Differences in Activation of Aryl Hydrocarbon Receptors of White Sturgeon Relative to Lake Sturgeon Are Predicted by Identities of Key Amino Acids in the Ligand Binding Domain
Differences in Activation of Aryl Hydrocarbon Receptors of White Sturgeon Relative to Lake Sturgeon Are Predicted by Identities of Key Amino Acids in the Ligand Binding Domain
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DOI：
10.1021/acs.est.5b00085
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发表时间：
2015-04-07
影响因子：
11.4
通讯作者：
Hecker, Markus
中科院分区：
文献类型：
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作者：
Doering, Jon A.;Farmahin, Reza;Hecker, Markus
二恶英类化合物（Dioxin-like compounds，DLCs）是一种全球性的环境污染物。DLC通过激活芳烃受体（AhR）引起其不良后果。然而，有有限的了解的机制，导致不同种类的鱼类之间的DLCs的敏感性的差异。了解这些机制对于保护暴露于DLCs的鱼类（包括濒危物种）的多样性至关重要。本研究探讨了两种濒危鱼类，白色鲟鱼（Acipenser transmontanus）和湖鲟鱼（Acipenser fulvescens）对DLCs反应的具体机制。它确定了是否可以根据配体结合结构域（LBD）中关键氨基酸的特性预测对AhR（AhR 1和AhR 2）激活的敏感性差异。白色鲟鱼比湖鲟对暴露于基于AhR 2激活的5种不同DLC的敏感性高3至30倍。基于AhR 1的激活，白色鲟鱼和湖鲟之间的敏感性没有差异。在迄今为止研究的所有鱼类中，由于暴露于DLC而导致的不良后果已被证明是通过激活AhR 2而不是AhR 1介导的。这表明，白色鲟鱼可能有更大的敏感性，在体内相对于湖鲟鱼。同源性建模和计算机诱变表明，对AhR 2激活的敏感性的差异是由白色鲟鱼（Ala-388）和湖鲟（Thr-388）AhR 2的LBD中388位关键氨基酸的差异引起的。这表明AhR 2的LBD中的关键氨基酸的身份可以预测在这些鱼和潜在的其他鱼中由DLC的体外激活和对DLC的体内敏感性。
Dioxin-like compounds (DLCs) are pollutants of global environmental concern. DLCs elicit their adverse outcomes through activation of the aryl hydrocarbon receptor (AhR). However, there is limited understanding of the mechanisms that result in differences in sensitivity to DLCs among different species of fishes. Understanding these mechanisms is critical for protection of the diversity of fishes exposed to DLCs, including endangered species. This study investigated specific mechanisms that drive responses of two endangered fishes, white sturgeon (Acipenser transmontanus) and lake sturgeon (Acipenser fulvescens) to DLCs. It determined whether differences in sensitivity to activation of AhRs (AhR1 and AhR2) can be predicted based on identities of key amino acids in the ligand binding domain (LBD). White sturgeon were 3- to 30-fold more sensitive than lake sturgeon to exposure to 5 different DLCs based on activation of AhR2. There were no differences in sensitivity between white sturgeon and lake sturgeon based on activation of AhR1. Adverse outcomes as a result of exposure to DLCs have been shown to be mediated through activation of AhR2, but not AhR1, in all fishes studied to date. This indicates that white sturgeon are likely to have greater sensitivity in vivo relative to lake sturgeon. Homology modeling and in silico mutagenesis suggests that differences in sensitivity to activation of AhR2 result from differences in key amino acids at position 388 in the LBD of AhR2 of white sturgeon (Ala-388) and lake sturgeon (Thr-388). This indicates that identities of key amino acids in the LBD of AhR2 could be predictive of both in vitro activation by DLCs and in vivo sensitivity to DLCs in these, and potentially other, fishes.