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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.
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| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |
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