Characterization of ticlopidine-induced developmental and teratogenic defects in Xenopus embryos and human endothelial cells.
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.
Aquaculture Management Division, National Fisheries Research and Development Institute, Busan, 619-705, South Korea.
Mi Seon
MS
Park
ABRC, CMRI, School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, 702-701, South Korea.
Jong-Woo
JW
Kim
ABRC, CMRI, School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, 702-701, South Korea.
Inji
I
Park
ABRC, CMRI, School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, 702-701, South Korea.
Hyun-Kyung
HK
Lee
ABRC, CMRI, School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, 702-701, South Korea.
Chowon
C
Kim
ABRC, CMRI, School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, 702-701, South Korea.
Changrae
C
Jo
ABRC, CMRI, School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, 702-701, South Korea.
Yoo-Kyung
YK
Kim
Aquaculture Management Division, National Fisheries Research and Development Institute, Busan, 619-705, South Korea.
Byung-Hwa
BH
Min
ABRC, CMRI, School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, 702-701, South Korea.
Jaewoong
J
Ryoo
ABRC, CMRI, School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, 702-701, South Korea.
Dong-Seok
DS
Lee
College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, 702-701, South Korea.
Jong-Sup
JS
Bae
Department of Pharmacology, College of Medicine, Kyungpook National University, Daegu, 700-422, South Korea.
Sang-Hyun
SH
Kim
Department of Pharmacology and Biomedical Science, Seoul National University College of Medicine, Seoul, 110-799, South Korea.
Sang Kyu
SK
Ye
Department of Anatomy, College of Medicine, Kyungpook National University, Daegu, 700-422, South Korea.
Mae-Ja
MJ
Park
ABRC, CMRI, School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, 702-701, South Korea. Electronic address: leeh@knu.ac.kr.
Hyun-Shik
HS
Lee
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004625:Embryo, Nonmammalian / Q000187:drug effects*; D042783:Endothelial Cells / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D013723:Teratogens / Q000633:toxicity*; D013988:Ticlopidine / Q000633:toxicity*; D014982:Xenopus laevis / Q000196:embryology*
D013723:Teratogens; D013988:Ticlopidine
Developmental toxicity; Embryogenesis; Teratogenicity; Ticlopidine; Xenopus