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Updated: Mar 14, 2026
Rapid Evaluation of Toxicity of Chemical Compounds Using Zebrafish Embryos
Published on: August 25, 2019
Mycophenolic Acid-Induced Developmental Defects in Zebrafish Embryos
Ling-Ling Jiang1, Mei-Hui Liu2, Jian-Ying Li3
1Institute of Translational Medicine, College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, People's Republic of China.
Abstract:
With the increasing use of mycophenolic acid (MPA) in solid organ transplantation, some clinical studies indicate that it is also a human teratogen. However, it is unknown by which mechanism MPA acts as a teratogen. Mycophenolic acid was a selective blocker of de novo purine synthesis, and its immunosuppressive effect is mediated by the inhibition of inosine monophosphate dehydrogenase, which could be a target for MPA-induced toxicity as well. The aim of our study was to examine the direct influence of MPA exposure on zebrafish (Danio rerio) embryos. Morphological defects including tail curvature and severe pericardial edema in zebrafish embryos caused by MPA (3.7-11.1 µmol/L) were found in a dose-dependent manner. The teratogenic index (25% lethal concentration value (LC25)/no observed adverse effect level ratio) was 16, which indicated MPA as a teratogen. Quantitative polymerase chain reaction analysis revealed that the expression level of impdh1b and impdh2 was significantly reduced by MPA treatment at 8 µmol/L (equals to LC25 level). All the toxic effects could be partially reversed by the addition of 33.3 µmol/L guanosine. Our results indicated that MPA impairs the development of zebrafish embryos via inhibition of impdh activity, which subsequently caused a guanosine nucleotide depletion in vivo.
Insights
Mycophenolic acid (MPA) causes birth defects in zebrafish embryos by inhibiting purine synthesis. Adding guanosine partially reversed these toxic effects, suggesting a mechanism involving nucleotide depletion.
Area of Science:
- Developmental toxicology
- Pharmacology
- Molecular biology
Background:
- Mycophenolic acid (MPA) is increasingly used in organ transplantation.
- Clinical studies suggest MPA is a human teratogen, but its mechanism is unclear.
- MPA inhibits de novo purine synthesis via inosine monophosphate dehydrogenase (IMPDH).
Purpose of the Study:
- To investigate the teratogenic effects of MPA on zebrafish embryos.
- To elucidate the mechanism underlying MPA-induced teratogenicity.
Main Methods:
- Zebrafish embryos were exposed to varying concentrations of MPA.
- Morphological defects were assessed.
- Quantitative polymerase chain reaction (qPCR) was used to analyze gene expression.
- Reversal studies with guanosine were performed.
Main Results:
- MPA caused dose-dependent morphological defects (tail curvature, pericardial edema) in zebrafish embryos.
- MPA significantly reduced impdh1b and impdh2 expression at the LC25 level.
- The teratogenic index was calculated as 16, confirming MPA's teratogenicity.
- Co-administration of guanosine partially reversed MPA-induced toxicity.
Conclusions:
- MPA is a teratogen in zebrafish embryos.
- MPA impairs embryonic development by inhibiting IMPDH activity.
- This inhibition leads to guanosine nucleotide depletion, causing developmental toxicity.
