title: Potential teratogenicity of methimazole: exposure of zebrafish embryos to methimazole causes similar developmental anomalies to human methimazole embryopathy.
abstract: While methimazole (MMI) is widely used in the therapy for hyperthyroidism, several groups have reported that maternal exposure to MMI results in a variety of congenital anomalies, including choanal and esophageal atresia, iridic and retinal coloboma, and delayed neurodevelopment. Thus, adverse effects of maternal exposure to MMI on fetal development have long been suggested; however, direct evidence for the teratogenicity of MMI has not been presented. Therefore, we studied the effects of MMI on early development by using zebrafish as a model organism. The fertilized eggs of zebrafish were collected immediately after spawning and grown in egg culture water containing MMI at various concentrations. External observation of the embryos revealed that exposure to high concentrations of MMI resulted in loss of pigmentation, hypoplastic hindbrain, turbid tissue in the forebrain, swelling of the notochord, and curly trunk. Furthermore, these effects occurred in a dose-dependent manner. Precise observation of the serial cross-sections of MMI-exposed embryos elucidated delayed development and hypoplasia of the whole brain and spinal cord, narrowing of the pharynx and esophagus, severe disruption of the retina, and aberrant structure of the notochord. These neuronal, pharyngeal, esophageal, and retinal anomalous morphologies have a direct analogy to the congenital anomalies observed in children exposed to MMI in utero. Here, we show the teratogenic effects of MMI on the development of zebrafish and provide the first experimental evidence for the connection between exposure to MMI and human MMI embryopathy.
authors: Department of Hygiene and Public Health I, Tokyo Women's Medical University, Tokyo 162-8666, Japan. komoike@research.twmu.ac.jp
authors: Yuta
authors: Y
authors: Komoike
authors: Masato
authors: M
authors: Matsuoka
authors: Kenjiro
authors: K
authors: Kosaki
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000002:abnormalities / Q000187:drug effects / Q000196:embryology / Q000473:pathology; D004625:Embryo, Nonmammalian / Q000002:abnormalities* / Q000187:drug effects / Q000473:pathology; D004781:Environmental Exposure / Q000009:adverse effects*; D004947:Esophagus / Q000002:abnormalities / Q000187:drug effects / Q000196:embryology / Q000473:pathology; D005315:Fetal Diseases / Q000139:chemically induced*; D006801:Humans; D008713:Methimazole / Q000009:adverse effects*; D009672:Notochord / Q000002:abnormalities / Q000187:drug effects / Q000196:embryology / Q000473:pathology; D010614:Pharynx / Q000002:abnormalities / Q000187:drug effects / Q000196:embryology / Q000473:pathology; D012160:Retina / Q000002:abnormalities / Q000187:drug effects / Q000196:embryology / Q000473:pathology; D013116:Spinal Cord / Q000002:abnormalities / Q000187:drug effects / Q000196:embryology / Q000473:pathology; D013723:Teratogens / Q000633:toxicity*; D015027:Zebrafish / Q000002:abnormalities* / Q000196:embryology*
chemical_list: D013723:Teratogens; D008713:Methimazole