title: Retinoic acid drives aryl hydrocarbon receptor expression and is instrumental to dioxin-induced toxicity during palate development.
abstract: BACKGROUND
  Palate development depends on complex events and is very sensitive to disruption. Accordingly, clefts are the most common congenital malformations worldwide, and a connection is proposed with fetal exposure to toxic factors or environmental contaminants, such as dioxins. There is increasing evidence that dioxin interferes with all-trans-retinoic acid (atRA), a hormone-like signal derived from vitamin A, which plays an essential role during embryonic development. Although similarities have been described between dioxin-induced toxicity and the outcome of altered atRA signaling during palate development, their relationship needs to be clarified.
  
  
  OBJECTIVE
  We used a genetic approach to understand the interaction between atRA and dioxin and to identify the cell type targeted by dioxin toxicity during secondary palate formation in mice.
  
  
  METHODS
  We analyzed the phenotype of mouse embryos harboring an atRA-sensitive reporter transgene or bearing null mutations for atRA-synthesizing enzymes (RALDH) or atRA receptors (RAR) and maternally exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) at gestation day 10.5.
  
  
  RESULTS
  We found that an intact atRA signal was required to enable TCDD to induce cleft palate. This mandatory atRA signal was generated through the activity of RALDH3 in the nasal epithelium and was transduced by RARγ (RARG) in the nasal mesenchyme, where it notably controlled aryl hydrocarbon receptor (Ahr) transcript levels. TCDD also did not alter the developmental pattern of atRA signaling during palate formation.
  
  
  CONCLUSIONS
  TCDD-induced alteration of secondary palate development in the mouse appears to depend on atRA signaling, which controls AHR expression. This mechanism is likely conserved throughout vertebrate evolution and may therefore be relevant in humans.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS UMR7104), Institut National de la Santé et de la Recherche Médicale (INSERM) U964, Université de Strasbourg, Illkirch, France.
authors.forename: Hugues
authors.initials: H
authors.lastname: Jacobs
authors.forename: Christine
authors.initials: C
authors.lastname: Dennefeld
authors.forename: Betty
authors.initials: B
authors.lastname: Féret
authors.forename: Matti
authors.initials: M
authors.lastname: Viluksela
authors.forename: Helen
authors.initials: H
authors.lastname: Håkansson
authors.forename: Manuel
authors.initials: M
authors.lastname: Mark
authors.forename: Norbert B
authors.initials: NB
authors.lastname: Ghyselinck
mesh_terms: D000818:Animals; D002972:Cleft Palate / Q000139:chemically induced* / Q000209:etiology / Q000235:genetics; D008648:Mesoderm / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D010159:Palate / Q000187:drug effects* / Q000196:embryology; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D060888:Real-Time Polymerase Chain Reaction; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D050697:Retinal Dehydrogenase / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin / Q000378:metabolism*; D000097768:Retinoic Acid Receptor gamma
chemical_list: D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D018168:Receptors, Retinoic Acid; D050697:Retinal Dehydrogenase; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin; D000097768:Retinoic Acid Receptor gamma; C000607071:RARA protein, human; C000607072:Rara protein, mouse; C508905:retinaldehyde dehydrogenase 3, mouse