Improvement of the evaluation method for teratogenicity using zebrafish embryos.
The zebrafish has been considered as a suitable animal model for drug discovery, especially for evaluation of the teratogenicity, due to their small size, rapid development, transparency, and developmental similarities to mammalian development. These features of zebrafish make it possible to maintain them in culture plates, evaluate the teratogenicity in short term, conduct morphological assessment of each organ without any autopsy operation. The purpose of the present study was to improve an evaluation method for the teratogenicity of test compounds with high throughput ability and prediction rateusing zebrafish embryos. In this study, we established a modified evaluation method as using non-dechorionated embryos and observation a limited number of parameters without grading. Zebrafish embryos were exposed to test compounds from 5-6 to 144 hr post-fertilization, (hpf) corresponding to the organogenesis period. Morphological changes or functional abnormalities induced by test compound treatments were assessed and scored at 11 endpoints, and the potential of teratogenicity was judged based on the score. As a validation assay of the system, the potentials of 59 known teratogenic or non-teratogenic test compounds were evaluated using the present standard zebrafish assay, and the teratogenicity was correctly predicted in 90% (53/59) of all compounds with low false negative and false positive rates. These results indicated that the evaluation method using zebrafish for the teratogenicity we have improved was a valuable tool for early stage screening in drug discovery.
Preclinical Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd.
Akihito
A
Yamashita
Hiroshi
H
Inada
Kazuhiro
K
Chihara
Toru
T
Yamada
Jiro
J
Deguchi
Hitoshi
H
Funabashi
D000818:Animals; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004625:Embryo, Nonmammalian / Q000187:drug effects*; D005188:False Negative Reactions; D005189:False Positive Reactions; D057166:High-Throughput Screening Assays; D038081:Organogenesis / Q000187:drug effects; D064793:Teratogenesis / Q000187:drug effects*; D013723:Teratogens / Q000633:toxicity*; D018675:Toxicity Tests / Q000379:methods*; D015027:Zebrafish / Q000196:embryology*
D013723:Teratogens