Phenotype anchoring in zebrafish reveals a potential role for matrix metalloproteinases (MMPs) in tamoxifen's effects on skin epithelium.

摘要: The zebrafish is a powerful alternative model used to link phenotypes with molecular effects discover drug mode of action. Using embryo-larval toxicity bioassay, we evaluated the tamoxifen--a widely anti-estrogen chemotherapeutic. Zebrafish exposed ≥ 10 μM tamoxifen exhibited unique necrotic caudal fin phenotype that was rapidly induced regardless developmental life-stage when treatment applied. To define tamoxifen's bioactivity resulting in this phenotype, targeted gene expression evaluate 100 transcripts involved tissue remodeling, calcium signaling, cell cycle and death, growth factors, angiogenesis hypoxia. most robustly misregulated tail were matrix metalloproteinases mmp9 mmp13a, 127 1145 fold, respectively. Expression c-fos, c-jun, ap1s1 also moderately elevated (3-7 fold), consistent AP-1 activity--a transcription factor regulates MMP expression. Immunohistochemistry confirmed high levels induction for MMP13a affected skin epithelial tissue. significantly attenuated or prevented by three functionally inhibitors: EDTA (metal chelator), GM 6001 (broad inhibitor), SR 11302 (AP-1 suggesting MMP-dependence. inhibited mmp9, putative target, igfbp1a. Overall, our studies suggest effect result perturbation system leading ectopic expression, cytotoxicity, phenotype. These help advance understanding non-classical action implicate possible role MMPs tissues such as skin.