Dithiocarbamates are teratogenic to developing zebrafish through inhibition of lysyl oxidase activity

Journal Article · Thu Apr 15 04:00:00 EDT 2010 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2009.12.028· OSTI ID:21344916

Boxtel, Antonius L. van, ^[1]; Kamstra, Jorke H ^[1]; Fluitsma, Donna M ^[2]; Legler, Juliette ^[1]

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1. Institute for Environmental Studies (IVM), VU University Amsterdam, De Boelelaan 1087, 1081 HV Amsterdam (Netherlands)
2. VU University Medical Centre (VUMC), VU University Amsterdam (Netherlands)

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.

• OSTI ID: 21344916
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 2 Vol. 244; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANIMALS
CARBAMATES
CARBONIC ACID DERIVATIVES
CARBOXYLIC ACID SALTS
CHELATING AGENTS
COMPLEXES
COPPER COMPLEXES
EMBRYOS
ENZYME INHIBITORS
ENZYMES
GENES
HALF-LIFE
MALES
MALFORMATIONS
MAMMALS
MAN
MEN
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANIC SULFUR COMPOUNDS
OXIDASES
OXIDOREDUCTASES
PATHOLOGICAL CHANGES
PESTICIDES
PRIMATES
PROTEINS
TERATOGENS
TOXICITY
TRANSITION ELEMENT COMPLEXES
VERTEBRATES