PUBLICATION
Glucocorticoids alter craniofacial development and increase expression and activity of matrix metalloproteinases in developing zebrafish (Danio rerio)
- Authors
- Hillegass, J.M., Villano, C.M., Cooper, K.R., and White, L.A.
- ID
- ZDB-PUB-080306-5
- Date
- 2008
- Source
- Toxicological sciences : an official journal of the Society of Toxicology 102(2): 413-424 (Journal)
- Registered Authors
- Keywords
- zebrafish, glucocorticoids, matrix metalloproteinases, RU486, development
- MeSH Terms
-
- Animals
- Craniofacial Abnormalities/chemically induced*
- Craniofacial Abnormalities/metabolism
- Craniofacial Abnormalities/pathology
- Dexamethasone/toxicity*
- Dose-Response Relationship, Drug
- Drug Interactions
- Embryo, Nonmammalian/abnormalities
- Embryo, Nonmammalian/drug effects
- Embryo, Nonmammalian/enzymology
- Female
- Gene Expression Regulation, Developmental/drug effects
- Glucocorticoids/toxicity*
- Hormone Antagonists/pharmacology
- Hydrocortisone/toxicity*
- Matrix Metalloproteinase 2/genetics
- Matrix Metalloproteinase 2/metabolism*
- Matrix Metalloproteinase 9/genetics
- Matrix Metalloproteinase 9/metabolism*
- Mifepristone/pharmacology
- Receptors, Glucocorticoid/antagonists & inhibitors
- Zebrafish*
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 18281261 Full text @ Toxicol. Sci.
- CTD
- 18281261
Citation
Hillegass, J.M., Villano, C.M., Cooper, K.R., and White, L.A. (2008) Glucocorticoids alter craniofacial development and increase expression and activity of matrix metalloproteinases in developing zebrafish (Danio rerio). Toxicological sciences : an official journal of the Society of Toxicology. 102(2):413-424.
Abstract
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 ( approximately 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping