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首页> 外文期刊>Environmental Science & Technology >Evolutionary Exploitation of Vertebrate Peroxisome Proliferator-Activated Receptor γ by Organotins
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Evolutionary Exploitation of Vertebrate Peroxisome Proliferator-Activated Receptor γ by Organotins

机译：有机锡对脊椎动物过氧化物酶体增殖物激活的受体γ的进化利用。

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摘要

Globally persistent man-made chemicals display ever-growing ecosystemic consequences, a hallmark of the Anthropocene epoch. In this context, the assessment of how lineage-specific gene repertoires influence organism sensitivity toward endocrine disruptors is a central question in toxicology. A striking example highlights the role of a group of compounds known as obesogens. In mammals, most examples involve the modulation of the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma). To address the structural and biological determinants of PPARy exploitation by a model obesogen, tributyltin (TBT), in chordates, we employed comparative genomics, transactivation and ligand binding assays, homology modeling, and site-directed-mutagenesis. We show that the emergence of multiple PPARs (alpha, beta and gamma) in vertebrate ancestry coincides with the acquisition of TBT agonist affinity, as can be deduced from the conserved transactivation and binding affinity of the chondrichthyan and mammalian PPAR gamma. The amphioxus single-copy PPAR is irresponsive to TBT; as well as the investigated teleosts, this is a probable consequence of a specific mutational remodeling of the ligand binding pocket. Our findings endorse the modulatory ability of man-made chemicals and suggest an evolutionarily diverse setting, with impacts for environmental risk assessment.
机译：全球持久的人造化学品显示出日益严重的生态后果，这是人类世纪的标志。在这种情况下，对谱系特异性基因谱系如何影响生物体对内分泌干扰物的敏感性的评估是毒理学的核心问题。一个引人注目的例子突出了一组称为致肥胖物的化合物的作用。在哺乳动物中，大多数实例涉及核受体过氧化物酶体增殖物激活的受体γ（PPARγ）的调节。为了解决模型致肥胖物三丁基锡（TBT）在脊索动物中对PPARγ的利用的结构和生物学决定因素，我们采用了比较基因组学，反式激活和配体结合测定，同源性建模和定点诱变。我们表明，在脊椎动物祖先中多个PPAR（α，β和γ）的出现与TBT激动剂亲和力的获得相吻合，这可以从软骨素和哺乳动物PPARγ的保守反式激活和结合亲和力推论得出。 Amphioxus单拷贝PPAR对TBT无反应；以及研究的硬骨鱼，这可能是配体结合口袋发生特定突变重塑的结果。我们的发现支持了人造化学物质的调节能力，并提出了进化上多样化的环境，对环境风险评估产生了影响。

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