Institute for Environmental Studies (IVM), VU University Amsterdam, De Boelelaan 1087, 1081 HV Amsterdam, The Netherlands.
Toxicol Appl Pharmacol. 2010 Apr 15;244(2):156-61. doi: 10.1016/j.taap.2009.12.028. Epub 2010 Jan 4.
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.
二硫代氨基甲酸盐（DTCs）是一类广泛应用于农业作为农药的化合物。因此，人类和野生动物无疑会接触到这些化学物质。尽管由于其半衰期短，DTCs 被认为相对安全，但已经证实它们对脊椎动物，特别是鱼类具有致畸性。在斑马鱼中，这些致畸作用的特征是脊索发育扭曲和前后轴缩短。DTCs 是已知的铜（Cu）螯合剂，但这并不能完全解释观察到的致畸作用。我们在这里表明，DTCs 会导致斑马鱼畸形，这些畸形与直接抑制一组称为赖氨酰氧化酶（LOX）的铜酶的致畸作用非常相似。此外，我们证明了三个 LOX 基因，lox、loxl1 和 loxl5b 的部分敲低，使发育中的胚胎对 DTC 暴露敏感。最后，我们表明 DTCs 在体外胺氧化酶测定中直接抑制斑马鱼 LOX 活性。总之，这些结果首次提供了证据表明，DTC 诱导的致畸作用至少部分是由 LOX 活性的直接抑制引起的。
