Methylxanthines induce structural and functional alterations of the cardiac system in zebrafish embryos
Ram Manohar Basnet1, Daniela Zizioli2, Michela Guarienti2
1Department of Molecular and Translational Medicine, University of Brescia, Viale Europa, 11, 25123, Brescia, Italy. rmb.basnet@gmail.com.
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.
Insights
Zebrafish embryos reveal varying toxicity of eight methylxanthines. Diprophylline showed minimal embryotoxicity and cardiac effects, while caffeine and others were highly toxic, impacting embryonic development and heart function.
Area of Science:
- Pharmacology
- Toxicology
- Developmental Biology
Background:
- Zebrafish embryos serve as a valuable model for pharmacological and toxicological research.
- Eight methylxanthines were investigated for their general toxicity and cardiovascular effects.
Purpose of the Study:
- To evaluate the embryotoxicity, teratogenicity, and cardiovascular effects of eight methylxanthines using zebrafish embryos.
- To compare the safety profiles of different methylxanthine compounds.
Main Methods:
- Methylxanthines were microinjected into zebrafish embryos at the 1-2 cell stage.
- Embryotoxicity, teratogenicity, and cardiac structural/functional alterations were assessed at various time points.
- Heart rate changes were monitored at 48 and 96 hours post-fertilization.
Main Results:
- Methylxanthines exhibited diverse toxicity; caffeine, IBMX, pentoxifylline, and theophylline were highly embryotoxic and teratogenic.
- Aminophylline, doxofylline, and etophylline showed toxicity at higher doses, while diprophylline exhibited minimal effects.
- Most methylxanthines induced fatal cardiac structural alterations and a transient increase in heart rate.
Conclusions:
- Methylxanthines pose potential risks of embryotoxicity, teratogenicity, and cardiac dysfunction during embryonic development.
- Diprophylline demonstrated a safer profile with lower toxicity compared to other methylxanthines studied.
- Findings highlight the importance of considering interspecies differences in methylxanthine toxicity assessments.
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