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 0-5 dpf, larvae were reared in aqueous solutions containing retinoic acid (0, 0.02, 0.2 or 2 nM) or valproic acid (0, 0.5, 5.0 or 50 uM). 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.

Plausibility of the zebrafish embryos/larvae as an alternative animal model for autism: A comparison study of transcriptome changes

“…Previous studies reported similar levels of hypoactivity [31]. However, these effects, observed in both the current and previous studies, might be related to a VPA-induced delay in zebrafish hatching (Fig 1).…”

Genetic and environmental modulation of neurodevelopmental disorders: Translational insights from labs to beds

“…Another common example of NDD-relevant prenatal drug exposure is valproic acid. Prescribed for maternal epilepsy and some neuropsychological disorders, this agent significantly increases risk for ASD in humans [38], and its early exposure causes similar ASD-like behavioral deficits in a wide range of animal models, including rodents [170], tadpoles [99] and zebrafish [16].…”

Ecotoxicity of the insensitive munitions compound 3-nitro-1,2,4-triazol-5-one (NTO) and its reduced metabolite 3-amino-1,2,4-triazol-5-one (ATO)

“…Importantly, the critical processes of zebrafish neurodevelopment are homologous to those in humans [14]. Neuronal effects of developmental chemical exposure on embryo and larval photomotor activity can be easily measured in zebrafish, widening the potential field of bioactivity that can be detected [15, 16]. It was found that developmental mortality/morphology endpoints, combined with the larval photomotor response, serve as a robust biological sensor for chemical hazard potential.…”