ToxSci Advance Access published online on February 14, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn010
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Glucocorticoids alter craniofacial development and increase expression and activity of matrix metalloproteinases in developing zebrafish (Danio rerio)
* Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901
To whom all correspondence should be addressed, Department of Biochemistry and Microbiology, 76 Lipman Drive, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901. Phone: 732-932-9763. Fax: 732-932-8965. Email: lawhite{at}aesop.rutgers.edu
Received October 25, 2007; revision received January 9, 2008; accepted January 10, 2008
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Abstract |
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Teratogenic effects are observed following long-term administration of glucocorticoids, although short-term glucocorticoid therapy is still utilized to reduce fetal mortality, respiratory distress syndrome and intraventricular hemorrhage in preterm infants. However, the mechanism of glucocorticoid-induced teratogenicity is unknown. We hypothesize that glucocorticoid-induced teratogenesis is mediated through the glucocorticoid receptor (GR) and results from altering the expression and activity of the matrix metalloproteinases (MMPs). During embryogenesis, degradation of the extracellular matrix to allow for proper cellular migration and tissue organization is a tightly regulated process requiring appropriate temporal and spatial expression and activity of the MMPs. Studies have demonstrated that MMP gene expression can be either inhibited or induced by glucocorticoids in a variety of model systems. Using the zebrafish (Danio rerio) as a model of development, the data presented here demonstrate that embryonic exposure to the glucocorticoids dexamethasone or hydrocortisone increased expression of two gelatinases, MMP-2 (
1.5-fold) and MMP-9 (7.6 to 9.0-fold), at 72 hours post-fertilization (hpf). Further, gelatinase activity was increased approximately 3-fold at 72 hpf following glucocorticoid treatment, and changes in craniofacial morphogenesis were also observed. Co-treatment of zebrafish embryos with each glucocorticoid and the GR antagonist RU486 resulted in attenuation of glucocorticoid-induced increases in MMP expression (52-84% decrease) and activity (41-94% decrease). Furthermore, the abnormal craniofacial phenotype observed following glucocorticoid exposure was less severe following RU486 co-treatment. These studies demonstrate that in the embryonic zebrafish, dexamethasone and hydrocortisone alter expression and activity of MMP-2 and -9, and suggest that these increases may be mediated through the GR
Key Words: zebrafish; glucocorticoids; matrix metalloproteinases; RU486; development.
jhillega{at}eden.rutgers.edu, cvillano{at}rci.rutgers.edu, cooper{at}aesop.rutgers.edu