PUBLICATION
Methylxanthines induce structural and functional alterations of the cardiac system in zebrafish embryos
- Authors
- Basnet, R.M., Zizioli, D., Guarienti, M., Finazzi, D., Memo, M.
- ID
- ZDB-PUB-171117-12
- Date
- 2017
- Source
- BMC pharmacology & toxicology 18: 72 (Journal)
- Registered Authors
- Keywords
- Cardiac dysfunction, Embryotoxicity, Heart rate, Methylxanthines, Teratogenicity
- MeSH Terms
-
- Animals
- Embryo, Nonmammalian
- Heart/drug effects*
- Heart/embryology
- Heart/physiology
- Heart Rate/drug effects
- Xanthines/toxicity*
- Zebrafish
- PubMed
- 29141695 Full text @ BMC Pharmacol Toxicol
Citation
Basnet, R.M., Zizioli, D., Guarienti, M., Finazzi, D., Memo, M. (2017) Methylxanthines induce structural and functional alterations of the cardiac system in zebrafish embryos. BMC pharmacology & toxicology. 18:72.
Abstract
Background Zebrafish embryos are emerging as a model for pharmacological and toxicological studies. We used zebrafish embryos to study the general toxicity and cardiovascular effects of eight methylxanthines: aminophylline, caffeine, diprophylline, doxofylline, etophylline, 3-isobutyl-1-methylxanthine (IBMX), pentoxifylline and theophylline.
Methods Microinjections of the eight methylxanthines were performed in 1-2 cell stage zebrafish embryos and the general toxicity and cardiovascular effects were analyzed at different time points. Embryotoxicity and teratogenicity were evaluated to understand the general toxicity of these compounds. Structural and functional alterations of the heart were evaluated to assess the cardiovascular effects.
Results Our results showed different activity patterns of the methylxanthines drugs. Caffeine, IBMX, pentoxifylline and theophylline were highly embryotoxic and teratogenic; aminophylline, doxofylline and etophylline were embryotoxic and teratogenic only at higher doses, and diprophylline showed a minimal (<10%) embryotoxicity and teratogenicity. Most of these drugs induced structural alteration of the heart in 20-40% of the injected embryos with the maximum dose. This structural alteration was fatal with the embryos ultimately dying within 120 hpf. All the drugs induced a transient increase in heart rate at 48 hpf which returned to baseline within 96 hpf. This functional effect of methylxanthines showed similarity to the studies done in humans and other vertebrates.
Conclusion Our results indicate the potential toxicity and teratogenicity of different methylxanthines in the embryos during embryonic development, the most sensitive period of life. Although interspecies differences need to be considered before drawing any conclusion, our study elucidated that a single exposure of methylxanthines at therapeutic range could induce cardiac dysfunction besides causing embryotoxicity and teratogenicity. Of all the drugs, diprophylline appeared to be safer, with lower degree of embryotoxicity, teratogenicity and cardiac toxicity as compared to other methylxanthines.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping