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Tris(1,3-dichloro-2-propyl) Phosphate Inhibits Early Embryonic Development by Binding to Gsk-3β Protein in Zebrafish
Zichen Yu1, Yongkang Zhang1, Ren Kong2
1College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China.
Abstract:
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.
Insights
Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) disrupts zebrafish embryonic development by upregulating beta-catenin. This occurs through inhibiting Gsk-3β kinase activity, revealing new toxicity mechanisms.
Area of Science:
- Environmental Toxicology
- Developmental Biology
- Molecular Toxicology
Background:
- Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) exposure causes abnormal zebrafish embryonic development.
- The precise molecular mechanisms underlying TDCIPP's developmental toxicity remain unclear.
- Understanding these mechanisms is crucial for interspecies extrapolation and hazard assessment.
Purpose of the Study:
- To elucidate the molecular mechanisms of early embryonic developmental toxicity induced by TDCIPP in zebrafish.
- To investigate the role of beta-catenin signaling pathway in TDCIPP-induced toxicity.
- To compare the mode of action of TDCIPP with a known developmental toxicant, 6-bromoindirubin-3'-oxime (BIO).
Main Methods:
- Zebrafish embryos were exposed to varying concentrations of TDCIPP (100, 500, 1000 μg/L) and BIO (35.62 μg/L) as a positive control.
- Observed effects on blastomere cell stacking and epiboly progression during mid blastula transition (MBT) stage.
- Analyzed the expression and nuclear accumulation of beta-catenin protein.
- Investigated the interaction of TDCIPP and BIO with Gsk-3β protein and its phosphorylation status.
Main Results:
- TDCIPP and BIO exposure led to abnormal blastomere stacking and delayed epiboly in zebrafish embryos.
- Both TDCIPP and BIO significantly upregulated beta-catenin protein expression and increased its nuclear accumulation.
- TDCIPP and BIO inhibited Gsk-3β kinase activity by decreasing phosphorylation at the TYR·216 site.
- This inhibition of Gsk-3β activity resulted in elevated beta-catenin levels and nuclear accumulation.
Conclusions:
- TDCIPP-induced early embryonic developmental toxicity in zebrafish is mediated by the upregulation and nuclear accumulation of beta-catenin.
- TDCIPP shares partially overlapping mechanisms of action with BIO, involving the inhibition of Gsk-3β kinase activity.
- These findings provide novel insights into the molecular pathways affected by TDCIPP during early zebrafish development.
