An ancestral nuclear receptor couple, PPAR-RXR, is exploited by organotins
An ancestral nuclear receptor couple, PPAR-RXR, is exploited by organotins
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DOI：
10.1016/j.scitotenv.2021.149044
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发表时间：
2021-07-21
影响因子：
9.8
通讯作者：
Castro, L. Filipe C.
中科院分区：
文献类型：
--
作者：
Capitao, Ana M. F.;Lopes-Marques, Monica;Castro, L. Filipe C.
环境中的化学物质已被报道会严重干扰多种动物的内分泌和代谢系统。最近的一个例子涉及开发的核受体（NR）的异二聚体对组成的过氧化物酶体增殖物激活受体/RXR（过氧化物酶体增殖物激活受体/类维生素A X受体），这表明在哺乳动物物种的脂质扰动。虽然这两种受体的基因直向同源物已被描述脊椎动物以外，没有功能的特性进行了原口类谱系的过氧化物酶体增殖物激活受体。我们提供了第一个功能分析的过氧化物酶体增殖物激活受体在髌骨属（软体动物），使用模型obesogens，如三丁基锡（TBT），三苯基锡（TPT），并提出了天然配体（脂肪酸分子）。为了获得进一步的了解，我们对PPAR进行了定点诱变，并用半胱氨酸（人类同源氨基酸和TBT锚残基）和丙氨酸取代酪氨酸277。此外，我们探讨了在体内暴露于模型肥胖剂TBT后脂肪酸谱的变化。我们的研究结果表明，TBT和TPT的表现作为一种拮抗剂的髌骨属物种。PPAR/RXR和酪氨酸277是重要的，但不是必不可少的TBT的反应。总之，这些结果表明软体动物PPAR-RXR对三丁基锡化合物的反应与环境相关浓度下报告的脂质分布改变之间存在关系。我们的研究结果强调了原口类和后口类谱系之间的比较分析的重要性，以破译环境化学物质的差异影响。(c)2021年由Elsevier B. V.出版
Environmental chemicals have been reported to greatly disturb the endocrine and metabolic systems of multiple animal species. A recent example involves the exploitation of the nuclear receptor (NR) heterodimeric pair composed by PPAR/RXR (peroxisome proliferator-activated receptor/retinoid X receptor), which shows lipid perturbation in mammalian species. While gene orthologues of both of these receptors have been described outside vertebrates, no functional characterization of PPAR has been carried in protostome lineages. We provide the first functional analysis of PPAR in Patella sp. (Mollusca), using model obesogens such as tributyltin (TBT), triphenyltin (TPT), and proposed natural ligands (fatty acid molecules). To gain further insights, we used site directed mutagenesis to PPAR and replaced the tyrosine 277 by a cysteine (the human homologous amino acid and TBT anchor residue) and an alanine. Additionally, we explored the alterations in the fatty acid profiles after an exposure to the model obesogen TBT, in vivo. Our results show that TBT and TPT behave as an antagonist of Patella sp. PPAR/RXR and that the tyrosine 277 is important, but not essential in the response to TBT. Overall, these results suggest a relation between the response of the mollusc PPAR-RXR to TBT and the lipid profile alterations reported at environmentally relevant concentrations. Our findings highlight the importance of comparative analysis between protostome and deuterostome lineages to decipher the differential impact of environmental chemicals. (c) 2021 Published by Elsevier B.V.