Exposure to the JNK inhibitor SP600125 (anthrapyrazolone) during early zebrafish development results in morphological defects

J Appl Toxicol. 2013 Jan;33(1):32-40. doi: 10.1002/jat.1708. Epub 2011 Jul 13.


SP600125 (anthrapyrazolone) is a synthetic polyaromatic chemical that inhibits c-Jun N-terminal kinase (JNK) signaling by interfering with phosphorylation of c-Jun. To determine the pharmacological impact of SP600125 on zebrafish development, we incubated embryos in various concentrations of SP600125 from 18 h postfertilization (hpf) to 48 hpf. Embryos treated with 1.25 µm appeared with occasional pericardium edema. Treatment with 12.5 µm resulted in complete mortality by 120 hpf, preventing an assessment of physiological defects. Embryos treated with 5 µm exhibited slowed overall growth, a delay in hatching and numerous morphological defects such as pericardium edema, yolk sac edema, swim bladder deflation, bent vertebrae and eye and jaw malformations. Whole-mount immunohistochemical studies using an anti-acetylated β-tubulin antibody confirmed developmental defects in the nervous system. Within the retina, fish treated with 1.25 µm showed a mild reduction of immunoreactivity. Immunoreactivity in the retina was further reduced in fish treated with 5 µm of SP600125. In these fish, eyes and olfactory organs were half the size compared with other groups. Multiple lenses were observed in 67% of these fish. A second experiment with a shorter exposure period of SP600125 (6 h) presented significantly fewer morphological defects. The treatment led to a delay in hatching, and increased incidences of swim bladder deflation and pericardium edema with increasing concentrations. In summary, SP600125 caused developmental abnormalities during zebrafish organogenesis starting at 1.25 µm and the defects were exacerbated with increasing concentrations. Our study suggests that SP600125 at 1.25 µm and beyond has devastating consequences for zebrafish development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Drug-Induced / enzymology
  • Abnormalities, Drug-Induced / etiology*
  • Abnormalities, Drug-Induced / pathology
  • Air Sacs / abnormalities
  • Air Sacs / drug effects
  • Air Sacs / enzymology
  • Animals
  • Anthracenes / toxicity*
  • Embryo, Nonmammalian / drug effects*
  • Embryo, Nonmammalian / embryology
  • Embryo, Nonmammalian / enzymology
  • Enzyme Inhibitors / toxicity*
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Longevity / drug effects
  • Nervous System Malformations / chemically induced*
  • Nervous System Malformations / enzymology
  • Nervous System Malformations / pathology
  • Olfactory Bulb / abnormalities
  • Olfactory Bulb / drug effects
  • Olfactory Bulb / enzymology
  • Pericardial Effusion / chemically induced
  • Pericardial Effusion / enzymology
  • Pericardial Effusion / pathology
  • Retina / abnormalities
  • Retina / drug effects
  • Retina / enzymology
  • Time Factors
  • Zebrafish


  • Anthracenes
  • Enzyme Inhibitors
  • pyrazolanthrone
  • JNK Mitogen-Activated Protein Kinases