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Zebrafish as a Model to Assess the Teratogenic Potential of Nitrite
Published on: February 16, 2016
Modelling lethality and teratogenicity of zebrafish (Danio rerio) due to β-lactam antibiotics employing the QSTR
1Drug Discovery and Development Laboratory (DDD Lab), Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India.
Abstract:
Nowadays, β-lactam antibiotics are one of the most consumed OTC (over-the-counter) medicines in the world. Its frequent use against several infectious diseases leads to the development of antibiotic resistance. Another unavoidable risk factor of β-lactam antibiotics is environmental toxicity. Numerous terrestrial as well as aquatic species have suffered due to the excessive use of these pharmaceuticals. In this present study, we have performed a toxicity assessment employing a novel in silico technique like quantitative structure-toxicity relationships (QSTRs) to explore toxicity against zebrafish (Danio rerio). We have developed single as well as inter-endpoint QSTR models for the β-lactam compounds to explore important structural attributes responsible for their toxicity, employing median lethal (LC50) and median teratogenic concentration (TC50) as the endpoints. We have shown how an inter-endpoint model can extrapolate unavailable endpoint values with the help of other available endpoint values. To verify the models' robustness, predictivity, and goodness-of-fit, several universally popular metrics for both internal and external validation were extensively employed in model validation (single endpoint models: r2 = 0.631 - 0.75, Q2F1 = 0.607 - 0.684; inter-endpoint models: r2 = 0.768 - 0.84, Q2F1 = 0.678 - 0.76). Again, these models were engaged in the prediction of these two responses for a true external set of β-lactam molecules without response values to prove the reproducibility of these models.
Insights
Quantitative structure-toxicity relationship (QSTR) models were developed to assess the environmental toxicity of beta-lactam antibiotics. These models predict toxicity in zebrafish, identifying key structural factors contributing to harm.
Area of Science:
- Environmental Toxicology
- Computational Chemistry
- Pharmacology
Background:
- Beta-lactam antibiotics are widely used over-the-counter (OTC) medicines, contributing to antibiotic resistance.
- Excessive use of these pharmaceuticals poses significant environmental risks, impacting aquatic and terrestrial species.
- Understanding the ecotoxicity of beta-lactams is crucial for mitigating environmental damage.
Purpose of the Study:
- To develop and validate in silico quantitative structure-toxicity relationship (QSTR) models for beta-lactam environmental toxicity.
- To identify structural attributes of beta-lactams that correlate with toxicity endpoints.
- To assess the predictive power of single and inter-endpoint QSTR models for zebrafish (Danio rerio) toxicity.
Main Methods:
- Development of single and inter-endpoint QSTR models using median lethal concentration (LC50) and median teratogenic concentration (TC50) data.
- Application of robust internal and external validation metrics (r², Q²F1) to assess model performance.
- Prediction of toxicity for an external set of beta-lactam molecules lacking response values to demonstrate model reproducibility.
Main Results:
- Single endpoint QSTR models achieved good fit and predictivity (r² = 0.631–0.75, Q²F1 = 0.607–0.684).
- Inter-endpoint QSTR models demonstrated enhanced performance and extrapolation capabilities (r² = 0.768–0.84, Q²F1 = 0.678–0.76).
- Validated models successfully predicted toxicity for external beta-lactam compounds, confirming reproducibility.
Conclusions:
- QSTR modeling provides a reliable in silico approach for assessing beta-lactam environmental toxicity.
- Inter-endpoint models offer a valuable strategy for extrapolating toxicity data and identifying key structural drivers.
- These findings support the development of safer pharmaceutical alternatives and informed environmental risk assessment.
