Dysregulatory effects of retinoic acid isomers in late zebrafish embryos

All-trans retinoic acid (atRA) and 9-cis retinoic acid (9cRA) are two natural derivatives of vitamin A that contribute to the normal vertebrate development by affecting gene expression through the retinoic acid signalling pathway. We show transcriptomic effects of the ectopic addition of atRA or 9cRA to zebrafish embryos at the posthatching embryonic stage. Exposure for 24 or 72 h to sublethal concentrations of both isomers resulted in characteristic transcriptome changes, in which many proliferation and development-related genes became underexpressed, whereas genes related to retinoid metabolism and some metabolic functions became overrepresented. While short and long exposures elicit essentially the same set of genes, atRA specifically induced expression of a specific subset of proteases, likely acting at the extracellular level, and of elements of the response to xenobiotics. These results reflect the well-known antiproliferative activity of retinoids, and they suggest a dysregulation of the developmental process at final stages of embryogenesis. They also indicate a potential role of endopeptidases as markers of developmental alterations, as well as their possible control by the retinoic signalling pathway. We propose to monitor mRNA levels of cyp16a, cyp16b, and cyp16c in zebrafish embryos as a bioassay for retinoid disruption.