Clinically approved iron chelators influence zebrafish mortality, hatching morphology and cardiac function
| Autor: | Jayachandran N. Kizhakkedathu, Neelima Nair, Jasmine L. Hamilton, Azadeh Hatef, Muhammad Imran ul-haq, Suraj Unniappan |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
lcsh:Medicine
Toxicology chemistry.chemical_compound Heart Rate Medicine and Health Sciences Cardiac Output lcsh:Science Zebrafish Multidisciplinary biology Reproduction Fishes Embryo Heart Anemia Hematology Animal Models Dose–response relationship Osteichthyes Toxicity embryonic structures Vertebrates Deferiprone medicine.drug Research Article animal structures Iron Chelating Agents Research and Analysis Methods Excretion Andrology Model Organisms Toxicity Tests medicine Animals Mortality Molecular Biology Techniques Iron Deficiency Anemia Molecular Biology Molecular Biology Assays and Analysis Techniques Dose-Response Relationship Drug Hatching Deferasirox lcsh:R Organisms Biology and Life Sciences Zebrafish Proteins biology.organism_classification Hemoglobinopathies chemistry Gene Expression Regulation lcsh:Q |
| Zdroj: | PLoS ONE PLoS ONE, Vol 9, Iss 10, p e109880 (2014) |
| ISSN: | 1932-6203 |
| Popis: | Iron chelation therapy using iron (III) specific chelators such as desferrioxamine (DFO, Desferal), deferasirox (Exjade or ICL-670), and deferiprone (Ferriprox or L1) are the current standard of care for the treatment of iron overload. Although each chelator is capable of promoting some degree of iron excretion, these chelators are also associated with a wide range of well documented toxicities. However, there is currently very limited data available on their effects in developing embryos. In this study, we took advantage of the rapid development and transparency of the zebrafish embryo, Danio rerio to assess and compare the toxicity of iron chelators. All three iron chelators described above were delivered to zebrafish embryos by direct soaking and their effects on mortality, hatching and developmental morphology were monitored for 96 hpf. To determine whether toxicity was specific to embryos, we examined the effects of chelator exposure via intra peritoneal injection on the cardiac function and gene expression in adult zebrafish. Chelators varied significantly in their effects on embryo mortality, hatching and morphology. While none of the embryos or adults exposed to DFO were negatively affected, ICL -treated embryos and adults differed significantly from controls, and L1 exerted toxic effects in embryos alone. ICL-670 significantly increased the mortality of embryos treated with doses of 0.25 mM or higher and also affected embryo morphology, causing curvature of larvae treated with concentrations above 0.5 mM. ICL-670 exposure (10 µL of 0.1 mM injection) also significantly increased the heart rate and cardiac output of adult zebrafish. While L1 exposure did not cause toxicity in adults, it did cause morphological defects in embryos at 0.5 mM. This study provides first evidence on iron chelator toxicity in early development and will help to guide our approach on better understanding the mechanism of iron chelator toxicity. |
| Databáze: | OpenAIRE |
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