Psychoactive pharmaceuticals as environmental contaminants may disrupt highly inter-connected nodes in an Autism-associated protein-protein interaction network.
Psychoactive pharmaceuticals as environmental contaminants may disrupt highly inter-connected nodes in an Autism-associated protein-protein interaction network.
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DOI：
10.1186/1471-2105-16-s7-s3
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发表时间：
2015
影响因子：
3
通讯作者：
Aho KA
中科院分区：
文献类型：
--
作者：
Kaushik G;Thomas MA;Aho KA
大多数特发性自闭症谱系障碍（ASD）病例可能是由遗传易感个体的未知环境触发因素引起的。这些触发因素可能包括胎儿母体暴露于微量药物，如卡马西平（CBZ）、文拉法辛（VNX）和氟西汀（FLX）。未代谢的药物通过各种途径进入饮用水，包括未经有效处理的污水。我们实验室以前的研究检查了用药物处理的小鱼大脑中基因组富集的程度。在这里，我们测试了一个假设，即鱼脑和人类细胞培养物中的基因，通过药物显着富集，在ASD相关蛋白质相互作用网络中具有独特的特征。我们通过使用10个网络指数比较这些组来实现这一点。生成了7212个蛋白质和33，461个相互作用的网络。我们发现，特定药物的富集基因集的网络特征彼此不同，并且与非富集ASD基因集不同。特别是，鱼脑中被CBZ和VNX富集的基因1）比整体网络中的基因具有更高的网络重要性，而那些被FLX富集的基因，以及2）在多元网络空间中与FLX和非富集的ASD基因不同。类似地，药物混合物（环境浓度）和丙戊酸盐（临床剂量）富集的人类细胞培养物中的基因具有相似的网络特征，并且比整个ASD网络中的基因具有更大的网络重要性。结果表明，ASD网络中的重要基因集特别容易受到环境浓度下药物的干扰。
Most cases of idiopathic autism spectrum disorder (ASD) likely result from unknown environmental triggers in genetically susceptible individuals. These triggers may include maternal exposure of a fetus to minute concentrations of pharmaceuticals, such as carbamazepine (CBZ), venlafaxine (VNX) and fluoxetine (FLX). Unmetabolized pharmaceuticals reach drinking water through a variety of routes, including ineffectively treated sewage. Previous studies in our laboratory examined the extent to which gene sets were enriched in minnow brains treated with pharmaceuticals. Here, we tested the hypothesis that genes in fish brains and human cell cultures, significantly enriched by pharmaceuticals, would have distinct characteristics in an ASD-associated protein interaction network. We accomplished this by comparing these groups using 10 network indices. A network of 7212 proteins and 33,461 interactions was generated. We found that network characteristics for enriched gene sets for particular pharmaceuticals were distinct from each other, and were different from non-enriched ASD gene sets. In particular, genes in fish brains, enriched by CBZ and VNX 1) had higher network importance than that in the overall network, and those enriched by FLX, and 2) were distinct from FLX and non-enriched ASD genes in multivariate network space. Similarly, genes in human cell cultures enriched by pharmaceutical mixtures (at environmental concentrations) and valproate (at clinical dosages) had similar network signatures, and had greater network importance than genes in the overall ASD network. The results indicate that important gene sets in the ASD network are particularly susceptible to perturbation by pharmaceuticals at environmental concentrations.