Retinoic acid signaling pathway perturbation impacts mesodermal-tissue development in the zebrafish embryo: Biomarker candidate identification using transcriptomics.

The zebrafish embryo (ZE) model provides a developmental model well conserved throughout vertebrate embryogenesis, with relevance for early human embryo development. It was employed to search for gene expression biomarkers of compound-induced disruption of mesodermal development. We were particularly interested in the expression of genes related to the retinoic acid signaling pathway (RA-SP), as a major morphogenetic regulating mechanism. We exposed ZE to teratogenic concentrations of valproic acid (VPA) and all-trans retinoic acid (ATRA), using folic acid (FA) as a non-teratogenic control compound shortly after fertilization for 4 h, and performed gene expression analysis by RNA sequencing. We identified 248 genes specifically regulated by both teratogens but not by FA. Further analysis of this gene set revealed 54 GO-terms related to the development of mesodermal tissues, distributed along the paraxial, intermediate, and lateral plate sections of the mesoderm. Gene expression regulation was specific to tissues and was observed for somites, striated muscle, bone, kidney, circulatory system, and blood. Stitch analysis revealed 47 regulated genes related to the RA-SP, which were differentially expressed in the various mesodermal tissues. These genes provide potential molecular biomarkers of mesodermal tissue and organ (mal)formation in the early vertebrate embryo. • ATRA and VPA retinoic acid pathway perturbation alter mesodermal-tissue development. • Transcriptomic changes were found for 7 mesodermal tissues. • 47 potential gene expression maldevelopment biomarkers were found. • 13 were considered potential early biomarkers of general mesodermal maldevelopment. • Some were considered novel potential early biomarkers of specific mesoderm organs. [ABSTRACT FROM AUTHOR]