Tris(1,3-dichloro-2-propyl) Phosphate Inhibits Early Embryonic Development by Binding to Gsk-3β Protein in Zebrafish

Recently, several studies have reported that exposure to tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) results in abnormal development of zebrafish embryos in blastocyst and gastrula stages, but molecular mechanisms are still not clear. This lacking strongly affects the interspecific extrapolation of embryonic toxicity induced by TDCIPP and hazard evaluation. In this study, zebrafish embryos were exposed to 100, 500 or 1000 μg/L TDCIPP, and 6-bromoindirubin-3'-oxime (BIO, 35.62 μg/L) was used as a positive control. Results demonstrated that treatment with TDCIPP or BIO caused an abnormal stacking of blastomere cells in mid blastula transition (MBT) stage, and subsequently resulted in epiboly delay of zebrafish embryos. TDCIPP and BIO up-regulated the expression of β-catenin protein and increased its accumulation in nuclei of embryonic cells. This accumulation was considered as a driver for early embryonic developmental toxicity of TDCIPP. Furthermore, TDCIPP and BIO partly shared the same modes of action, and both of them could bind to Gsk-3β protein, and then decreased the phosphorylation level of Gsk-3β in TYR·216 site and lastly inhibited the activity of Gsk-3β kinase, which was responsible for the increased concentrations of β-catenin protein in embryonic cells and accumulation in nuclei. Our findings provide new mechanisms for clarifying the early embryonic developmental toxicity of TDCIPP in zebrafish.