In vitro biolayer interferometry analysis of acetylcholinesterase as a potential target of aryl-organophosphorus flame-retardants.
In vitro biolayer interferometry analysis of acetylcholinesterase as a potential target of aryl-organophosphorus flame-retardants.
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DOI：
10.1016/j.jhazmat.2020.124999
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发表时间：
2020-12
影响因子：
13.6
通讯作者：
Qipeng Shi;W. Guo;Qiancheng Shen;Jian Han;Lei Lei-Lei;Lianguo Chen;Lihua Yang;C. Feng;Bingsheng Zhou-B
中科院分区：
文献类型：
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作者：
Qipeng Shi;W. Guo;Qiancheng Shen;Jian Han;Lei Lei-Lei;Lianguo Chen;Lihua Yang;C. Feng;Bingsheng Zhou-B
有机磷阻燃剂(OPFR)已被认为是一种神经毒物，但其潜在的神经毒性和机制仍不清楚。在此，我们以斑马鱼为模型生物，研究了部分OPFR的神经毒性。三类OPFR(芳基OPFR、氯化OPFR和烷基OPFR)在斑马鱼幼体(受精后2-144小时)与抑制乙酰胆碱酯酶(AChE)的神经毒性化学物质毒死蜱(CPF)一起进行了环境相关浓度(3-1500 NM)的测试。暴露于芳基OPFR和CPF可抑制AChE活性，而氯化和烷基OPFR不抑制这些酶的活性。用生物层析干涉法(BLI)检测OPFR和AChE之间的相互作用。结合和解离反应曲线表明，与CPF一样，三种选择的芳基OPFR，三苯基磷酸盐(TPHP)、三甲苯基磷酸盐(TCP)和甲酚基二苯基磷酸盐(CDP)都直接与AChE结合。Tphp、Tcp、Cdp和Cpf的亲和常数Kd分别为2.18U×10−4、5.47U×10−5、1.05U×10−4和1.70U×10−5M。此外，分子对接显示，Tphp、Tcp、Cdp和Cpf与AChE结合，滑翔评分分别为−为7.8、−为8.3、−为8.1和−为7.3。此外，计算的OPFR与AChE之间的结合亲和力与BLI测量的KD值有很好的相关性。目前的研究表明，芳基OPFR可以作为有效的AChE抑制剂，因此可能对水生生物构成重大的生态风险。
Organophosphorus flame retardants (OPFRs) have been implicated as neurotoxicants, but their potential neurotoxicity and mechanisms remain poorly understood. Herein, we investigated the neurotoxicity of selected OPFRs using zebrafish as a model organism. Environmentally relevant concentrations (3–1500 nM) of three classes of OPFRs (aryl-OPFRs, chlorinated-OPFRs, and alkyl-OPFRs) were tested in zebrafish larvae (2–144 h post-fertilisation) alongside the neurotoxic chemical chlorpyrifos (CPF) that inhibits acetylcholinesterase (AChE). Exposure to aryl-OPFRs and CPF inhibited AChE activities, while chlorinated- and alkyl-OPFRs did not inhibit these enzymes. Biolayer interferometry (BLI) was used to probe interactions between OPFRs and AChE. The association and dissociation response curves showed that, like CPF, all three selected aryl-OPFRs, triphenyl phosphate (TPHP), tricresyl phosphate (TCP) and cresyl diphenyl phosphate (CDP), bound directly to AChE. The affinity constant (KD) for TPHP, TCP, CDP and CPF was 2.18 × 10−4, 5.47 × 10−5, 1.05 × 10−4and 1.70 × 10−5M, respectively. In addition, molecular docking revealed that TPHP, TCP, CDP and CPF bound to AChE with glide scores of − 7.8, − 8.3, − 8.1 and − 7.3, respectively. Furthermore, the calculated binding affinity between OPFRs and AChE correlated well with theKDvalues measured by BLI. The present study revealed that aryl-OPFRs can act as potent AChE inhibitors, and may therefore present a significant ecological risk to aquatic organisms.