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Acta Biochimica et Biophysica Sinica 2009 41(1):86-96; doi:10.1093/abbs/gmn010
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© The Author 2009. Published by ABBS Editorial Office in association with Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences

Effects of methotrexate on the developments of heart and vessel in zebrafish

Shuna Sun1, Yonghao Gui1,*, Yuexiang Wang2, Linxi Qian2, Xuefei Liu2, Qiu Jiang2 and Houyan Song2

1 Children's Hospital, Fudan University, Shanghai 201102, China
2 Department of Molecular Genetics, Shanghai Medical College and Key Laboratory of Molecular Medicine, Ministry of Education, Fudan University, Shanghai, 200032, China

* Corresponding author: Tel, 86-21-6403-7254; Fax, 86-21-6403-8992; E-mail, yhgui{at}shmu.edu.cn


  Abstract

Methotrexate (MTX), an antagonist of folic acid, can inhibit dihydrofolate reductase (DHFR) which is of great importance in the synthesis of tetrahydrofolic acid and embryonic development. In this study, we found that after being exposed to 1.5 mM MTX at 6–10 hours post-fertilization, zebrafish embryos fail to form normal cardiovascular system. In MTX-treated embryos, the morphological development of ventricle and atrium was disrupted, the cardiac twist was abnormal, the heart rate and ventricular shortening fraction were reduced, and the vascular development was disrupted. We also found that either microinjection with dhfr–gfp mRNA or treatment with folinic acid calcium salt pentahydrate (CF) could cause improved development in the heart and vessels in MTX-treated embryos, which proved that MTX induced the malformations by inhibiting DHFR. The transcript levels of genes such as hand2, mef2a, mef2c, and flk-1 were reduced in MTX-treated embryos. Compared with the MTX-treated group, the transcript levels of hand2, mef2a, mef2c, and flk-1 were increased in the MTX + dhfr–gfp mRNA-injected group and in the MTX + CF group. Our results indicated that the disrupted development of the heart and vessels in MTX-treated embryos is related to the reduced transcript levels of hand2, mef2a, mef2c, and flk-1.

Keywords    methotrexate; folic acid; heart; vessel; gene transcript level; zebrafish

Received: May 30, 2008; Accepted: September 16, 2008
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