Journal
ACTA PHARMACOLOGICA SINICA
Volume 34, Issue 8, Pages 1101-1107Publisher
ACTA PHARMACOLOGICA SINICA
DOI: 10.1038/aps.2013.48
Keywords
artemisinin; dihydroartemisinin; zebrafish; flk1; VEGF; angiogenesis; embryotoxicity
Funding
- Ministry of Science and Technology of China [2012BAK01B00, 2011BAK10B00, 2009CB919000]
- National Natural Science Foundation [81125020, 91029715, 31070680, 31101261, 81242002, 31200569]
- Science and Technology Commission of Shanghai Municipality [12XD1407000, 12431900500, 10391902100]
- Xuhui Central Hospital [CRC2011001, CRC2011004]
- Director Foundation [20090101]
- Key Labortory of Food Safety Research of Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
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Aim: To investigate the embryotoxicity of dihydroartemisinin (DHA), the main active metabolite of artemisinin, in zebrafish, and explore the corresponding mechanisms. Methods: The embryos of wild type and TG (flk1:GFP) transgenic zebrafish were exposed to DHA. Developmental phenotypes of the embryos were observed. Development of blood vessels was directly observed in living embryos of TG (flk1:GFP) transgenic zebrafish under fluorescence microscope. The expression of angiogenesis marker genes vegfa, flk1, and flt1 in the embryos was detected using real-time PCR and RNA in situ hybridization assays. Results: Exposure to DHA (1-10 mg/L) dose-dependently caused abnormal zebrafish embryonic phenotypes in the early developmental stage. Furthermore, exposure to DHA (10 mg/L) resulted in more pronounced embryonic angiogenesis in TG (flk1:GFP) zebrafish line. Exposure to DHA (10 mg/L) significantly increased the mRNA expression of vegfa, flk1, and flt1 in the embryos. Knockdown of the flk1 protein partially blocked the effects of DHA on embryogenesis. Conclusion: DHA causes abnormal embryonic phenotypes and promotes angiogenesis in zebrafish early embryonic development, demonstrating the potential embryotoxicity of DHA.
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