Assessment of Risks of Dioxins for Aryl Hydrocarbon Receptor-Mediated Effects in Polar Bear (Ursus maritimus) by in Vitro and in Silico Approaches.,Environmental Science & Technology

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Assessment of Risks of Dioxins for Aryl Hydrocarbon Receptor-Mediated Effects in Polar Bear (Ursus maritimus) by in Vitro and in Silico Approaches.
Environmental Science & Technology ( IF 10.8 ) Pub Date : 2020-01-13 , DOI: 10.1021/acs.est.9b05941
Ji-Hee Hwang ₁ , Kurunthachalam Kannan ₂ , Thomas J Evans ₃ , Hisato Iwata ₄ , Eun-Young Kim ₁

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Polar bear (Ursus maritimus) populations accumulate dioxins and related compounds (DRCs) at levels that are of health concern. The toxicities of DRCs are primarily mediated via aryl hydrocarbon receptor (AHR) signaling pathway. To evaluate the sensitivity and responses to DRCs in polar bears, we assessed the activation potencies of polar bear-specific AHR (pbAHR) by DRCs through in vitro and in silico approaches. In vitro assays showed that the pbAHR was as sensitive to DRCs as C3H/lpr mouse AHR, which is well-known to be highly sensitive to DRCs. Comparison of pbAHR transactivation potencies indicated that TCDF, 2,3,4,7,8-PeCDF, and BaP exhibited high induction equivalency factors (IEFs). Considering the accumulation levels of DRCs in polar bears, PCB126 was found to be the most active inducer of pbAHR. The in vitro transactivation potencies of ligands of pbAHR showed a significant relationship with in silico ligand docking energies in a pbAHR homology model. The protein ligand interaction fingerprint (PLIF) analysis showed different interaction patterns depending on the ligands. Several amino acids which are highly conserved among mammals may be involved in species-specific responses via backbone interactions with neighboring amino acid residues which are specific to pbAHR. We document high susceptibility of polar bears to DRCs, through a mechanistic approach, for the first time.

中文翻译：

通过体外和计算机模拟方法评估北极熊中的二恶英类化合物对芳烃受体介导的影响的风险。

北极熊（Ursus maritimus）种群积累的二恶英和相关化合物（DRC）的水平与健康有关。DRC的毒性主要通过芳烃受体（AHR）信号传导途径介导。为了评估北极熊对DRC的敏感性和响应，我们通过体外和计算机模拟方法评估了DRC对北极熊特异性AHR（pbAHR）的激活能力。体外测定表明，pbAHR对DRC的敏感性与C3H / lpr小鼠AHR一样，众所周知，C3H / lpr小鼠AHR对DRC高度敏感。pbAHR反式激活潜能的比较表明，TCDF，2、3、4、7、8-PeCDF和BaP表现出高诱导当量因子（IEF）。考虑到北极熊中DRC的积累水平，发现PCB126是pbAHR的最活跃诱导剂。在pbAHR同源性模型中，pbAHR配体的体外反式激活能力与计算机配体对接能密切相关。蛋白质配体相互作用指纹图谱（PLIF）分析显示出不同的相互作用模式，具体取决于配体。在哺乳动物中高度保守的几种氨基酸可能通过与pbAHR特异的相邻氨基酸残基的骨架相互作用而参与物种特异性反应。我们首次通过机械方法记录了北极熊对DRC的高度敏感性。在哺乳动物中高度保守的几种氨基酸可能通过与pbAHR特异的相邻氨基酸残基的骨架相互作用而参与物种特异性反应。我们首次通过机械方法记录了北极熊对DRC的高度敏感性。在哺乳动物中高度保守的几种氨基酸可能通过与pbAHR特异的相邻氨基酸残基的骨架相互作用而参与物种特异性反应。我们首次通过机械方法记录了北极熊对DRC的高度敏感性。

更新日期：2020-01-13

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