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Updated: Jun 25, 2026
A Doxorubicin-induced Cardiomyopathy Model in Adult Zebrafish
Published on: June 7, 2018
Exposure to the antineoplastic ifosfamide alters molecular pathways related to cardiovascular function, increases
Cole D English1, Kira J Kazi1, Isaac Konig2
1Center for Environmental and Human Toxicology, Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32611, USA.
Abstract:
Ifosfamide is an alkylating antineoplastic drug used in chemotherapy, but it is also detected in wastewater. Here, the objectives were to (1) determine teratogenic, cardiotoxic, and mitochondrial toxicity potential of ifosfamide exposure; (2) elucidate mechanisms of toxicity; (3) characterize exposure effects on larval behavior. Survival rate, hatch rate, and morphological deformity incidence were not different amongst treatments following exposure levels up to 1000 µg/L ifosfamide over 7 days. RNA-seq reveled 231 and 93 differentially expressed transcripts in larvae exposed to 1 µg/L and 100 µg/L ifosfamide, respectively. Several gene networks related to vascular resistance, cardiovascular response, and heart rate were affected, consistent with tachycardia observed in exposed embryonic fish. Hyperactivity in larval zebrafish was observed with ifosfamide exposure, potentially associated with dopamine-related gene networks. This study improves ecological risk assessment of antineoplastics by elucidating molecular mechanisms related to ifosfamide toxicity, and to alkylating agents in general.
Insights
Ifosfamide exposure in zebrafish larvae did not cause developmental deformities but altered gene expression and behavior. This research clarifies toxicity mechanisms for environmental risk assessment of chemotherapy drugs.
Area of Science:
- Environmental Toxicology
- Molecular Pharmacology
- Ecotoxicology
Background:
- Ifosfamide, an alkylating antineoplastic drug, is a pharmaceutical pollutant found in wastewater.
- Understanding the ecotoxicological impact of ifosfamide is crucial for environmental risk assessment.
Purpose of the Study:
- To assess the teratogenic, cardiotoxic, and mitochondrial toxicity of ifosfamide in aquatic organisms.
- To elucidate the molecular mechanisms underlying ifosfamide toxicity.
- To characterize behavioral changes in larval zebrafish upon ifosfamide exposure.
Main Methods:
- Zebrafish larvae were exposed to varying concentrations of ifosfamide (up to 1000 µg/L) over 7 days.
- Survival, hatch rates, and morphological deformities were assessed.
- RNA sequencing (RNA-seq) was employed to analyze gene expression changes, and larval behavior was observed.
Main Results:
- No significant differences in survival, hatch rate, or morphology were observed at tested ifosfamide concentrations.
- RNA-seq identified differential expression of transcripts related to cardiovascular function and vascular resistance.
- Tachycardia and hyperactivity were observed in ifosfamide-exposed zebrafish larvae, linked to dopamine-related gene networks.
Conclusions:
- Ifosfamide exposure at environmentally relevant levels can induce sub-lethal effects, including cardiovascular and behavioral alterations in zebrafish.
- Molecular mechanisms involve changes in gene networks regulating heart rate and neurotransmission.
- This study provides valuable insights into the ecological risks of ifosfamide and similar antineoplastic agents.
