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This study investigated triclosan (TCS) and its environmental derivative 2,4,6-trichlorophenol (2,4,6-TCP) using zebrafish as a vertebrate model for a comprehensive, multi-level assessment that included morphological, physiological, biochemical, neurobehavioral, and molecular endpoints. Acute exposure of zebrafish embryos to gradient concentrations of TCS and 2,4,6-TCP induced pronounced developmental malformations, including shortened somites, yolk sac edema, spinal curvature, and delayed or absent swim bladder inflation, with clear dose-response relationships. Benchmark dose (BMD) analysis revealed compound-specific teratogenic sensitivities: pericardial edema was the most sensitive endpoint for TCS, accompanied by significant inhibition of body length and eye size, whereas yolk sac area was the most sensitive indicator for 2,4,6-TCP. The differences in morphological teratogenicity may be attributed to distinct target organs and modes of action. The LC50 values for 120 hpf zebrafish larvae were 0.591mg/L for TCS and 1.137mg/L for 2,4,6-TCP, respectively. Both ECOSAR predictions and experimental results consistently indicated that TCS exhibited significantly higher developmental toxicity and lethality than 2,4,6-TCP for fish, Daphnia, and green algae. Behavioral analyses demonstrated that both TCS and 2,4,6-TCP significantly suppressed spontaneous locomotor activity of zebrafish larvae and disrupted light-dark response behaviors, indicating potential neurotoxic effects. Mechanistic investigations revealed that both TCS and 2,4,6-TCP induced oxidative stress, resulting in excessive accumulation of reactive oxygen species (ROS) in the brain, pericardium, and spine regions. This oxidative damage led to reduced neuronal proliferation, excessive neuronal apoptosis, and abnormal neurodevelopment. Neurobiochemical indicators further demonstrated impaired neurotransmitter transmission and cholinergic system dysfunction, characterized by decreased serotonin (5-HT) levels and inhibited acetylcholinesterase (AChE) activity. Target gene prediction and bioinformatics analyses identified 441 and 173 potential target genes for TCS and 2,4,6-TCP, respectively. Pathway enrichment analysis revealed that TCS primarily affected embryonic development by activating oxidative stress, inflammatory response, and endocrine disruption-related signaling pathways, whereas 2,4,6-TCP regulated developmental abnormalities by interfering with neurotransmitter transport, synaptic formation, and structural differentiation. Further analysis identified the top ten hub genes involved in the associated regulatory pathways, among which only three genes (hsp90aa1, esr1, and gfra) were shared between the two compounds. Approximately 70% of the identified hub genes were compound-specific. Protein-protein interaction (PPI) network analysis revealed that TCS was primarily enriched in the mitophagy, p53signaling, NOD-like receptor signaling, and necroptosis pathways, mediated by key regulators such as pparg, bcl2l1, casp3a, stat3, mmp9, src, and stat1a. In contrast, 2,4,6-TCP predominantly regulated the MAPK signaling pathway, cell cycle pathway, and progesterone mediated oocyte maturation pathway through cdc25b, top2a, cdk1, ptpn11a, pdgfrb, flt1, and erbb2. Four neurodevelopment-related hub genes were further screened and validated by RT-qPCR, confirming the mechanistic differences between TCS and 2,4,6-TCP.
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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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