title: Persistent behavioral effects following early life exposure to retinoic acid or valproic acid in zebrafish.
abstract: BACKGROUND
  Moderate to severe dysregulation in retinoid signaling during early development is associated with a constellation of physical malformations and/or neural tube defects, including spina bifida. It is thought that more subtle dysregulation of this system, which might be achievable via dietary (i.e. hypervitaminosis A) or pharmacological (i.e. valproic acid) exposure in humans, will manifest on behavioral domains including sociability, without overt physical abnormalities.
  
  
  METHODS
  During early life, zebrafish were exposed to low doses of two chemicals that disrupt retinoid signaling. From 0 to 5dpf, larvae were reared in aqueous solutions containing retinoic acid (0, 0.02, 0.2 or 2nM) or valproic acid (0, 0.5, 5.0 or 50μM). One cohort of zebrafish was assessed using a locomotor activity screen at 6-dpf; another was reared to adulthood and assessed using a neurobehavioral test battery (startle habituation, novel tank exploration, shoaling, and predator escape/avoidance).
  
  
  RESULTS
  There was no significant increase in the incidence of physical malformation among exposed fish compared to controls. Both retinoic acid and valproic acid exposures during development disrupted larval activity with persisting behavioral alterations later in life, primarily manifesting as decreased social affiliation.
  
  
  CONCLUSIONS
  Social behavior and some aspects of motor function were altered in exposed fish; the importance of examining emotional or psychological consequences of early life exposure to retinoid acting chemicals is discussed.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Jordan M
authors.initials: JM
authors.lastname: Bailey
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Oliveri
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Nishika
authors.initials: N
authors.lastname: Karbhari
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Roy A J
authors.initials: RA
authors.lastname: Brooks
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Amberlene J
authors.initials: AJ
authors.lastname: De La Rocha
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Sheila
authors.initials: S
authors.lastname: Janardhan
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC 27710, USA; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: edlevin@duke.edu.
authors.forename: Edward D
authors.initials: ED
authors.lastname: Levin
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D006185:Habituation, Psychophysiologic / Q000187:drug effects; D007814:Larva / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D013216:Reflex, Startle / Q000187:drug effects; D012919:Social Behavior; D014212:Tretinoin / Q000009:adverse effects*; D014635:Valproic Acid / Q000009:adverse effects*; D015027:Zebrafish / Q000254:growth & development*
chemical_list: D014212:Tretinoin; D014635:Valproic Acid
keywords: Behavior; Cognition; Development; Retinoic acid; Social behavior; Vitamin A valproic acid; Zebrafish