Embryonic Exposure to UV-328 Impairs the Cell Cycle in Zebrafish ( Danio rerio ) by Inhibiting the p38 MAPK/p53/Gadd45a Signaling Pathway.

The benzotriazole UV stabilizer UV-328 is well known for its potent antioxidative properties; however, there are concerns about how it may affect signaling nodes and lead to negative consequences. This study identified the key signaling cascades involved in oxidative stress in zebrafish ( Danio rerio ) larvae and evaluated the cell cycle arrests and associated developmental alternations. Exposure to UV-328 at 0.25, 0.50, 1.00, 2.00, and 4.00 μg/L downregulated gene expression associated with oxidative stress ( cat , gpx , gst , and sod ) and apoptosis ( caspase-3 , caspase-6 , caspase-8 , and caspase-9 ) at 3 days postfertilization (dpf). The transcriptome aberration in zebrafish with disrupted p38 mitogen-activated protein kinase (MAPK) cascades was validated based on decreased mRNA expressions of p38 MAPK (0.36-fold), p53 (0.33-fold), and growth arrest and DNA damage-inducible protein 45 α (Gadd45a) (0.52-fold) after a 3- and 14-day exposure alongside a correspondingly decreased protein expression. The percentage of cells in the Gap 1 (G1) phase increased from 69.60% to a maximum of 77.07% ( p < 0.05) in the 3 dpf embryos. UV-328 inhibited the p38 MAPK/p53/Gadd45a regulatory circuit but promoted G1 phase cell cycle arrest, abnormally accelerating the embryo hatching and heart rate. This study provided mechanistic insights that enrich the risk profiles of UV-328.