The projection of plant protection products' (PPPs) toxicity to non-target organisms at early stages of their development is challenging and demanding. Recent developments in bioanalytics, however, have facilitated the study of fluctuations in the metabolism of biological systems in response to treatments with bioactives and the discovery of corresponding toxicity biomarkers. Neonicotinoids are improved insecticides that target nicotinic acetylocholine receptors (nAChR) in insects which are similar to mammals. Nonetheless, they have sparked controversy due to effects on non-target organisms. Within this context, mammalian cell cultures represent ideal systems for the development of robust models for the dissection of PPPs' toxicity. Thus, we have investigated the toxicity of imidacloprid, clothianidin, and their mixture on primary mouse (Mus musculus) neural stem/progenitor (NSPCs) and mouse neuroblastoma-derived Neuro-2a (N2a) cells, and the undergoing metabolic changes applying metabolomics. Results revealed that NSPCs, which in vitro resemble those that reside in the postnatal and adult central nervous system, are five to seven-fold more sensitive than N2a to the applied insecticides. The energy equilibrium of NSPCs was substantially altered, as it is indicated by fluctuations of metabolites involved in energy production (e.g. glucose, lactate), Krebs cycle intermediates, and fatty acids, which are important components of cell membranes. Such evidence plausibly suggests a switch of cells' energy-producing mechanism to the direct metabolism of glucose to lactate in response to insecticides. The developed pipeline could be further exploited in the discovery of unintended effects of PPPs at early steps of development and for regulatory purposes.

中文翻译：

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使用代谢组学挖掘新烟碱类吡虫啉和噻虫胺对原代小鼠神经干/祖细胞化学稳态和能量平衡的影响

植物保护产品 (PPPs) 对非目标生物在其开发早期阶段的毒性具有挑战性和要求。然而，生物分析的最新发展促进了对生物系统代谢波动的研究，以响应生物活性物质的治疗和相应毒性生物标志物的发现。新烟碱类是改进的杀虫剂，其靶向类似于哺乳动物的昆虫中的烟碱型乙酰胆碱受体 (nAChR)。尽管如此，由于对非目标生物的影响，它们引发了争议。在此背景下，哺乳动物细胞培养代表了开发用于剖析 PPP 毒性的稳健模型的理想系统。因此，我们研究了吡虫啉、噻虫胺、及其在原代小鼠（Mus musculus）神经干/祖（NSPC）和小鼠神经母细胞瘤衍生的 Neuro-2a（N2a）细胞上的混合物，以及应用代谢组学进行的代谢变化。结果表明，在体外与出生后和成人中枢神经系统中存在的 NSPC 相似，NSPC 对所用杀虫剂的敏感性是 N2a 的 5 到 7 倍。NSPCs 的能量平衡发生了实质性的改变，这可以通过参与能量产生的代谢物（例如葡萄糖、乳酸）、三羧酸循环中间体和脂肪酸（细胞膜的重要组成部分）的波动来表明。这些证据似乎表明，细胞的能量产生机制转变为响应杀虫剂的葡萄糖直接代谢为乳酸。