Off-Target Stoichiometric Binding Identified from Toxicogenomics Explains Why Some Species Are More Sensitive than Others to a Widely Used Neonicotinoid.
Off-Target Stoichiometric Binding Identified from Toxicogenomics Explains Why Some Species Are More Sensitive than Others to a Widely Used Neonicotinoid.
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DOI：
10.1021/acs.est.0c05125
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发表时间：
2021-02
影响因子：
11.4
通讯作者：
S. Short;A. Robinson;E. Lahive;A. Green Etxabe;Szabolcs Hernádi;M. Pereira;P. Kille;D. Spurgeon
中科院分区：
文献类型：
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作者：
S. Short;A. Robinson;E. Lahive;A. Green Etxabe;Szabolcs Hernádi;M. Pereira;P. Kille;D. Spurgeon
新烟碱类目前在120个国家获得使用许可，这使得准确的非目标物种敏感性预测至关重要。不幸的是，这样的预测充满了不确定性，因为敏感性只能从少数测试物种中推断出来，而新烟碱敏感性在密切相关的分类群之间可能存在很大差异。将经典毒理学与新生毒理学基因组学相结合可以极大地提高敏感性预测和识别意想不到的易感物种。结果表明，5种蚯蚓对新烟碱类吡虫啉的差异物种敏感性（DSS）为50 ~ 30倍。这种差异不能用不同的毒性动力学来解释。此外，比较经典烟碱乙酰胆碱受体（nAChR）靶标亚基基因的关键基序表达，预测配体结合域（lbd）的差异很小。相比之下，lbd中预测的差异确实发生在高表达但非经典的靶标乙酰胆碱结合蛋白（achbp）上。关键是，预测的AChBP散度能够解释DSS。我们提出，具有高吡虫啉亲和性的非突触achbp的高表达水平降低了吡虫啉与参与重要突触神经传递的关键nAChRs的结合。这项研究提供了一个清晰的例子，说明如何对复杂多亚单位受体中关键基序表达的实用询问可以预测观察到的DSS，从而为基本非靶物种的敏感性预测提供信息。
Neonicotinoids are currently licensed for use in 120 countries, making accurate nontarget species sensitivity predictions critical. Unfortunately, such predictions are fraught with uncertainty, as sensitivity is extrapolated from only a few test species and neonicotinoid sensitivities can differ greatly between closely related taxa. Combining classical toxicology with de novo toxicogenomics could greatly improve sensitivity predictions and identify unexpectedly susceptible species. We show that there is a >30-fold differential species sensitivity (DSS) for the neonicotinoid imidacloprid between five earthworm species, a critical nontarget taxon. This variation could not be explained by differential toxicokinetics. Furthermore, comparing key motif expression in subunit genes of the classical nicotinic acetylcholine receptor (nAChR) target predicts only minor differences in the ligand binding domains (LBDs). In contrast, predicted dissimilarities in LBDs do occur in the highly expressed but nonclassical targets, acetylcholine binding proteins (AChBPs). Critically, the predicted AChBP divergence is capable of explaining DSS. We propose that high expression levels of putative nonsynaptic AChBPs with high imidacloprid affinities reduce imidacloprid binding to critical nAChRs involved in vital synaptic neurotransmission. This study provides a clear example of how pragmatic interrogation of key motif expression in complex multisubunit receptors can predict observed DSS, thereby informing sensitivity predictions for essential nontarget species.