Experimental Dissection of Metalloproteinase Inhibition-Mediated and Toxic Effects of Phenanthroline on Zebrafish Development.
Metalloproteinases are zinc-dependent endopeptidases that function as primary effectors of tissue remodeling, cell-signaling, and many other roles. Their regulation is ferociously complex, and is exquisitely sensitive to their molecular milieu, making in vivo studies challenging. Phenanthroline (PhN) is an inexpensive, broad-spectrum inhibitor of metalloproteinases that functions by chelating the catalytic zinc ion, however its use in vivo has been limited due to suspected off-target effects. PhN is very similar in structure to phenanthrene (PhE), a well-studied poly aromatic hydrocarbon (PAH) known to cause toxicity in aquatic animals by activating the aryl hydrocarbon receptor (AhR). We show that zebrafish are more sensitive to PhN than PhE, and that PhN causes a superset of the effects caused by PhE. Morpholino knock-down of the AhR rescues the effects of PhN that are shared with PhE, suggesting these are due to PAH toxicity. The effects of PhN that are not shared with PhE (specifically disruption of neural crest development and angiogenesis) involve processes known to depend on metalloproteinase activity. Furthermore these PhN-specific effects are not rescued by AhR knock-down, suggesting that these are bona fide effects of metalloproteinase inhibition, and that PhN can be used as a broad spectrum metalloproteinase inhibitor for studies with zebrafish in vivo.
Department of Biology, University of New Brunswick, Fredericton, NB E3B 5A3, Canada. tellis9@uwo.ca.
Tonya R
TR
Ellis
Department of Biology, University of New Brunswick, Fredericton, NB E3B 5A3, Canada. bryanc@unb.ca.
Bryan D
BD
Crawford
D000818:Animals; D047108:Embryonic Development / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D045726:Metalloproteases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009432:Neural Crest / Q000187:drug effects; D010618:Phenanthrolines / Q000494:pharmacology* / Q000633:toxicity; D011485:Protein Binding; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004791:Enzyme Inhibitors; D010618:Phenanthrolines; D029961:Zebrafish Proteins; D045726:Metalloproteases
angiogenesis; aryl hydrocarbon receptor; in vivo study; metalloproteinase; metalloproteinase inhibitor; neural crest; phenanthroline; poly aromatic hydrocarbon toxicity; zebrafish