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

UV-328 inhibits p38 MAPK/p53/Gadd45asignaling cascadesat environmentally relevant concentrations, inducing cell cycle G1arrest in zebrafish (Danio rerio) larvae. The benzotriazole UV stabilizer UV-328 is well knownfor its potentantioxidative properties; however, there are concerns about how itmay affect signaling nodes and lead to negative consequences. Thisstudy identified the key signaling cascades involved in oxidativestress in zebrafish (Danio rerio) larvaeand evaluated the cell cycle arrests and associated developmentalalternations. Exposure to UV-328 at 0.25, 0.50, 1.00, 2.00, and 4.00 & mu;g/L downregulated gene expression associated with oxidativestress (cat, gpx, gst, and sod) and apoptosis (caspase-3, caspase-6, caspase-8, and caspase-9) at 3 days postfertilization (dpf). The transcriptomeaberration in zebrafish with disrupted p38 mitogen-activated proteinkinase (MAPK) cascades was validated based on decreased mRNA expressionsof p38 MAPK (0.36-fold), p53 (0.33-fold), and growth arrest and DNAdamage-inducible protein 45 & alpha; (Gadd45a) (0.52-fold) aftera 3- and 14-day exposure alongside a correspondingly decreased proteinexpression. The percentage of cells in the Gap 1 (G1) phase increasedfrom 69.60% to a maximum of 77.07% (p < 0.05)in the 3 dpf embryos. UV-328 inhibited the p38 MAPK/p53/Gadd45a regulatorycircuit but promoted G1 phase cell cycle arrest, abnormally acceleratingthe embryo hatching and heart rate. This study provided mechanisticinsights that enrich the risk profiles of UV-328.

Automated summary

This study identified the key signaling cascades involved in oxidative stress in zebrafish larvae and evaluated the cell cycle arrests and associated developmental alterations caused by UV-328 exposure. UV-328 inhibited the p38 MAPK/p53/Gadd45a regulatory circuit, leading to G1 phase cell cycle arrest and abnormal embryo hatching and heart rate.