PUBLICATION
Dithiocarbamates are teratogenic to developing zebrafish through inhibition of lysyl oxidase activity
- Authors
- van Boxtel, A.L., Kamstra, J.H., Fluitsma, D.M., and Legler, J.
- ID
- ZDB-PUB-100105-41
- Date
- 2010
- Source
- Toxicology and applied pharmacology 244(2): 156-161 (Journal)
- Registered Authors
- Legler, Juliette
- Keywords
- Dithiocarbamate, Teratogenic, Zebrafish, Lysyl oxidase, Inhibition, Developmental toxicity, Pesticide
- MeSH Terms
-
- Abnormalities, Drug-Induced/embryology
- Abnormalities, Drug-Induced/enzymology*
- Animals
- Enzyme Inhibitors/toxicity
- Gene Knockdown Techniques/methods
- Protein-Lysine 6-Oxidase/antagonists & inhibitors*
- Protein-Lysine 6-Oxidase/genetics
- Protein-Lysine 6-Oxidase/metabolism*
- Teratogens/toxicity*
- Thiocarbamates/toxicity*
- Zebrafish
- Zebrafish Proteins/antagonists & inhibitors*
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- PubMed
- 20045017 Full text @ Tox. App. Pharmacol.
- CTD
- 20045017
Citation
van Boxtel, A.L., Kamstra, J.H., Fluitsma, D.M., and Legler, J. (2010) Dithiocarbamates are teratogenic to developing zebrafish through inhibition of lysyl oxidase activity. Toxicology and applied pharmacology. 244(2):156-161.
Abstract
Dithiocarbamates (DTCs) are a class of compounds that are extensively used in agriculture as pesticides. As such humans and wildlife are undoubtedly exposed to these chemicals. Although DTCs are thought to be relatively safe due to their short half lives, it is well established that they are teratogenic to vertebrates, especially to fish. In zebrafish these teratogenic effects are characterized by distorted notochord development and shortened anterior to posterior axis. DTCs are known copper (Cu) chelators but this does not fully explain the observed teratogenic effects. We show here that DTCs cause malformations in zebrafish that highly resemble teratogenic effects observed by direct inhibition of a group of cuproenzymes termed lysyl oxidases (LOX). Additionally, we demonstrate that partial knockdown of three LOX genes, lox, loxl1 and loxl5b, sensitizes the developing embryo to DTC exposure. Finally, we show that DTCs directly inhibit zebrafish LOX activity in an ex vivo amine oxidase assay. Taken together, these results provide the first evidence that DTC induced teratogenic effects are, at least in part, caused by direct inhibition of LOX activity.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping