Evolutionary Exploitation of Vertebrate Peroxisome Proliferator-Activated Receptor γ by Organotins
Evolutionary Exploitation of Vertebrate Peroxisome Proliferator-Activated Receptor γ by Organotins
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DOI：
10.1021/acs.est.8b04399
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发表时间：
2018-12-04
影响因子：
11.4
通讯作者：
Castro, L. Filipe C.
中科院分区：
文献类型：
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作者：
Capitao, Ana M. F.;Lopes-Marques, Monica S.;Castro, L. Filipe C.
全球持续存在的人造化学物质显示出日益严重的生态系统后果，这是人类世时代的一个标志。在这种背景下，评估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是毒理学中的一个中心问题。一个突出的例子突出了一组被称为肥胖症的化合物的作用。在哺乳动物中，大多数例子涉及核受体过氧化物酶体增殖物激活受体伽马(PPAR伽马)的调节。为了研究模式致病因子三丁基锡(TBT)在脊椎动物中利用PPARy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分析、同源建模和定点突变。我们表明，脊椎动物祖先中出现多个PPAR(α、β和伽马)与TBT激动剂亲和力的获得是一致的，这可以从软骨鱼类和哺乳动物PPAR伽马的保守的反式激活和结合亲和力中推断。文昌鱼的单拷贝PPAR对TBT没有反应；与所研究的硬骨鱼一样，这可能是配体结合口袋的特定突变重塑的结果。我们的发现证实了人造化学品的调节能力，并提出了一个进化上多样化的环境，对环境风险评估产生了影响。
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.