title: Clinically approved iron chelators influence zebrafish mortality, hatching morphology and cardiac function.
abstract: 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.
authors.affiliation: The Centre for Blood Research, Department of Pathology and Laboratory Medicine, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Jasmine L
authors.initials: JL
authors.lastname: Hamilton
authors.affiliation: Veterinary Biomedical Sciences, Laboratory of Integrative Neuroendocrinology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors.forename: Azadeh
authors.initials: A
authors.lastname: Hatef
authors.affiliation: The Centre for Blood Research, Department of Pathology and Laboratory Medicine, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Imran ul-Haq
authors.affiliation: Veterinary Biomedical Sciences, Laboratory of Integrative Neuroendocrinology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors.forename: Neelima
authors.initials: N
authors.lastname: Nair
authors.affiliation: Veterinary Biomedical Sciences, Laboratory of Integrative Neuroendocrinology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors.forename: Suraj
authors.initials: S
authors.lastname: Unniappan
authors.affiliation: The Centre for Blood Research, Department of Pathology and Laboratory Medicine, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia, Canada; Department of Chemistry, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Jayachandran N
authors.initials: JN
authors.lastname: Kizhakkedathu
mesh_terms: D000818:Animals; D002302:Cardiac Output / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006321:Heart / Q000187:drug effects* / Q000502:physiology*; D006339:Heart Rate / Q000187:drug effects; D007502:Iron Chelating Agents / Q000633:toxicity*; D009026:Mortality; D012098:Reproduction / Q000187:drug effects*; D018675:Toxicity Tests; D015027:Zebrafish / Q000033:anatomy & histology / Q000196:embryology / Q000235:genetics / Q000502:physiology*; D029961:Zebrafish Proteins / Q000235:genetics
chemical_list: D007502:Iron Chelating Agents; D029961:Zebrafish Proteins