Characterization of ticlopidine-induced developmental and teratogenic defects in Xenopus embryos and human endothelial cells

• Ticlopidine dose-dependently induces developmental toxicities and embryonic malformations in Xenopus embryos.
• Ticlopidine treatment induces cardiac and hepatic defects.
• Ticlopidine treatment causes hemorrhagic malformations.
• Ticlopidine treatment inhibits blood and lymph vessel formation in Xenopus tadpoles.
• Ticlopidine treatment inhibits VEGF-induced angiogenesis in HUVECs.

Ticlopidine is an anti-platelet drug that inhibits platelet aggregation via the functional alteration of platelet membranes. However, the mechanism underlying the adverse developmental effects of ticlopidine has not been clearly demonstrated. In this study, we evaluated the developmental toxicity and teratogenicity of ticlopidine on Xenopus laevis embryos and in human umbilical vein endothelial cells (HUVECs) using a frog embryo teratogenesis assay-Xenopus (FETAX) and blood and lymph vessel formation assays. Ticlopidine induced teratogenicity and inhibited growth, as evidenced by mortality rates and embryo lengths, respectively. Moreover, ticlopidine induced severe hemorrhages and inhibited both blood and lymph vessel formation by modulating the expression of xMsr and Prox1 in Xenopus embryos. Additionally, Nkx2.5 and Cyl104 levels were perturbed by ticlopidine exposure, and more extensive aberrations were observed in the liver and heart using whole-mount in situ hybridization. In addition, ticlopidine reduced branching in HUVECs by blocking the effect of the angiogenic vascular endothelial growth factor (VEGF). Results from this study suggest that ticlopidine is a developmental toxicant and teratogen and therefore this is a step forward in our understanding of the effects of ticlopidine during developmental processes.