Organophosphate flame retardants (OPFRs) have been widely detected in multiple environment media and have many adverse effects with complex toxicity mechanisms. However, the early molecular responses to OPFRs have not been fully elucidated, thereby making it difficult to assess their risks accurately. In this work, we systematically explored the point of departure (POD) of biological pathways at genome-wide level perturbed by 14 OPFRs with three substituents (alkyl, halogen, and aryl) using a dose-dependent functional genomics approach in at 24 h exposure. Firstly, our results demonstrated that the overall biological potency at gene level (POD) ranged from 0.013 to 35.079 μM for 14 OPFRs, especially the tributyl phosphate (TnBP) exhibited the strongest biological potency with the least POD. Secondly, we found that structural characteristics of carbon number and logK were significantly negatively correlated with POD, and carbon number and logK also significantly affected lipid metabolism associated processes. Thirdly, these early biological pathways of OPFRs toxification were found to be involved in lipid metabolism, oxidative stress, DNA damage, MAPK signaling pathway, and amino acid and carbohydrate metabolism, among which the lipid metabolism was the most sensitive molecular response perturbed by most OPFRs. More importantly, we identified one resistant mutant strain with knockout of () gene participated in steroid biosynthesis pathway, which can serve as a key yeast strain of OPFRs toxification. Overall, our study demonstrated an effective platform for accurately assessing OPFRs risks and provided a basis for further green OPFRs development.

中文翻译：

---

通过剂量依赖性酵母功能基因组学方法评估有机磷酸酯阻燃剂的生物活性

有机磷酸酯阻燃剂（OPFR）已在多种环境介质中广泛检测到，并具有许多不良影响和复杂的毒性机制。然而，OPFR 的早期分子反应尚未完全阐明，因此很难准确评估其风险。在这项工作中，我们使用剂量依赖的功能基因组学方法，在 24 小时暴露下，系统地探索了受 14 个具有三个取代基（烷基、卤素和芳基）的 OPFR 扰动的全基因组水平生物途径的出发点 (POD)。 。首先，我们的结果表明，14 个 OPFR 在基因水平（POD）的总体生物效价范围为 0.013 至 35.079 μM，尤其是磷酸三丁酯（TnBP）表现出最强的生物效价，且 POD 最小。其次，我们发现碳数和logK的结构特征与POD显着负相关，并且碳数和logK也显着影响脂质代谢相关过程。第三，OPFRs中毒的这些早期生物学途径被发现涉及脂质代谢、氧化应激、DNA损伤、MAPK信号通路以及氨基酸和碳水化合物代谢，其中脂质代谢是大多数OPFRs干扰的最敏感的分子反应。 。更重要的是，我们鉴定了一种敲除参与类固醇生物合成途径的()基因的抗性突变菌株，该菌株可以作为OPFRs中毒的关键酵母菌株。总体而言，我们的研究展示了准确评估 OPFR 风险的有效平台，并为进一步绿色 OPFR 开发提供了基础。