Sustainable molecular design of less hazardous chemicals promises to reduce risks to public health and the environment. Computational chemistry modeling coupled with alternative toxicology models (e.g., larval fish) present unique high-throughput opportunities to understand structural characteristics eliciting adverse outcomes. Numerous environmental contaminants with reactive properties can elicit oxidative stress, an important toxicological response associated with diverse adverse outcomes (i.e., cancer, diabetes, neurodegenerative disorders, etc.). We examined a common chemical mechanism (bimolecular nucleophilic substitution (SN2)) associated with oxidative stress using property-based computational modeling coupled with acute (mortality) and sublethal (glutathione, photomotor behavior) responses in the zebrafish (Danio rerio) and the fathead minnow (Pimephales promelas) models to identify whether relationships exist among biological responses and molecular attributes of industrial chemicals. Following standardized methods, embryonic zebrafish and larval fathead minnows were exposed separately to eight different SN2 compounds for 96 h. Acute and sublethal responses were compared to computationally derived in silico chemical descriptors. Specifically, frontier molecular orbital energies were significantly related to acute LC50 values and photomotor response (PMR) no observed effect concentrations (NOECs) in both fathead minnow and zebrafish. This reactivity index, LC50 values, and PMR NOECs were also significantly related to whole body glutathione (GSH) levels, suggesting that acute and chronic toxicity results from protein adduct formation for SN2 electrophiles. Shared refractory locomotor response patterns among study compounds and two alternative vertebrate models appear informative of electrophilic properties associated with oxidative stress for SN2 chemicals. Electrophilic parameters derived from frontier molecular orbitals were predictive of experimental in vivo acute and sublethal toxicity. These observations provide important implications for identifying and designing less hazardous industrial chemicals with reduced potential to elicit oxidative stress through bimolecular nucleophilic substitution.

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转向危害较小的工业化合物：耦合量子力学计算，生物标志物响应和行为特征，以鉴定替代脊椎动物模型中SN2亲电试剂的生物活性。

危害性较小的化学品的可持续分子设计有望减少对公共健康和环境的危害。计算化学建模与替代毒理学模型（例如幼体鱼）结合提供了独特的高通量机会，以了解引起不良后果的结构特征。具有反应性的许多环境污染物会引起氧化应激，这是与各种不良后果（例如，癌症，糖尿病，神经退行性疾病等）相关的重要毒理学反应。我们使用基于属性的计算模型，结合了急性（死亡率）和亚致死性（谷胱甘肽，斑马鱼（Danio rerio）和黑头min鱼（Pimephales promelas）模型中的光动力行为）响应，以识别生物学响应和工业化学品的分子属性之间是否存在关系。按照标准化方法，将斑马鱼幼虫和黑头fat鱼分别暴露于八种不同的SN2化合物96小时。将急性和亚致死反应与计算得出的计算机化学描述符进行了比较。特别是，在黑头min鱼和斑马鱼中，前沿分子轨道能量与急性LC50值和光动力反应（PMR）无显着影响浓度（NOEC）显着相关。该反应指数，LC50值和PMR NOEC也与全身谷胱甘肽（GSH）含量显着相关，提示急性和慢性毒性是由SN2亲电试剂的蛋白质加合物形成引起的。研究化合物和两个替代脊椎动物模型之间共享的难治性运动反应模式似乎表明与SN2化学物质氧化应激相关的亲电子特性。源自前沿分子轨道的亲电参数可预测体内实验性急性和亚致死毒性。这些观察结果对于鉴定和设计危害较小的工业化学品具有重要意义，该化学品通过双分子亲核取代引发氧化应激的可能性降低。研究化合物和两个替代脊椎动物模型之间共享的难治性运动反应模式似乎表明与SN2化学物质氧化应激相关的亲电子特性。源自前沿分子轨道的亲电参数可预测体内实验性急性和亚致死毒性。这些观察结果对于鉴定和设计危害较小的工业化学品具有重要意义，该化学品通过双分子亲核取代引发氧化应激的可能性降低。研究化合物和两个替代脊椎动物模型之间共享的难治性运动反应模式似乎表明与SN2化学物质氧化应激相关的亲电子特性。源自前沿分子轨道的亲电参数可预测体内实验性急性和亚致死毒性。这些观察结果对于鉴定和设计危害较小的工业化学品具有重要意义，该化学品通过双分子亲核取代引发氧化应激的可能性降低。