通过整合网络毒理学、转录组学及斑马鱼体内实验,探究烷基磷酸酯(TiBP),溴代磷酸酯(TDBPP)和氯代磷酸酯(TCPP)的毒性差异及其分子机制,旨在揭示不同结构有机磷阻燃剂毒性效应.结果表明,卤素的引入影响网络毒理学预测的准确性和全面性,斑马鱼实验进一步证实网络毒理学与转录组学分析结合更能全面反应有机磷阻燃剂的毒性机制.在急性毒性方面,TDBPPLC50最低(922.3μg/L),其次为TiBP(21.14mg/L)和TCPP(37.56mg/L).在作用机制方面,3种化合物通过不同基因-通路网络引发毒性,其中TDBPP与TCPP因卤素取代基表现出更强的代谢-内分泌干扰,表现为中剂量暴露下,脂质堆积程度较对照组分别升高1.6倍和2倍.而TiBP以神经-免疫毒性为特征.低剂量下,TiBP的非卤代结构使其对斑马鱼神经传导抑制更敏感表现为对运动能力抑制最强(移动速度和移动距离降幅约50%).高剂量下,TCPP的氯原子通过增强受体结合能力,在神经、代谢和免疫多系统表现出优势毒性;TDBPP的溴代结构虽急性毒性最高,但等毒性剂量下的综合效应弱于TCPP,可能与其代谢致癌性的时间滞后相关.本研究采用多维度整合策略揭示了有机磷阻燃剂的分子结构对其生物效应的影响.
Abstract
By integrating network toxicology, transcriptomics, and in vivo zebrafish assays, this study systematically investigated the differential toxicities and underlying molecular mechanisms of an alkyl phosphate (TiBP), a brominated phosphate (TDBPP), and a chlorinated phosphate (TCPP), with the aim of elucidating structure-dependent toxic effects of organophosphate flame retardants (OPFRs). The results showed that the halogens affected the accuracy and comprehensiveness of network toxicology predictions. Zebrafish experiments further confirmed that combining network toxicology with transcriptomic analysis provided a more comprehensive characterization of OPFR-induced toxic mechanisms. In terms of acute toxicity, TDBPP exhibited the lowest LC₅₀ (922.3μg/L), followed by TiBP (21.14mg/L) and TCPP (37.56mg/L). Mechanistically, the three compounds elicited toxicity through distinct gene-pathway networks. Owing to their halogen substituents, TDBPP and TCPP showed stronger metabolic and endocrine disruption, as evidenced by a 1.6-fold and 2-fold increase in lipid accumulation, respectively, compared with the control group under medium-dose exposure. In contrast, TiBP predominantly induced neuroimmune toxicity. At low doses, the non-halogenated structure of TiBP rendered zebrafish more sensitive to neuroconductive inhibition, resulting in the strongest inhibition of locomotor ability, with approximately 50% reductions in both swimming speed and distance. At high doses, the presence of chlorine atoms in TCPP enhanced receptor binding ability, resulting in predominant toxicity across the neural, metabolic, and immune systems. Although the brominated structure of TDBPP conferred the highest acute toxicity, its comprehensive effect at equitoxic doses was weaker than that of TCPP, potentially due to a delayed manifestation of metabolism-associated carcinogenicity. Overall, this study employed a multi-dimensional integrative strategy to elucidate how molecular structural features of OPFRs govern their biological effects.
关键词
有机磷阻燃剂 /
网络毒理学 /
转录组学 /
斑马鱼 /
结构-毒性关系
Key words
organophosphate flame retardants /
network toxicology /
transcriptomics /
zebrafish /
structure-toxicity relationship
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基金
国家自然科学基金资助项目(22106118)
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