John Wiley & Sons, Ltd.

Characterization of retinoic acid induced neurobehavioral effects in developing zebrafish

Retinoic signaling plays an important role in cell proliferation and differentiation. Disruption of retinoic signaling via excessive or deficient retinoic acid (RA) can cause teratogenic effects on developing embryos. Similar to RA, many xenobiotic environmental pollutants have been found to disrupt retinoic signaling through binding and eliciting agonistic activity on retinoic acid receptors (RARs). Currently, studies of RA or RA‐like compounds in aquatic organisms have mainly focused on teratogenicity and few studies explore their neurobehavioral toxicity. In the present study, we use RA as an example to explore the neurobehavioral toxicity associated with developmental exposure of RA‐like compounds in zebrafish. Our findings confirmed RA's teratogenic effects such as bent spine, malformed tail, and pericardial edema in developing zebrafish with an EC50 of 2.47 nM. RA‐induced cell apoptosis at 24 hpf was consistently found in the eye and tail regions of embryos. Spontaneous movement as characterized by tail bend frequency was significantly increased in zebrafish embryos following exposure to 2 nM and 8 nM RA. Relatively low dose RA exposure of 2 nM led to fast locomotion behavior in the dark period, and hyperactivity when subjected to light‐dark photoperiod stimulation. The 2 nM RA exposure also led to alterations of neurobehavior and optic nerve related genes with nog and hox underexpressed, while rgr, rho and opn1sw1 overexpressed. Increased expression of opn1sw1 and rho was confirmed by whole mount in situ hybridization. Whether the misexpression of these genes leads to the neurobehavior changes merits further study. Our findings demonstrated that low dose RA exposure perturbed the visual system, optic nerve development and caused hyperactivity in developing zebrafish. Environ Toxicol Chem © 2013 SETAC

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