1. ZEBRAFISH EMBRYOS AS TOXICOLOGICAL MODELS
ZF: ZebraFish Model
Elisabet Teixidó
• Small size
Investigadora CERETOX • Short generation time (3-4 months)
elisabet.teixido@gmail.com
• Large number of offspring
• Ex utero development
• Rapid embryonic development
JORNADA TOX® •
•
Transparency of the embryos
Embryonic stages (≤ 5 dpf) are not regulated
1 de Febrero de 2013 • Evolutionary well-conserved human drug targets
Parc Científic de Barcelona
ZEBRAFISH EMBRYO TOXICITY TEST DEVELOPMENTAL TOXICOLOGY
Classification as teratogen
(+/-)
TI ZFET Mammals humans
(LC50/EC50) TI>1.5
Lethal and Valproic acid 3.3 + + + CRANIOFACIAL ALTERATIONS
teratogenic
+ + ?
endpoints Caffeine 6.2
CONTROL
Embryo exposure All-trans retinoic acid 26.8 + + +
Egg collection
Control of fertilization 26º C
success 14 h/10 h ligth/dark Methoxyacetic acid 2.9 + + ?
ETHANOL 1%
Salicylic sodium salt 3.2 + + -
Hydroxyurea 1.3 - + ?
What’s the difference?
Boric acid 2.9 + + +
Paraoxon-methyl 8.8 + - ?
D-(+)-glucose / - - -
Ascorbic acid / - - -
Overall concordance 80%!
SAFETY PHARMACOLOGY: CARDIOTOXICITY ASSAY WHAT CAN PROVIDE THE ZEBRAFISH MODEL?
Heartbeat regularity: QT prolonging drugs
VENTRICLE - ATRIUM Intermediate step between cell-based test and mammalian test
VENTRICULAR AND ATRIAL RATE
CONTROL VENTRICULAR RATE 250
Screening of chemical libraries
Heart rate (beats/min)
200
Ventricle
Atrium
150 Used as tool to group and prioritize chemicals
100
Reduce the number of mammals used in experimental toxicology
50
TERFENADINE
0
Control Terfenadine Isoprenaline
Potential to provide a level of predictivity as good or better than current
10µM 1mM
models
Stroke volume (pL) Cardiac output (pL/sec)
Control 239.7 ± 13.3 659.7 ± 26.6 Excellent model to study drug-induced cardiac irregularities such as QT
Terfenadine 10 µM 298.0 ± 18.1 346.9 ± 21.9
Isoprenaline 1 mM 326.5 ± 34.7 1108.7 ± 112.8
prolongation
1