Persistent Behavioral Effects Following Early Life Exposure to Retinoic Acid or Valproic Acid in Zebrafish

Background. During pregnancy, women are administered a variety of medications and supplements. Some of these drugs have been hypothesized to induce behavioral and/or morphological abnormalities in the developing fetus; these abnormalities may persist into adulthood, permanently impairing cognitive domains or anatomical features in the fetus. In this study, we used zebrafish embryos as a model system to study how prenatal exposure to certain doses of retinoic acid and valproic acid may be associated with persisting behavioral abnormalities. Methods. During early life, zebrafish were exposed to either retinoic or valproic acid. From 0-5 dpf (days post-fertilization), 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). Fish were screened in early life for physical malformation; those exhibiting no critical physical malformations were subjected to behavioral testing. One cohort of zebrafish was assessed during early life (6-dpf) using a locomotor activity screen; another cohort was reared to adulthood and assessed using a neurobehavioral test battery (startle habituation, novel tank exploration, shoaling, and predator escape/avoidance). Results: No significant increase in physical malformation was observed in the experimental group as compared to the control group. Both retinoic acid and valproic acid exposure during development disrupted larval activity and induced behavioral changes that persisted into later life, manifesting most significantly as decreased social affiliation. Conclusions: Social behavior and some aspects of motor function were altered in fish exposed to retinoic or valproic acid early in life.