: Berard
authors.affiliation: INRS-Institut Armand-Frappier, Laval, QC, Canada.
authors.forename: Cathy
authors.initials: C
authors.lastname: Vaillancourt
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
authors.forename: Barbara F
authors.initials: BF
authors.lastname: Hales
mesh_terms: D000284:Administration, Oral; D000818:Animals; D005260:Female; D020567:Fetal Weight; D005333:Fetus; D051524:Fibroblast Growth Factor 8 / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006330:Heart Defects, Congenital / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008098:Litter Size; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010920:Placenta / Q000187:drug effects; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044403:Receptor, Serotonin, 5-HT2B / Q000235:genetics / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors / Q000009:adverse effects*; D015398:Signal Transduction / Q000187:drug effects; D000069470:Venlafaxine Hydrochloride / Q000009:adverse effects*
chemical_list: D044403:Receptor, Serotonin, 5-HT2B; D050486:Serotonin Plasma Membrane Transport Proteins; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors; C493232:Slc6a4 protein, rat; D051524:Fibroblast Growth Factor 8; D012701:Serotonin; D000069470:Venlafaxine Hydrochloride
keywords: antidepressants; congenital heart defect; pregnancy; teratogen; ventricular septal defect